Next Article in Journal
Physical Activity and Thyroid Cancer Risk: A Case-Control Study in Catania (South Italy)
Previous Article in Journal
Social Support—A Protective Factor for Depressed Perinatal Women?
Previous Article in Special Issue
In Vivo Comparison of the Phenotypic Aspects and Molecular Mechanisms of Two Nephrotoxic Agents, Sodium Fluoride and Uranyl Nitrate
Article Menu
Issue 8 (April-2) cover image

Export Article

Int. J. Environ. Res. Public Health 2019, 16(8), 1427; https://doi.org/10.3390/ijerph16081427

Review
Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health
EnviroManagement Services, 11 Riverview, Doherty’s Rd, P72 YF10 Bandon, Co. Cork, Ireland
Received: 27 January 2019 / Accepted: 8 April 2019 / Published: 21 April 2019

Abstract

:
In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.
Keywords:
Na+, K+-ATPase; fluoride; molecular mechanisms of inhibition; Na+, K+-ATPase and pathological states; cognitive impairment; neurological diseases; metabolic diseases; lung diseases; cancer

1. Introduction

Sodium, potassium-activated adenosine triphosphatase ( Na + , K + -ATPase) is an integral protein in the plasma membrane that transports Na+-ions to the outside and K+-ions to the inside of the cell at the expense of ATP, and thus maintains sodium and potassium homeostasis in animal cells [1,2]. Na + , K + -ATPase (NKA) is responsible for the electrochemical gradient across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons, as well as for the transport of other ions and metabolites necessary for the regulation of the cellular ionic homeostasis [3]. In addition, to its function in maintaining cell homeostasis, NKA activity plays a crucial role in the function of neurotransmitter transporters essential for regulating neurotransmitter signaling and homeostasis [4]. By using the energy from ATP to establish asymmetric distributions of ions across the cell membrane, NKA couples metabolic energy to cellular functions and to signaling events both between and within cells [5].
Given the importance of NKA in cellular homeostasis and intracellular signaling, impairment or downregulation of NKA activity has been implicated in many pathophysiological conditions, including asthma and allergic diseases, metabolic disorders, cancer, cardiovascular and degenerative brain diseases, as well as neuropsychological disorders [3,6,7,8,9,10,11,12,13,14], as illustrated in Figure 1 and discussed below.
Previous studies have shown that inhibition of NKA activity has been found to accelerate depletion of adenosine triphosphate (ATP), induce mitochondrial depolarization, suppress reactive oxygen species (ROS) scavenging, and enhance ROS production and oxidative stress [15,16,17]. It is known that a causal relationship has been identified between NKA enzyme inhibition and airway hyperreactivity [18]. Consistent with this, NKA inhibition is associated with asthma [19,20] and chronic obstructive pulmonary disease (COPD) [21]. Furthermore, loss of NKA activity is associated with allergic diseases [22,23] including allergic rhinitis [24] and blood diseases including thalassemia and sickle cell anaemia [25]. Extensive studies show that NKA is essential for sperm mobility and male fertility [26,27,28,29]. In addition, loss of NKA activity is also associated with rheumatoid arthritis [30,31], metabolic syndrome [32], including; chronic kidney disease [33,34,35]; diabetes mellitus [36,37]; diabetic nephropathy and cardiomyopathy [38,39,40]; cardiovascular complications [32,41,42,43]; hypertension [40,44,45,46,47,48,49,50,51,52] and obesity [11]. Loss of NKA activity is also implicated in degenerative eye diseases including cataract formation and age related macular degeneration [53]. In addition to inflammatory disorders as noted previously, loss of NKA activity has been found to be associated with tumour invasiveness, metastasis, and tissue fibrosis [54], kidney cancer [54], prostate cancer [55], bladder cancer [56] and urothelial cancer [57]. Consistent with these findings showing an association between loss of NKA in carcinoma and cancer progression, an isoform of the β subunit of NKA has been found to be a tumour-suppressor [58] and its expression along with total NKA activity has been found to be markedly reduced in prostate cancer [55] and kidney cancer [59]. Moreover, the adhesion molecule on glia (AMOG), another isoform of β subunit of NKA has been found to inhibit glioma cell invasion, while its downregulation increases invasion in glial cells [60]. Downregulation of the alpha 1 subunit of NKA has also been implicated in colorectal cancer [61].
Furthermore, a great body of evidence associates neurotoxicity with a reduction of NKA activity, suggesting that reduction in NKA activity may be a link between several common neurotoxic mechanisms [14,15,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]. Loss of NKA is associated with autism [65,66,69]; Alzheimer’s disease [66,80,81]; Parkinson’s disease [82]; amyotrophic lateral sclerosis [70,82]; Down syndrome and Huntington’s disease [69]; depression and mood disorders [71,72,73,74]; bipolar disorder [14,75,76] and schizophrenia [15,77,79], as well as in animal models of depression [83,84]. Interestingly, NKA activity has been found to be significantly lower in subjects with phenylketonuria [85], a disease associated with intellectual disability, seizures, behavioural problems and mental disorders. Of note, loss of NKA activity has also been found to be associated with neonatal seizures and epilepsy [86,87]. It is also known that recovery of NKA activity in the hippocampus is responsible for neuroprotection [88]. Experimental studies have also shown that impairment of NKA activity in neonatal brain of rats leads to increased anxiety-like behaviour and memory impairment. Interestingly, in this study treatment with folic acid was found to reverse the inhibition of NKA and alleviated cognitive deficits associated with enzyme inhibition [89]. As NKA activity is essential for synaptic and neural functionality [3] and since NKA has been shown to trigger dendritic growth [90]; hence, it is possible that reduction in the activity of this enzyme may disrupt normal brain development. In this context, it has been demonstrated in-vivo that NKA inhibition causes selective neuronal loss in rodents [91]. In addition, it has been demonstrated that the extent of neuronal loss observed roughly paralleled inhibition of the enzyme [92]. It has been reported loss of NKA activity causes impairments in the sodium pump leading to neuronal hyperexcitability in the CNS [10,93,94]. NKA inhibition also increases neuronal susceptibility to glutamate excitotoxicity contributing to neurotoxicity [95,96]. Furthermore, NKA impairment has been found to downregulate the synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, leading to synaptic transmission defects and cognitive impairment [97]. Of note, researchers have also identified glutamatergic neurotransmission dysregulation and cognitive dysfunctions in major psychiatric disorders: including, schizophrenia, depressive disorders and suicidal behaviours [98,99,100,101]. Excess extra-cellular glutamate leading to excitotoxicity has also been suggested to play a role in in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer’s disease and Huntington’s disease [102].
A relationship between glutamate excitotoxicity and neuroinflammation in autism has also been ascertained [103,104]. Moreover, in animal studies, loss of AMPA receptors have been found to result in early-onset motor deficits, hyperactivity, cognitive defects, behavioural seizures and sleep disorders [105]. Taken together, these findings suggest a possible causal link between loss of NKA activity and childhood neurodevelopmental disorders that present with motor deficits, hyperactivity and cognitive defects including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). Moreover, it is important to note that ADHD is highly comorbid with other psychiatric or neurodevelopment disorders associated with loss of NKA including, major depressive disorder and schizophrenia [106,107], which again supports the hypothesis that loss of NKA is implicated in the pathophysiology of ADHD. Importantly, NKA is also critical for sodium iodide symporter (NIS) functionality and iodine transport [108,109,110]. Thus, NKA inhibition may contribute to iodine deficiency [110]. Iodine deficiency can lead to hypothyroidism [111,112]. Interestingly, hypothyroidism has also been found to decrease NKA activity [113,114]. Crucially, Schmitt et al. found that hypothyroidism at a critical period of development in utero can result in permanent inhibition of NKA activity [114]. Moreover, Ahmed et al. showed that the hypothyroid status during pregnancy and lactation produced inhibitory effects on NKA as well as Ca(2+)-ATPase and Mg(2+)-ATPase in different brain regions of the offspring [115]. Further studies have established that hypothyroidism leads to marked reduction in dendritic branching in the rat brain [116], which is consistent with loss of NKA activity as previously described.
It is well established that NKA activity is inhibited by fluoride [117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138]. Furthermore, the results from human studies provide a biological gradient by which serum fluoride levels inhibit NKA activity in adults [137,138]. Considering the exclusion criteria and number of participants in these latter studies, these findings are significant. Notably, the inhibitory effect was found to occur in adults at serum fluoride levels < 5.0 µM and the inhibitory effects increased significantly as serum F levels increased in a dose dependent manner. [137,138]. For example, Arulkumar et al. observed that at serum ionic fluoride levels of 14.75 µM the activity of NKA declined by approximately 60 per cent compared to controls [137]. Considering that NKA activity is inhibited by hypothyroidism, the potential role of water fluoridation or fluoride intake with respect to increased prevalence of hypothyroidism must not be overlooked [139,140]. Interestingly, Kheradpisheh et al. in a case control study recently found that fluoride levels in drinking water has impacts on thyroid hormones even in the standard concentration of less than 0.5 mg/L. Among healthy participants without thyroid disease median TSH levels were found to increase when drinking water fluoride levels increased from 0–0.29 mg/L to 0.3–0.5 mg/L. Moreover, among subjects with clinically diagnosed hypothyroidism the effects of fluoride intake from drinking water on TSH were highly significant [140]. This finding is consistent with the Peckham study in England, which reported an increased prevalence of hypothyroidism, in communities where drinking water was artificially fluoridated [139]. As previously described, loss of NKA activity has been implicated in the pathogenesis of neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Therefore, it is plausible that fluoride inhibition of NKA may have previously unforeseen consequences on public health and health inequalities, particularly in countries where drinking water is artificially fluoridated. However, studies examining the molecular mechanisms by which fluoride may contribute to such health inequalities are lacking. This relationship is particularly important given that exposure to fluoride can occur through water, food and other common sources such as dental products, in addition to occupational and environmental exposures. Although much information has become available in recent decades, the molecular mechanisms of fluoride inhibition of NKA remain to be defined. The lack of detailed information on the molecular mechanisms underlying how fluoride inhibits NKA activity impedes our understanding of how fluoride exposure may also contribute to pathological states. Consequently, the objective of this current study is to elucidate the molecular mechanisms and biological pathways by which fluoride inhibits NKA activity. In addition, this study examines the potential implications of fluoride induced loss of NKA activity on human health and disease inequalities.

2. The Role of Fluoride in Oral Health and Sources of Fluoride Exposure

While the focus of this study is directed toward the molecular mechanisms underlying how fluoride inhibits NKA, it is also necessary to discuss a number of important findings from the literature regarding the role of fluoride (F) in oral health and sources of F exposure, in order to better understand the importance of cumulative exposures.
It is acknowledged that F has no known essential function in human growth and development and no signs of F deficiency have been identified [141]. However, F is considered to have played a major role in the reduction of dental caries in the past decades in the industrialized countries. It is added as an anti-caries agent to a variety of vehicles, particularly drinking water and toothpastes. Though F is not essential nutrient, it has been recognized for some time that topical, rather than systemic exposure of F controls carious lesion development [142,143,144,145]. However, caries development is not a F deficiency disease [141]. Interestingly, a key mechanism in the anti-caries effect of F is the direct inhibition of ATPases activity in oral bacteria [146,147,148,149].
Today, community water fluoridation and F toothpaste are considered the most common sources of F exposure in the USA [142,150]. In countries such as Ireland, the UK, Australia and New Zealand, where habitual tea drinking is commonplace, the major dietary source of F is tea consumption [151,152,153]. In addition to tea, fluoridated water, and toothpaste other sources of F exposure include other beverages produced from fluoridated water (powdered infant formula, fruit juices, soft drinks, coffee, beers); pesticide residues in foods, foods processed or cooked in fluoridated water; foods grown in soil containing F or irrigated with fluoridated water; consumption of foods with elevated F levels (i.e., seafood and processed chicken); foods cooked in Teflon cookware; tobacco consumption; use of fluoridated mouthwash; use of medical inhalers containing fluoridated gases, and fluoridated medications, in addition to other environmental or occupational exposures to F [153]. Although the amount of F ingested in diet can be theoretically measured in dietary intake studies, by measuring the F content in foods and beverages, the most reliable and accurate method of measuring F exposure is by measuring the F content in serum/plasma, bone or urinary F levels. As NKA activity is present in blood and considering the evidence that F levels in blood inhibit NKA activity, it is therefore necessary to learn more about how different sources of F exposure contribute to blood F levels in humans. Moreover, understanding the routes of F exposure in infancy is essential when considering the long-term health implications of chronic F exposure on NKA activity and implications for health and well-being long term. Furthermore, the magnitude of exposure can be examined by comparing breast fed infants in low F communities to formula fed infants in fluoridated communities, as shown in Table 1 below.
The F level in breast milk from mothers in a low F community where drinking water F levels less than 0.16 mg/L are 0.004 mg/L and 0.009 mg/L in breast milk from mothers residing in communities where drinking water F levels are 1.0 mg/L [154]. Elsewhere it has been reported that the concentration of F in cows’ milk is ten-fold higher than human milk and typically ranges from 0.03 to 0.06 ppm [155]. However, past studies have shown that F concentrations in cow’s milk can vary significantly depending on the F level of water provided to dairy herds. For example, Gupta et al. demonstrated that when the F concentration in drinking water was 0.47, 0.82 and 1.32 mg/L the F concentrations in cow’s milk was 0.016, 0.074 and 0.18 mg/L respectively [156]. Interestingly, a recent study conducted by researchers at Newcastle University and Teesside University in England reported that the mean F content in whole milk products available in a fluoridated region of the UK was 0.08 ppm [157]. This data indicates that dairy herds in the region were provided with mains fluoridated water as a source of drinking water. Moreover, previous studies have reported that F values in cow’s milk ranging from 0.1–0.4 mg/L are consistent those found in F poisoned dairy herds [158]. From the above data it is obvious that the source of F– in drinking water provided to dairy herds can influence the F content in milk used for the manufacture of powdered infant formula. It has also been reported that the F content in powdered infant formula products can vary depending on the source of water used in processing and that the use of optimally fluoridated mains can result in higher F levels in powdered infant formula products. Thus, in certain western countries where drinking water is fluoridated significant variations in the F content in powdered infant formula products have been reported [159,160,161]. However, it is widely acknowledged the main contributor to the F intake in infants is the F content in water used to reconstitute powdered infant formulas. It should also be noted that formulas mixed with optimally fluoridated water provide the highest mean F daily intake [162].
In areas naturally low in water F and dietary F intake exclusively breast-fed infants aged less than 12 months have been reported to have a mean ionic serum F– levels of 0.22 μM [163]. By contrast, in fluoridated communities in the United States the mean F level in infants aged 4–6 months and 7–12 months has been reported to be 4.22 ± 3.7 µM, and 1.56 ± 0.53 µM, respectively [164]. Moreover, the mean ionic plasma F level in infants with renal failure during their first 18 months of life was 6.3 µM compared to 3.16 µM in age matched controls [164]. As is evident from this study, plasma F levels varied significantly among infants aged 4–6 months with the maximum F levels being approximately 8 µM. The variations reported reflect the peak plasma F levels associated with proximity to feeding and the use of breast milk versus optimally fluoridated water used to reconstitute powdered infant formulas. It must be emphasized that the F levels reported in this study are not unexpected, as a previous study conducted by Anderson et al. in the Republic of Ireland reported that the consumption of infant formula reconstituted with fluoridated water may result in F doses above the recommended tolerable upper intake level for healthy adults [165]. A current study conducted in the USA further supports this observation. In this study, it was reported that the use of optimally fluoridated water (0.7 mg/L) in the preparation of infant formula resulted in 36.8% of infants exceeding the UL [166]. Furthermore, in this study, it was reported that among bottle fed infants the highest bioavailability of F occurs in the first six months of life [166]. Importantly, this also coincides with the period when F excretion is impaired in infants due to immature kidney function [167,168]. Thus, the decline in plasma F concentrations after 6 months of age observed by Warady and associates coincides with the development of renal function and increased urinary excretion of F. Further studies conducted in another fluoridated city in the USA reported that when infants were fed milk-based formula reconstituted with non-fluoridated water, the mean plasma F concentrations two hrs post feeding was 0.77 μM, despite the lack of direct exposure to fluoridated water [169]. This finding reflects the higher plasma F levels in mothers in fluoridated than non-fluoridated communities. Furthermore, this study demonstrated that a dose of 0.25 mg of F administered to twenty infants aged one to eighteen months two hours after their last feed resulted in mean peak plasma F levels of 3.3 µM (range 2.52–4.85 µM). Consistent with the findings of Warady and associates, the authors of this latter study acknowledged that the F intake and exposure for infants fed powdered infant formula reconstituted with fluoridated water would be significantly higher than those reported in their study, though for some unexplained reason they did not attempt to measure ionic plasma F levels in infants provided powdered infant formula reconstituted with tap water in a community with fluoridated drinking water [169].
Table 1. Fluoride levels in human milk, cow’s milk and infant formula and serum/plasma fluoride levels in infants less than 12 months of age in fluoridated and non-fluoridated communities.
Table 1. Fluoride levels in human milk, cow’s milk and infant formula and serum/plasma fluoride levels in infants less than 12 months of age in fluoridated and non-fluoridated communities.
Non Fluoridated
Region mg/L
Fluoridated
Region mg/L
Reference
Human milk x ¯ = 0.004 x ¯ = 0.009[154,161]
Cow’s Milk x ¯ = 0.0160.074–0.18[156]
Cow’s milk based powdered0.02–0.180.49–1.40[159]
infant formula reconstituted
with tap water
Non-FluoridatedFluoridatedReference
Ionic F levelsIonic F levels
µMµM
Fully Breast-fed infants
1–6 months x ¯ = 0.22 [163]
Formula fed
1–6 months x ¯ = 0.29 [163]
Breast fed with semi solids
6–12 months x ¯ = 0.35 [163]
(0.10–0.67)
Aged 1 month 0.89[169]
Aged 7 months 0.53[169]
Breast and formula fed
Aged 4–6 months x ¯ = 4.33[164]
(0.52–8.0)
Aged 7–12 months x ¯ = 1.56[164]
with semi solids (1.03–2.1)
Aged 4–18 months x ¯ =   3.16
A mention should be made that the F levels in infants residing in a fluoridated community in the USA as measured by Warady and associates are within the range observed to cause inhibition of NKA activity in adults [137,138]. Indeed, the levels are also higher than what has been observed among workers occupationally exposed to F in aluminum smelting factories at the end of the working day in Sweden [170] and Japan [171]. Notably, Ehrnebo and Ekstrand reported that the mean plasma F levels in workers at the end of their shift were 2.54 μM [170], while Kono reported serum F levels ranging from 2.21 to 3.47 µM among exposed workers [171]. Moreover, the ionic F levels in blood in infants reported by Warady and associates are within the range known to be associated with skeletal and non-skeletal fluorosis in humans. A review of literature addressing ionic F levels associated with skeletal and non-skeletal fluorosis in humans has been the subject of an earlier study by Waugh et al. [153]. However, it should be also noted that the F levels reported by Warady and associates for infants aged 4–6 months were two fold higher than those reported for 60-day old non-diabetic weaning Wistar rats fed drinking water with a F concentration of 50 mg/L, while the plasma F levels in infants with chronic kidney disease were comparably to diabetic rats fed drinking water with 50 mg/L [172]. Toxicity studies using 3-week old weaning male Wistar rats provided F in drinking water at concentrations of 50 mg/L for 60 days lead to mean ionic plasma F levels of 3.78 µM [173], which is similar to reported for (A/J) mice given 50 mg/L F in drinking water for 11 weeks (mean serum F levels of 3.31 µM) [174]. Collectively, these findings suggest that in fluoridated community’s plasma F levels in maternal cord blood and human neonates in early infancy are comparable to the plasma F levels in rodents administered drinking water with a F level of approximately 50 mg/L.
Moreover, studies involving adult human subjects in countries without water fluoridation have demonstrated that the consumption of single cup of tea containing between 1.4 and 2 mg/L F result in peak plasma F levels of approximately 3–4 µM. [175,176]. It is necessary to note that the frequency of F dosage is known to affect plasma F levels due to the terminal plasma half-life of F. Thus, multiple low dose exposures can result in higher steady state plasma F levels than single dose exposure to higher doses [177,178,179]. Hence, habitual consumption of tea can result in skeletal fluorosis [153]. Moreover, currently about one-fifth of the currently marketed pharmaceuticals are organofluorine compounds and almost one-third of the top 100 top-selling drugs are organofluorine compounds. Fluoridated pharmaceuticals include antidepressants, anti-inflammatory agents, antimalarial drugs, antipsychotics, antiviral agents and steroids [180]. While there is a paucity of information on the biotransformation of fluoridated pharmaceuticals in general, several synthetic organic fluoride drugs which have been found to undergo high rates of biotransformation and defluorination resulting in significantly elevated plasma F levels and in some instances chronic F intoxication in humans. While it is beyond the scope of this present study to review the literature on fluoridated pharmaceuticals, of the fluoridated drugs currently on the market, Voriconazole is acknowledged to cause chronic F intoxication, resulting in musculoskeletal chronic pain disorders and skeletal fluorosis [181,182]. Skiles et al. reported that elevated plasma F levels of 24.3 μM after 6 months of voriconazole treatment resulted in skeletal fluorosis. Once F toxicity was confirmed and voriconazole was discontinued, within 3 weeks plasma F level declined to 6.7 μM [181]. Furthermore, the use of fluoridated anaesthesia such as sevoflurane can provide 20 times the total daily dietary intake from all sources of fluoridated food and water combined [183], resulting in peak plasma F levels in the range of 50 μM [184].
Dental-care products are also a major source of F exposure especially for children, because many tend to use more toothpaste than is advised, their swallowing control is not as well developed as that of adults, and many children under the care of a dentist undergo fluoride treatments [150]. The use of topical fluoride gels which contain high concentrations of F have been reported to significantly increase children’s F plasma levels up to 79 μM after treatment. Among adults the use of F gels can result in peak plasma F levels of 51 μM [185,186]. Researchers found that the peak concentration was normally reached within 1 to 2 h of treatment and remained significantly elevated for up to 14 h [185]. The most commonly used fluoride-containing dental product is toothpaste. The vast majority of toothpastes sold today contains between 1000 ppm and 1500 ppm. Human studies have demonstrated that ingested F in toothpaste is readily absorbed into systemic circulation resulting in rapid rise in plasma ionic F levels [187]. A recent study involving healthy adults aged between 20–35y residing in a non-fluoridated community in England observed that when subjects were given a non-fluoridated toothpaste plasma F levels, as measured in the morning after toothbrushing declined significantly from approximately 3.2 µM to 0.67 µM, respectively [188]. In another study conducted among adults residing in non-fluoridated community in Scotland, it was found that brushing twice a day (morning and evening) with toothpaste containing 1000 ppm and 1500 ppm for four weeks was found to increase plasma F levels at midday to 1.18 and 1.33 µM respectively, compared to 0.7 µM in subjects using non-fluoride toothpaste [189]. The differences in plasma F levels observed in these latter studies can be accounted for the half-life of F in systemic circulation. After a single dose of F plasma concentrations rise to a peak within one hour and decrease back to baseline with a half-life of two-three hours [176]. Therefore, taking the time differences in sampling of blood the results observed by Zohoori et al. and Jacobson are almost identical. Taken together, this data shows that a single brushing with F toothpaste in the morning can provide a dose of F comparable to consuming a cup of black tea with a F content of 1.4–2.0 mg/L [175,176]. Similar to tea, case reports also indicate that skeletal fluorosis can occur from excessive use of F toothpaste [190]. Kurtlan et al. reported a case study of an adult American male aged 52 yrs who developed skeletal fluorosis from brushing his teeth six times per day. Laboratory evaluation of blood found serum F levels ranged from 15 to 18.0 µM [190]. The subject did not reside in a fluoridated community and had no known occupational or environmental exposure to F apart from toothpaste. The patient stated that he did not swallow toothpaste, used non-fluoridated mouthwash, had semi-annual dental visits, but without F treatments, did not drink tea or wine, and had not chewed tobacco, inhaled snuff, or cooked with Teflon pots. Within 8 months of documentation of skeletal fluorosis and after avoiding fluoridated dental products, serum F decreased to < 2.5 µM [190]. It is also important to note that the European Academy of Paediatric Dentistry (EAPD) recommend that children who are below the age of two should use toothpastes with low fluoride concentrations (less than 500 ppm) [191]. For children aged 2–7 years, a pea sized amount of F dentifrice (0.25 g) has been recommended [192,193,194]. However, several studies examining toothpaste usage by children aged 3–6 years have consistently shown that the amount of toothpaste used on toothbrushes typically varies from 0.35 to 3.5 g which can lead to excessive F intake [194,195], particularly among children who brush twice daily or more. A current study in a fluoridated community in England involving young children aged 4 to 6-years of age residing reported that the contribution of toothpaste to total dietary F intake was 53% [196]. In this study, the highest total daily F intake (4.439 mg/day = 0.22 mg/kgbw/day) was for a 5-year-old child of which 72% (3.217 mg/day = 0.16 mg/kgbw/day) was from toothpaste ingestion [196]. In summary, the above studies illustrate that in evaluating the effects of F, consideration must be given to effects of cumulative exposures and their contribution to total F intake and ionic plasma F levels. As NKA is found in plasma and bound to plasma membranes, it is the ionic F levels in systemic circulation and within cells that interacts with NKA functionality. The remainder of this study addresses NKA regulation and the molecular mechanisms by which F inhibits enzyme activity and the most significant health risks likely to be associated with F-induced inhibition of enzyme activity.

3. Na+, K+-ATPase Regulation by Phosphorylation/Dephosphorylation

NKA is a plasma membrane embedded protein in all animal cells. NKA consists of two noncovalently linked α and β subunits. The alpha subunit is also known as the catalytic or functional subunit, since it contains the binding sites for protein kinase, protein phosphatase and transmembrane ion transport activities [197,198,199]. The catalytic α-subunit is responsible for conversion of ATP energy to transport of Na+ and K+ across cell membranes and has ATP and cardiac glycosides binding sites. The β-subunit is responsible for delivery and insertion of alpha one in cell membranes [200,201,202]. Thus, plasma membrane expression of the NKA requires the assembly of its alpha- and β- subunits [3] and the β subunit must interact with α subunit in order to accomplish ion transport [203]. The presence of magnesium facilitates the binding of ATP to NKA thereby providing the chemical energy required for ion channel function and secondary active transport [2]. Functionally, it has been identified that the activity of NKA is inhibited by phosphorylation. Furthermore, cyclic adenosine monophosphate (cAMP)-dependent protein kinase, (PKA) and protein kinase C (PKC) catalyse the phosphorylation of the enzyme [204]. It is well proven that PKC phosphorylates the NKA α subunit, leading to a decrease in enzyme activity [205,206,207,208,209,210,211,212,213].

4. Molecular Mechanisms by which Fluoride Inhibits Na+, K+-ATPase Activity

Despite the large number of studies demonstrating that F inhibits NKA activity, the molecular mechanisms of down-regulation are not yet clearly understood [214]. To address the limitations in understanding of the molecular mechanisms of down-regulation it was first necessary to identify modulatory mechanisms from published literature. Thus, a review of literature was undertaken using PubMed and other search engines (Google, Google Scholar, ResearchGate, Yahoo) to source pertinent research articles and publications. Second, in order to elucidate the molecular mechanisms by which F may inhibit NKA activity, evidence was sought from published literature including human, animal and in vitro studies to examine how F interacted with each of the biological pathways identified. As illustrated in Figure 2 and summarized in Table 2, NKA activity is downregulated by a variety of hormones, proteins, metalloenzymes, neuropeptides and cytokines. Furthermore, regulatory mechanisms governing circulating inorganic phosphate, glucose homeostasis and adenosine-triphosphate production play a crucial role in downregulating enzyme activity.

4.1. The Role of Protein Kinase RNA-like ER Kinase (PERK) in Regulating Na+, K+-ATPase Activity and the Influence of Fluoride on PERK Activity

As previously described, the β subunit of NKA regulates both the activity and the conformational stability of α subunit and plasma membrane expression of the NKA requires the assembly of its α-and β-subunits. Thus, inhibition of the β subunit leads to reduced expression and lower enzyme activity. It is also important to note that NKA β subunit expression and maturation requires the interaction of Wolfram Syndrome 1 (WFS1) protein [215]. Furthermore, it has been shown that reduced expression of WFS1 results in reduced expression of NKA β subunit [202]. It has been reported that WFS1 expression is induced by protein kinase RNA-like ER kinase (PERK) [216]. Recent in vivo studies examining the role of genetics in response to F exposure found that chronic F exposure inhibits the expression of PERK [217]. Taken together, this data suggests that F may also inhibit WFS1 protein expression, leading to inhibition of NKA expression and activity.

4.2. The role of Protein Kinase C (PKC) in Regulating Na+, K+-ATPase Activity and the Influence of Fluoride in Regulating PKC Activity

Phosphorylation is a widely used, reversible means of regulating enzymatic activity [218]. It is further known that phosphorylation of the NKA catalytic subunit inhibits enzyme activity [204]. Protein kinase C (PKC) is critical to phosphorylation [219] and as previously described it is well proven that PKC phosphorylation of the α subunit of NKA leads to a decrease in its enzyme activity [206,207,208,209,210,211,212,213]. Conversely, inhibition of PKC has been found to stimulate NKA enzyme activity [220,221].
Interestingly, Bocanera et al. also reported that PKC pathway inhibits thyroid iodide uptake in calf thyroid cells by an action distal to cAMP generation and probably because of a decrease in NKA activity [222]. As previously described, hypothyroidism has also been found to decrease the activity of NKA [113,114,115]. and there is evidence from human studies that water fluoridation and elevated F levels in drinking water may contribute to hypothyroidism [139,140]. Hypothyroidism has also been shown to significantly upregulate PKC expression and activity [223,224]. Furthermore, it is also well established that activation of PKC is a physiological action of F-induced cellular toxicity [133,225,226,227,228,229,230]. Overall, these data suggest that F activation of PKC is a key mechanism underlying F inhibition of NKA activity and that the contributory effect of F exposure to hypothyroidism may further potentiate inhibition.

4.3. The Role of Cyclic Adenosine-Monophosphate (cAMP) in Regulating Na+, K+-ATPase Activity and the Influence of Fluoride in Regulating cAMP

The possibility that cAMP or cyclic AMP may play a role in regulation of NKA activity was reported three decades ago [231]. Subsequent studies have confirmed that cAMP inhibits NKA activity [232,233,234]. Although not completely elucidated, it is important to examine the molecular mechanisms by which this inhibition occurs. The precise mechanism of action will be defined in in the following section elucidating the molecular mechanism by which F alters cAMP and adenosine-triphosphate (ATP) bioavailability.
It is also established that F increases the conversion of ATP to cAMP by stimulation of adenylyl cyclase [235,236]. Consistent with this, evidence from human and animal studies show that F stimulates cAMP production [237,238,239,240,241,242,243,244,245,246,247,248] leading to increased concentrations of cAMP in plasma, saliva, urine, and tissues. Moreover, in vitro human tissue models have demonstrated that F in micromolar concentrations of 1–10 µM significantly increases the synthesis of cAMP in a dose dependent manner [249]. In addition, thyroid-stimulating-hormone (TSH) is known to be a potent stimulant of adenylyl cyclase activity resulting in increased synthesis of cAMP [250,251]. Furthermore, early in vitro studies by Wolf and Jones documented the largely identical effect of F and TSH on adenyl cyclase activity resulting in increased stimulation of cAMP [252]. Consistent with this, several in vitro studies have shown a synergistic effect of F and TSH on adenylate cyclase activity resulting in increased cAMP production [253,254]. Evidence from human studies also show that F induces TSH production [140,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269]. In this scenario, a positive feedback loop exists that may amplify the effects of TSH and F on cAMP activity, which may explain the synergistic effect of F and TSH on cAMP production.
In elucidating the molecular mechanisms by which increased production of cAMP inhibits NKA activity, it is necessary to emphasise that the conversion of ATP to cAMP leads to a reduction in ATP molecules. Since energy supply is a limiting factor controlling NKA activity, ATP depletion leads to inhibition of enzyme activity. As described above, F increases the conversion of ATP to cAMP. Further studies have shown that F inhibits ATP bioavailability [270,271]. Indeed, studies have shown that F induces depletion of ATP in erythrocytes (red blood cells) [271]. Consistent with these findings, several studies have reported that ATP depletion induced by F leads to inhibition of NKA in erythrocytes [126,128]. Furthermore, it is known that the breakdown of glucose by glycolysis is a major source of ATP [272]. Enolase is required to allow glycolysis to proceed [273] and inhibition of enolase leads to depletion of ATP [274]. Given that it is well established that F inhibits glycolysis via inhibition of enolase [275,276,277,278]. it is not surprising that recent in vitro studies found that inhibition of glycolysis by F contributed to reduced NKA activity [136]. However, it is important to also note that F inhibition of enolase is significantly stronger in the presence of phosphate [278]; the significant of which will be discussed later in this study. Taken together, this data demonstrates that F stimulation adenylyl cyclase and TSH secretion leads to increased synthesis of cAMP reducing the bioavailability of ATP thereby contributing to inhibition of enzyme activity. Furthermore, it seems reasonable to suggest that the mechanisms outlined above elucidate why previous studies found that hypothyroidism was associated with lower NKA activity [113,114,115].
However, in addition to the role of cAMP in depleting ATP, it has also been reported that cAMP inhibits NKA activity by enhancing phosphorylation of the NKA α subunit [279]. As previously described, it is well proven that phosphorylation of the α subunit, leads to a decrease in its enzyme activity [206,207,208,209,210,211,212,213]. Therefore, strong evidence indicates that the action of F in upregulating cAMP may lead to inhibition of NKA activity by two distinct pathways, by reducing ATP bioavailability and increasing phosphorylation of the α subunit of NKA.

4.4. The Influence of Magnesium in Regulating Na+, K+-ATPase Activity and the Influence of Fluoride on Magnesium Homeostasis

The human body contains around 25 g of magnesium [280]. Magnesium is necessary for the functioning of over 300 enzymes in humans [281], with 90% of total body magnesium being contained in bones and muscles (~63% and ~27%  respectively), 90% of which is bound and with only 10% being free [282]. In the serum, 32% of magnesium is bound to albumin, whereas 55% is free [280]. As previously discussed, Jorgensen et al. elucidated that the presence of magnesium facilitates the binding of ATP to NKA, thereby providing the chemical energy required for ion channel function and secondary active transport [2].
F is known to form complexes with magnesium and increased concentrations of magnesium reduce F absorption in the gastrointestinal tract [150]. This action would also result in reduced absorption of magnesium. Experimental studies have shown that low magnesium diets significantly enhance F absorption [283] and F accumulation in calcified tissue retards the mobilization of skeletal magnesium [284]. Furthermore, as magnesium is bound to albumin, loss of albumin in urine can lead to enhanced excretion of magnesium and lower levels of magnesium in systemic circulation. In line with this, I recently elucidated how the loss of albumin in urine and resultant hypoalbuminemia (low levels of albumin in blood) contribute to iodine deficiency and that F acts to induce increased urinary excretion of albumin and hypoalbuminemia [110]. Therefore, evidence would strongly suggest that F exposure can lead to magnesium deficiency. Consistent with these hypothesis, human studies have shown that F significantly reduced serum magnesium along with other trace metals including manganese, copper and zinc [285,286,287]. In agreement, animal studies have also found that F exposure results in decreased serum magnesium [288,289,290,291,292]. Thus, the above data suggests that F can inhibit NKA activity by lowering serum magnesium thereby impairing ATP binding to NKA.

4.5. The Influence of Calcineurin, Calmodulin and Manganese in Regulating Na+, K+-ATPase Activity and the Influence of Fluoride on Calcineurin, Calmodulin and Manganese Homeostasis

It has also been reported that the dephosphorylation (activation) of NKA is mediated by calmodulin-dependent calcineurin (Cn), a serine/threonine phosphatase [204,208,293]. Therefore, inhibition of Cn will lead to downregulation of NKA activity. Although the molecular pathway has not been completely elucidated, it has also been reported that Cn is inhibited by F [294,295,296]. However, it is known that Cn binds to calmodulin (CaM) and the complex of Cn and CaM is the active species of the phosphatase. Furthermore, aside from CaM, Cn requires an additional divalent metal ion such as manganese for structural stability and full activity [297]. Manganese is also a crucial activator of Cn activity [298,299].
It has been shown that F upregulates the activation of adenylate cyclase by CaM [300] and activation of adenylate cyclase increases the intracellular level of cAMP [301]. As previously described, adenylate cyclase is the enzyme which catalyses the conversion of ATP to cAMP, thus increased cAMP synthesis reducing the bioavailability of ATP. As previously noted, cAMP has been observed to inhibit NKA activity and the molecular mechanisms of inhibition have been described. However, CaM has also been found to inhibit NKA activity. in human red blood cells [302]. Furthermore, previous studies have shown that CaM can mediate the phosphorylation of acetylcholine receptor and CaM stimulation of phosphorylation was enhanced most in the presence of F [303]. Revealingly, studies have shown that the presence of F inhibited the activation of phosphodiesterase by CaM [304]. Interestingly, phosphodiesterase is responsible for the hydrolysis (breakdown) of cAMP [305], a crucial finding that may elucidate why F exposure is associated with increased concentrations of cAMP.
Furthermore, chronic F intake has been shown to significantly reduce serum manganese levels in humans along with other trace metals including magnesium, copper and zinc [286]. Lower manganese accumulation in skeletal tissue has also been observed in humans suffering from fluorosis [306]. In agreement, several animal studies have also found that excessive F exposure resulted in decreased manganese in serum [292,307,308], as well as in reduced manganese in liver, kidney, heart, lung and muscle tissue [309,310,311,312]. Collectively, this data suggests that F enhances the activation of adenylate cyclase by CaM leading in increased production of cAMP. Furthermore, the ability of F to enhance the phosphorylation activity of CaM suggests that F may contribute to the inhibitory effects of CaM on NKA enzyme activity. In addition, the contributory effect of F reducing manganese bioavailability suggests that this action may also be a potential mechanism in F inhibition of Cn activity. As previously described, manganese is a crucial activator of Cn and also binds to Cn ensuring structural stability and full enzyme activity. Thus, lower manganese reduces Cn expression. Furthermore, as the dephosphorylation of NKA is mediated by Cn, reduced expression of Cn or inhibition of Cn activity contributes to enhanced phosphorylation, which in turn leads to inhibition of enzyme activity.

4.6. The Role of Cyclic Guanosine Monophosphate (cGMP) and Nitric Oxide in Regulating Na+, K+-ATPase Activity and the Contribution of Fluoride to Regulating cGMP and Nitric Oxide

It is also known that an important intracellular second messenger cyclic guanosine monophosphate (cGMP) inhibits NKA activity. [231,313,314,315]. The seminal study by de Oliveira et al. demonstrated cGMP inhibited NKA activity and that cGMP activation was induced by nitric oxide (NO) [315]. Accordingly, NO generating compounds play an important role in regulating NKA activity. Consistent with this finding, several studies have observed that NO inhibits the molecular activity of renal NKA [232,313,316,317,318,319]. Several studies have also shown that F induces NO synthesis in vivo [320,321,322,323,324,325,326]. Furthermore, experimental studies have shown that F stimulates cGMP in the kidney and thyroid [327,328]. Hence, the above data suggests that F inhibits NKA activity by stimulating NO expression and cGMP activity.

4.7. Cytokine TGF-β1 Inhibits NKA Activity

Transforming growth factor β 1 or TGF-β1 has been found to inhibit the expression of the β-subunit of NKA required for enzyme function [55]. As previously noted, plasma membrane expression of the NKA requires the assembly of its α- and β- subunits [3] and the β subunit must interact with α subunit in order to accomplish ion transport [203]. Hence, TGF-β1 inhibition of β-subunit expression leads to inhibition of NKA expression and protein activity.
It has been reported that TGF-β1 plays an important role in fluorosis and increased levels of TGF-β1 have been suggested as an important marker in the evaluation of the pathological action of F in bone tissue [329,330]. In vivo and in vitro experimental studies of fluorosis have shown that F upregulates TGF-β1 protein and mRNA expression in bone cells [329,331,332,333]. Importantly, calcitonin (CT), a hormone that is secreted by parafollicular cells of the thyroid gland, has been found to be a potent stimulator of TGF-β1 protein synthesis as well as TGF-β1 mRNA expression [334]. Furthermore, a large body of evidence from epidemiological studies has demonstrated that F is a potent inducer of CT expression in humans [335,336,337,338,339,340]. Of fundamental importance, is the seminal research by Chen and associates in providing a biological dose-exposure response relationship for F exposure in humans on CT expression at relatively low F intakes. Notably, in this study, it was demonstrated that differential expression of CT occurs when urinary F levels exceeded 0.38 mg/L [338]. Taken together, this data suggests that the contribution of F in enhancing the expression of TGF-β1 via upregulation of CT is another mechanistic pathway whereby F inhibits NKA mRNA expression and protein activity.

4.8. The Role of Inorganic Phosphate in Regulating Na+, K+-ATPase Activity

In light of the fact that phosphorylation inhibits NKA activity, rationality postulates that elevated levels of inorganic phosphate (Pi) will also act as an inhibitor of NKA activity. In support of this hypothesis, it has previously been reported that Pi plays a role in phosphorylation of NKA [341] and high concentrations of Pi inhibit enzyme activity [342]. Furthermore, previous studies have also shown that Pi inhibits phosphatase activity of calcineurin (Cn) [343]. As previously described, dephosphorylation of NKA is mediated by Cn [2]. Hence, evidence suggests that higher levels of Pi may contribute to inhibition of NKA activity by decreasing dephosphorylation activity of Cn. Moreover, it is well established that alkaline phosphatase (ALP) is an enzyme responsible for catalysing dephosphorylation of phosphate esters, which leads to liberating Pi [344]. As ALP levels rise; more Pi is liberated [345]. Thus, ALP enzymatic activity plays a role in regulating Pi levels. This also suggests that ALP must play a role in regulating NKA functionality. ALP is found in normal osteoblasts, and the mode of action of F in stimulating APL activity in humans is well recognized [242,346,347,348,349,350,351]. It is also well established that F acts to increase osteoblast formation [150]. It has been demonstrated in vitro that F at concentrations as low as 0.1 μM increase the expression of ALP and stimulate the proliferation of osteoblasts [352]. Furthermore, it is known that ALP activity increases in the presence of CT [353].
As previously described, F is a potent inducer of CT. Moreover, it is also known that the protein RANKL (receptor activator of nuclear factor-KB ligand) increases osteoclast number, bone resorption, and subsequently Pi release [354,355]. Furthermore, Pi uptake by osteoclasts require sodium-dependent phosphate (Na-Pi) transporters that are dependent on ATPase activity. The energy requirement to drive this process is high, thus, a large amount ATP is required [356]. Inhibitors of Na-Pi-cotransporters or ATPase or reduced ATP bioavailability result in inhibition of bone Pi resorption [356], leading to increased plasma Pi levels. As previously described, F reduces ATP bioavailability and impairs glycolysis, and it is well established that F is an inhibitor of ATPase. Furthermore, recent in vivo studies with rodents and subsequent in vitro studies on bone tissues found that low dose F exposure stimulates expression of RANKL [357]. As previously elucidated, RANKL stimulates Pi release. Consistent with the mechanisms elucidated above, several human and animal studies have shown that F intake can enhance Pi levels [349,358,359,360,361,362,363,364,365,366,367]. As Pi has been found to inhibit NKA activity, this provides a further mechanistic pathway by which F inhibits NKA activity. Furthermore, as previously elucidated, F inhibition of enolase is also significantly stronger in the presence of Pi [278] and F inhibition of enolase has previously been found to inhibit NKA activity [136].

4.9. Dopamine Inhibits Na+-K+-ATPase Activity

It is known that dopamine (DA) inhibits NKA activity [231,368,369,370,371,372,373,374,375] though the molecular mechanisms of inhibition remain elusive. Furthermore, it has also been reported that PKC and cAMP signalling contribute to dopaminergic inhibition of NKA activity [376]. To understand how DA inhibits NKA activity, it is important to point out that DA has been found to directly stimulate cAMP [377,378,379]. Furthermore, Vortherms et al. reported that persistent activation of DA receptors results in a compensatory increase in cAMP accumulation [378]. As previously elucidated, the production of cAMP leads to a reduction in ATP, which is required for NKA enzyme activity.
Several experimental animal and in-vitro studies on tissues/cells have demonstrated that F stimulates DA release [227,380,381,382,383], although how this occurs is not well understood. However, other studies suggest that this may be due to the effect of F on hypothalamus function. It is well established that the hypothalamus regulates pituitary TSH secretion by releasing thyrotropin-releasing hormone (TRH) [384,385] and excess TSH is associated with iodine deficiency and hypothyroidism [110]. In addition to TRH induced release of TSH, TRH stimulates DA release [386,387,388]. Furthermore, it has also been observed that hypothyroidism increases DA receptor sensitivity by increasing receptor concentration [389]. As previously described, human studies have consistently found that F can stimulate TSH production in humans [140,255,269]. Thus, F must also induce TRH secretion. Furthermore, the stimulatory effect of F on DA release has been observed in animal studies with drinking water F levels of 1 mg/L [382]. Interestingly, in this study, the highest levels of DA release were observed at 5 mg/L F in water above which DA release was found to decrease. Consistent with this finding, it has reported that stimulant-induced increases in endogenous DA levels trigger feedback mechanisms that inhibit DA neuron firing [390]. Interestingly, inhibitors of NKA have also been found to almost completely abolish the TRH-induced DA releasing effect [378]. Therefore, it is also plausible that the reduction in DA release at higher F doses may reflect the enhanced inhibitory of F on NKA activity which in turn inhibits TRH induced DA release. It is also important to understand that biosynthesis of TRH in the hypothalamus is dependent on ATP [391]. Thus, increased TRH synthesis leads to a reduction in ATP bioavailability. As previously elucidated NKA function requires ATP. In addition to the animal studies which found that F induces DA release, evidence from human studies have found that the level of DA in foetal brain tissue is elevated in foetuses of F-exposed mothers with dental fluorosis, compared to foetuses from mothers without dental fluorosis living in non-F endemic areas [392]. Collectively, these results provide strong evidence that the ability of F to upregulate TRH or TSH secretion may contribute to DA dysfunction leading to enhanced DA release which in turn may contribute to NKA inhibition by a mechanistic action that appears to involve cAMP production and decreased bioavailability of ATP.

4.10. Parathyroid Hormone Inhibits Na(+)-K(+)-ATPase Activity

One of the major regulators and inhibitors of proximal renal tubule NKA activity is parathyroid hormone (PTH) [374,393,394,395,396]. Further research has shown that PTH inhibits NKA through activation of PKC [393,397,398], cAMP [395] and phospholipase A2 (PLA2), pathways [397]. Furthermore, human studies have shown that when urinary F levels are in excess of 1 mg/L PTH expression is significantly enhanced compared to subjects with urinary F levels less than 0.5 mg/L [399]. It is important to point out that Schwartz et al. demonstrated that lowering of blood ionized calcium by an amount as low as 0.02 mmol/L (0.08 mg/L) within 30 min can elicit an immediate large, transient peak release of PTH amounting to 6–16 times the baseline concentration [400]. Of critical importance, Karademir et al. demonstrated that serum calcium levels were 0.075 mmol/L and 0.1 mmol/L lower among subjects with urinary F levels of 0.70 mg/L and 0.90 mg/L respectively, compared to controls with urinary F levels of 0.20 mg/L [260]. Taken together, these findings provide a basis for the hypothesis that F- induced PTH release contributes to NKA inhibition by a mechanistic pathway that involves PKC, cAMP and PLA2. The association between F and PLA2 expression will be discussed in the following section.

4.11. Hyperglycaemia Inhibits Na+ K+ ATPase Activity via Activation of PGE2 Production

It is known that NKA activity is inhibited by elevated glucose concentrations although the mechanism of suppression remains largely unknown [401,402,403,404,405]. It has also been reported that inhibition of NKA activity by hyperglycaemia could be an important etiological factor of chronic complications in diabetic patients [406]. Importantly, a large number of human and animal studies have demonstrated that F exposure can induce hyperglycaemia [363,407,408,409,410,411,412,413,414,415,416,417,418,419,420]. Consistent with this, the U.S. National Research Council (NRC) reported that the conclusions from available studies is that sufficient F exposure appears to bring about increases in blood glucose or impaired glucose tolerance in some individuals and the increase the severity of some types of diabetes [150]. Again, it has been shown that mechanistic pathway by which hyperglycaemia inhibits NKA activity is via activation of PKC and phospholipase A2 (PLA2), resulting in the liberation of arachidonic acid (AA) and increased the production of prostaglandin E2 (PGE2), which are known inhibitors of NKA activity [406,421,422]. Importantly, several in vitro human tissue models have consistently demonstrated that F in micromolar concentrations of 1–10 µM significantly increases the synthesis of cAMP, AA, PGE2 and PLA2 in a dose dependent manner [249,423,424]. Taken together these observations provide a basis for the hypothesis that F-induced hyperglycaemia contributes to NKA inhibition. Furthermore, evidence suggests that F may also inhibit NKA activity directly via stimulation of PLA2 synthesis, leading to increased production of AA and PGE2.
It is also important to point out that nuclear transcription factor kappa-B (NF-κB) has been previously reported to be involved in the up-regulation of COX-2 and generation of PGE2 [425,426]. It is well established that F activates the NF-κB mRNA expression in a wide variety of cell types and including monocytes, macrophages as well as lung, kidney and brain tissue [427,428,429,430,431,432,433,434]. This stimulatory effect has been observed at F concentrations of 2.5 µM [427]. However, the seminal study by Misra et al. demonstrated that beryllium fluorides at concentrations as low as 0.002 uM significantly upregulated the activation of NF-κB in macrophages [435], indicating that beryllium fluoride complexes have much greater cytotoxicity and genotoxicity than F alone. With an increasing interest in beryllium, concern has raised specifically about the risks of co-exposure to beryllium and F [435]. Human biomonitoring studies have determined that the mean concentration of beryllium in breast milk is 0.008 µg/L [436]. However, a UK study found that the mean concentration of beryllium in ten different brands of powdered infant formula products was 1.1 µg/L [437]. In view of the fact that infant formula products contain such high levels of beryllium and that beryllium is known to bind with high affinity to the electronegative F [438,439,440,441] raises particular concerns considering that infant formula products are reconstituted with fluoridated tap water in countries with water fluoridation.

4.12. Advanced Glycation end Products Inhibit Na+ K+ ATPase

Finally, it is known that the inhibition of enolase results in the formation of advanced glycation end products (AGEs) [442] and AGEs inhibit NKA enzyme activity [443]. Again, the mechanistic pathway has been elucidated to involve activation of AA metabolism via PLA2 activation [443]. It has been known for many decades that enolase is particularly sensitive to F inhibition [275,276,277]. Furthermore, recent in vivo rodent studies demonstrated that chronic long-term exposure for six months to F via drinking water significantly increased expression of receptors for advanced glycation end products (RAGE), increased RAGE proteins and increased levels of AGEs in cells. A significant increase in the expression NADPH oxidase 2 (NOX2) was also observed among specimens exposed to fluorine for 6 months. Notably these effects were found to occur at concentrations of just 5 mg/L in drinking water, which is the equivalent to approximately 0.5 mg/L in drinking water for humans. Simultaneous in vitro research with SH-SY5Y cells originating from human neuroblastoma confirmed these results [444]. Taken together these observations provide a basis for the hypothesis that F-induced inhibition of enolase contributes to NKA inhibition by activation of AGEs, which in turn leads to activation of PLA2 and the synthesis of AA which is metabolised to PGE2.

5. Discussion

As noted from the preceding data, F inhibition of NKA activity is complex and multifactorial. In summary, evidence is provided to show that activation of PKC, cAMP, cGMP, NO, Pi, PLA2, AA and PGE2 inhibit NKA activity and that F upregulates PKC, cAMP, cGMP, NO, PLA2, AA, PGE2 and enhances Pi levels in systemic circulation. Furthermore, evidence is presented to show that Cn regulates NKA activity and that F inhibits CN activity, in part, by regulating the bioavailability of manganese and Pi, as well as by altering the phosphorylation activity of CaM. In addition, evidence is provided to show that F enhances the activation of adenylate cyclase by CaM, leading to increased levels of cAMP and further evidence is provided to show that F inhibits the activation of phosphodiesterase by CaM, which is responsible for the breakdown of cAMP. I further elucidate that the presence of magnesium facilitates the binding of ATP to NKA, thereby providing the chemical energy required for ion channel function and secondary active transport. I have described how F contributes to magnesium deficiency by forming complexes with magnesium thereby lowering the absorption of magnesium and F in the gastrointestinal tract leading to reduced bioavailability. I have further elucidated that F retards the mobilization of magnesium in bone and can increase the excretion of magnesium in urine bound to ALB.
In the present study, I have further elucidated the molecular mechanisms by which hypothyroidism lowers NKA activity. In addition, I describe how F inhibition of enolase leads to inhibition of glycolysis thereby reducing ATP production. As ATP is required for NKA function, lower levels of ATP in turn may lead to inhibition of enzyme activity. Furthermore, evidence is presented to show that NKA activity is inhibited by cAMP and that F acts to induce cAMP production. Moreover, in this study I have elucidated that there are two distinct mechanisms by which cAMP inhibits NKA activity. This can occur through loss of ATP, as well as the direct effect of cAMP in enhancing phosphorylation of the NKA α subunit. In this study, I also describe how the pituitary hormone TSH increases cAMP production and further evidence is provided to show that F upregulates TSH secretion leading to a positive feedback mechanism that may result in inhibition of enzyme activity. I have further described how Pi has been found to inhibit NKA activity. I have further elucidated the role of ALP and RANKL in Pi release and the contribution of F to increased mRNA expression of RANKL and ALP activity, which contributes to increased concentration of Pi in serum. Moreover, I have described how ALP activity is increased in the presence of CT and that F is a potent inducer of CT activity. I have also described how CT stimulates TGF-β1 protein synthesis as well as TGF-β1 mRNA expression and that TGF-β1 inhibits the expression of the β-subunit of NKA required for enzyme function.
Further evidence is presented to show that NKA activity is inhibited by dopamine, PTH and glucose. In addition, evidence is presented demonstrating that F upregulates dopamine, glucose and PTH activity. Further analysis reveals that the mechanism of dopamine inhibition of NKA is via increased production of cAMP. It has also been elucidated in this study that NKA inhibition by PTH and hyperglycaemia is regulated by activation of PLA2, AA and PGE2. In addition, there is evidence demonstrating that stimulation of AGEs inhibits NKA activity and that F inhibition of enolase results in the formation of AGEs. Again, the mechanistic pathway by which AGEs inhibit NKA enzyme activity is via activation of the PLA2 pathway leading to enhanced expression of AA and PGE2. I have also elucidated how F induces NF-κB mRNA expression in a wide variety of cell types and how NF-κB activation leads to increased PGE2 production. Consistent with these findings, evidence is provided from several in vitro studies with human cell lines that have consistently demonstrated that F at biologically relevant exposures, ranging from 1–10 µM, increases the synthesis of cAMP, PLA2, AA and PGE2 in a dose dependent manner. Moreover, evidence from human studies confirm that F exposure as measured by serum F levels in adults, inhibits NKA activity in vivo at levels within the same range observed in human cell in-vitro studies showing increased activation of cAMP, PLA2, AA and PGE2. While this effect on NKA was found to occur in adults at serum F levels < 5.0 µM, at higher mean serum F levels of 14.75 µM the activity of NKA declined by approximately 60 per cent compared to controls [137,138]. Moreover, the serum F levels observed in the control groups of either of these two studies were comparable to the mean fasting serum F concentrations recently reported among healthy adults of similar age residing in a non-fluoridated community (drinking water F level < 0.3 mg/L) in the UK [188]. This data suggests that total F intake among adults in western countries where drinking water is fluoridated or where habitual tea drinking is commonplace and where F toothpaste is widely available would fall within the range observed to cause inhibition of NKA. Furthermore, it is important to acknowledge that in addition to inhibiting NKA activity, Arulkumar et al. also found that the activity of adenosine 5′ triphosphatase (ATPases), Mg(2+) ATPases, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), paraoxonase 1 (PON1) and arylesterase (ARE) declined in a dose dependent manner with increasing serum F concentrations [137]. Clearly, further studies are warranted to explain the wider implications associated with F inhibition of these important enzymes. For example, loss of ARE and PON1 is associated with metabolic syndrome and are considered independent risk factors for cardiovascular disease [445]. Moreover, downregulation of AChE causes inflammatory hyperactivation of the CNS and peripheral nervous system [446,447]. Moreover, the U.S.A. National Academy of Sciences NRC previously reported that F downregulates AChE and suggested that this action may contribute to increases the risk of developing Alzheimer’s disease [150].
Returning to the hypothesis/question posed at the beginning of this study, it is important to assess the implications of F inhibition of NKA activity on human health and disease inequalities. As I have described, loss of NKA activity has been implicated in many pathophysiological conditions, including asthma and allergic diseases, metabolic disorders, cancer, cardiovascular disease, as well as neurodevelopmental and degenerative brain diseases. Past studies have further suggested that inhibitors of NKA may also contribute to disorders associated with loss of NKA activity [18]. This hypothesis is supported by two current studies which infer a causal association between F exposure and pathophysiological states associated with loss of NKA activity including iodine deficiency [110] and degenerative eye diseases [53]. Among the many molecular mechanisms identified in these latter studies was the contribution of F to loss of NKA activity.
As I already described, loss of NKA activity has been implicated in asthma [19,20], and allergic diseases such as allergic rhinitis [22,23,24]. Moreover, the seminal study by Gentile et al. provided both correlative and mechanistic evidence for a causal relationship between NKA enzyme inhibition and airway hyperreactivity (or bronchial hyperresponsiveness) among asthmatic and allergic subjects [18]. Furthermore, Gentile et al. concluded that inhibitors of NKA could play a role in the pathogenesis of AHR in human beings. Indeed, this observation has already been reported in several studies including environmental and occupational exposure studies. For example, Søyseth et al. found that exposure to atmospheric fluorides corresponded to an increase bronchial hyperresponsiveness in children aged 7–13 years [448]. As described in this current study, F has consistently been found to inhibit NKA activity. Therefore, evidence suggests that F may also play a role in the pathogenesis of bronchial hyperresponsiveness and inflammatory respiratory diseases. Moreover, earlier occupational epidemiological work by Søyseth et al. suggested that F exposure was likely to be a causative agent in causing asthmatic symptoms among workers in the aluminium smelting industry [449]. Of fundamental importance, a positive dose-response association was observed between bronchial responsiveness and plasma F levels, such that an increase in the plasma F level of 0.5 µM was associated with an increase in the dose–response slope by a factor of 1.11 (95% CI, 1.05 to 1.17). Furthermore, the authors hypothesized that an increase of plasma F of 3.4 µM would be associated with a doubling of bronchial responsiveness [449]. The association between bronchial responsiveness and elevated plasma F is important, as several studies have found that increased bronchial responsiveness is associated with asthma [450,451,452,453,454] and impaired lung function [455,456,457].
This leads us to perhaps the most significant evidence revealed in this current study regarding postnatal and early infant chronic F exposure which has been found to occur in communities with artificially fluoridated drinking water (AFDW). As previously elucidated the plasma F levels in infants residing in communities with optimally fluoridated water can be extremely high, due to the reconstitution of powdered infant formula with fluoridated tap water. As described, past research has shown that the mean plasma F levels in infants residing in a community with AFDW during their first 18 months of life was 3.16 μM, with significantly higher plasma F levels measured in infants aged 4–6 months (mean 4.22 µM with a maximum of ~ 8 µM). I have previously elucidated that this level of exposure is comparable to that observed among adult workers occupationally exposed to F in the aluminium industry and within the range observed in human studies associated with endemic fluorosis. Importantly, the plasma F levels are also within the reported range in human studies to cause inhibition of NKA activity in adult subjects.
However, it is not enough to simply extrapolate from research among adults. As previously described, infants have a lower low glomerular filtration rate which results in higher retention of F. The infant also has an immature blood-brain barrier [458,459] and neonates and infants have lower antioxidant activities than adults [460,461]. Moreover, as previously described, infants can be exposed to beryllium fluoride complexes from the consumption of powdered in formula reconstituted with fluoridated tap water. The interaction of beryllium with F is critical, as it has been shown that beryllium F complexes are significantly more toxic than F or beryllium alone, resulting in significantly increased production of NF-κB, which leads to increased production of PGE2. As previously elucidated PGE2 is known to inhibit NKA activity. Therefore, it is plausible that the inhibitory effects of chronic F exposure on NKA activity may be higher in neonates and infants that adults, particularly in communities where drinking water is artificially fluoridated or where F levels in drinking water are naturally elevated. Because newborns and infants are the group most different anatomically and physiologically from adults, they exhibit the most pronounced quantitative differences in sensitivity to chemical exposures. For this reason, the U.S.A. National Research Council [462] and others [463] propose using a 10-fold factor when extrapolating results from studies using adult exposures when estimating safe exposures to chemical toxins for the protection of infants. Given that this exposure has been found to occur at such a sensitive period of development and that loss of NKA activity represents an interconnected molecular function in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, which is also connected with other pathophysiological states, this suggests the possibility that chronic F exposure in infancy could have profound implications for neurobehavioral function and later health. Indeed, it would be naive to assume that such exposure during this critical period of development is without negative consequence to long term health. Clearly, further studies are warranted to explore these relationships. Failure to do so leads to conclusions and recommendations regarding water fluoridation that are not reliable, and therefore public health practices that are not reliably safe and effective. In addition, the fact that F has been found to activate NF-κB mRNA expression in a variety of cells types including brain, lung and kidney tissue is highly relevant. As previously described NF-κB increases production of PGE2, and PGE2 inhibits NKA activity. This elucidation may explain why NF-κB activation has been linked to many neurological disorders including autism [464,465,466,467], Alzheimer’s disease [468,469,470,471], Parkinson’s disease [472,473], as well as asthma, COPD, diabetes and cancer [474,475].
Furthermore, in view of my demonstration that F exposure and loss of NKA plays a role in inflammatory lung diseases, this suggests that the significantly higher burden of childhood respiratory disorders documented in Australia, New Zealand, the Republic of Ireland (RoI) and North America compared to other developed peer countries without AFDW, as noted in large scale epidemiological studies [476,477,478,479], may be causally associated with chronic F exposure in infancy and F-induced inhibition of NKA. It is important to note that in Australia, just 15% of infants are fully breastfed to six months of age [480] with 80% of infants provided with powdered infant formula at 6 months of age and 95% at 12 months [481]. Moreover, the RoI has the lowest prevalence of breastfeeding internationally [482]. A recent Irish birth cohort study found that only 14% of babies were exclusively breastfed at two months of age and just 1% at six months [483]. Similar low breastfeeding prevalence rates to Ireland have been reported among Maori and Pacific Island women in New Zealand [484] and among mothers from lower socio-economic backgrounds in the United States [485]. In 2009, Siew et al. measured the F concentrations in 21 milk based powdered infant formula products available in the United States and reported that the F levels ranged from 0.03–0.27 ppm when prepared with deionized distilled water. However, twenty-five per cent of the products were found to contain F levels ranging from 0.22–0.27 ppm F [161]. Any of these products when reconstituted with AFDW would result in F levels exceeding the UL for healthy adults. It is also important to note that in countries where AFDW is widely available the prevalence of childhood asthma has increased dramatically and disproportionally to other peer countries in recent decades and this increase parallels the increased prevalence of dental fluorosis. For example, in late 1960s and 1970s asthma prevalence among children in Australia [486] and the USA [487] was less than 4%. Similarly, in 1983, asthma prevalence among children aged 4–19 years of age was 4.4% in the RoI [488]. In contrast, Masoli et al. reported that the prevalence of current asthma symptoms among children aged 13–14 years in the USA, RoI, Australia and New Zealand were 21%, 28%, 30% and 32% respectively in 2004 [489]. Today, the burden of asthma in countries with water fluoridation is of sufficient magnitude to warrant its recognition as a priority disorder in government health strategies. As mentioned, these dramatic changes mirror almost exactly the changes in prevalence of dental fluorosis which occurred during the same period. To illustrate this point, in the RoI, Whelton et al. reported that in 1984 the prevalence of dental fluorosis among 8 and 15-year olds in the RoI was 6% and 5% respectively, increasing to 23% and 36% in 2002 [490]. Similarly, in the US the prevalence of dental fluorosis was 9% among individuals born in the period 1961–1970, compared to 41% among all US children born between 1984–1985 [491]. In Australia, the prevalence of dental fluorosis among children born in 1989/90 was reported to be 34.7% [492]. Interestingly, breastfeeding practices in France are among the lowest in Europe and lower than North America, Australia and New Zealand [482]. In comparison to the United States, RoI and Australia, a study conducted in France in 1998 reported that 97% of children had no sign of dental fluorosis, and 3% mild, very mild or doubtful fluorosis without aesthetic consequences [493]. A similar study conducted in Germany in 2007, reported that the prevalence of dental fluorosis among children aged 15 years ranged from 7.1% to 11.3% [494]. Notably, childhood asthma prevalence in Europe, including Germany and France is significantly lower than Australia, New Zealand, RoI and North America [476,477,478,479]. Despite these obvious associations, no study has ever been conducted to examine the causal association between chronic F intake in infancy and childhood asthma. Clearly, given the burden of childhood asthma in countries with AFDW such studies are warranted.
As previously discussed, I have also elucidated that maternal hypothyroidism in pregnancy can results in loss of NKA activity in offspring that leads to marked reduction in enzyme activity in later life. Animal models of F-induced hypothyroidism have also shown that excessive intake of F in drinking water and prenatal F intoxication of mothers induces hypothyroidism in offspring [495,496,497]. Interestingly, a recent animal study also found that maternal exposure to F during pregnancy and early postnatal life exposure had deleterious impact on learning and memory of offspring which was mediated by reduced mRNA expression of glutamate receptor subunits in the hippocampus [498]. Furthermore, the inhibition of glutamate receptors by F was found to occur in a dose dependent manner. Clearly, inhibition of mRNA expression of glutamate receptors can lead to a loss of glutamate receptors. Loss of glutamate receptors can subsequently lead to excessive activation due to their impaired expression, which can lead to enhanced excitotoxicity from chronic glutamate toxicity. These elucidations strongly suggest that chronic F exposure can attenuate adverse effects associated with glutamate excitotoxicity. Consistent with this hypothesis, an earlier study by Blaylock suggested that F exposure may contribute to glutamate induced excitotoxicity, thought the effects of F on mRNA expression of glutamate receptors were not known at that time [499]. While these observations may not be part of the original goal of this study, they are clearly important because, as previously discussed, loss of NKA has been suggested to enhance glutamate excitotoxicity [95,96] and glutamate excitotoxicity is associated with major psychiatric disorders [98,99,100,101], neurodegenerative diseases [102] and autism [103,104]. Furthermore, it is also important to note, that in addition to inhibition of glutamate receptors, it has also been found that maternal exposure to F during pregnancy results in inhibition of mRNA levels of M1 and M3-muscarinic acetylcholine receptors (mAChRs) in offspring [500]. Similar results have been observed in adult rodents chronically exposed to F in drinking water [501]. Interestingly, in addition to loss of NKA activity, a reduction or deficiency in mAChR have also been implicated in the pathophysiology of many major diseases of the CNS including schizophrenia [502], bipolar and major depression [503], Alzheimer’s disease [504] and ADHD [505]. Loss of M3 mAChRs has also been found to result in impairments in glucose tolerance and insulin release [506]. Taken together, these results further strengthen the hypothesis that F exposure can contribute to etiology and pathophysiology of a diverse range of disorders.
Furthermore, in this study I have described how F exposure can result in increased TSH and higher TSH is associated with iodine deficiency and hypothyroidism. Consistent with these findings, I have discussed how evidence from human studies indicate that water fluoridation is associated with increased prevalence of hypothyroidism [139]. Moreover, it is well acknowledged that iodine deficiency and maternal hypothyroidism is associated with increased risk of cognitive impairment in offspring [507,508,509], along with increased risk of ASD and ADHD [510,511,512,513,514,515], schizophrenia [516], epilepsy and seizures [517]; and asthma [518]. As elucidated in this study, loss of NKA activity has been found to play a central role in these disorders. This evidence further supports the hypothesis that prenatal loss of NKA is implicated in disorders associated with maternal hypothyroidism. Taken together, these findings suggest the possibility that paternal exposure to F can have epigenetic transgenerational effects on future generations. Indeed, this observation has already been observed in several rodent studies [519,520,521,522]. It is not known however, whether inhibition of NKA activity during the early postnatal period and early infancy can persist during the entire lifespan. Nonetheless, this possibility clearly exists, as several studies have found that early life exposure to environmental chemicals and stress can result in epigenetic changes by reprogramming gene expression patterns, which persist into adulthood [523,524,525,526,527]. Clearly, further research is warranted to elucidate whether chronic F exposure in early infancy results in epigenetic changes in gene expression. This is particularly important given the seminal research of Liu et al. where they found that chronic F exposure resulting in dental fluorosis, altered the expression of over 960 genes in children compared to controls without dental fluorosis, including 71 robustly up-regulated genes and 60 robustly down-regulated genes [528].
Moreover, in this study I have elucidated that chronic F exposure has been found to inhibit the expression of PERK, which is required to stimulate WFS1 expression. I have further described how loss of WFS1 expression leads to reduced expression of the NKA β sub unit which is required for expression of NKA on plasma membranes and for enzyme activity. Thus, F inhibition of PERK can lead to reduced NKA expression and lower enzyme activity. Interestingly, loss of WFS1 activity is also associated with increased risk of psychiatric disorders [529,530,531], as well as juvenile-onset diabetes, progressive neurologic degeneration, and endocrine dysfunction [532,533]. The association between loss of WFS1 and juvenile diabetes is particularly interesting considering the dramatic increase in juvenile diabetes in the United States in recent decades [534], which also happens to coincide with the dramatic rise in dental fluorosis observed in the United States in recent decades [535,536]. Moreover, it should be noted that an association has been found between drinking water F levels and incidence of childhood-onset type 1 diabetes has been observed in Canada [537]. Furthermore, a recent ecological study in the USA reported an association between water fluoridation and diabetes [538]. Revealingly, studies have also shown that PERK protects pancreatic β-cells from ER stress [532] and PERK deficiency is associated with hyperglycaemia and increased apoptosis in β-cells [539]. Taken together, these observations may explain why loss of NKA activity has been found to be associated with psychiatric disorders, metabolic syndrome and diabetes. They also provide insights into molecular mechanisms by which chronic F exposure may contribute to these disorders.
In this present study, I have also elucidated that evidence from human studies implicate loss of NKA with the pathogenesis of COPD [21]. According to WHO, COPD will move from fifth leading cause of death in 2002, to fourth place in the rank projected to 2030 worldwide [540]. Notably, in the USA, death rates for COPD doubled between 1970 and 2002 [541]. It is also evident that the RoI, New Zealand and Australia, have by far the highest prevalence rates for COPD among developed countries despite having an adult smoking prevalence well below the OECD average [542]. Interestingly, Australia, New Zealand and the RoI, also have the highest age-standardised incidence rates of cancer worldwide for men and women together being ranked 1st, 2nd and 3rd, with the USA in 5th place [543,544]. As previously described, several studies have also found that loss of NKA is implicated with carcinoma and cancer progression [54,55,56,57,58,59,60]. Since loss of NKA has been found to be associated with both cancer risk and inflammatory respiratory lung diseases, this suggests a plausible scenario that F intake may be a contributory factor to the high burden of COPD and cancer in countries with artificial water fluoridation. While these associations are self-evident, they are merely observations and do not prove causality, nevertheless a causal biological mechanism exists, making the hypotheses plausible. Clearly, additional studies in this important area of investigation are also warranted.
Past studies have also shown that reduced NKA activity may underlie the pathophysiological aspects linked to the prehypertensive status in humans [40,545]. Additionally, it has been widely documented that inhibition of NKA activity is associated with hypertension [44,45,46,47,48,49,50,51,52,53]. Again, several human studies have found that exposure to excessive F is closely associated with hypertension [546,547,548,549,550]. Similar observations have been observed in experimental studies with rodents [551,552,553,554,555,556]. Interestingly, activation of the TRH system, with increased production of TRH and an upregulation of its receptors has also been implicated in the pathogenesis of hypertension [557]. As previously, described, TRH regulates the secretion of TSH and stimulates the secretion of DA, which can lead to inhibition of NKA activity. As previously described, evidence from human studies have shown that F can induce TSH secretion. Therefore, F must also induce TRH secretion. This elucidation may explain why increased TRH release is associated with lower NKA activity. Moreover, these findings are consistent with the hypothesis that F exposure contributes to pathological states associated with loss of NKA activity.
Furthermore, in this current study, I have provided compelling evidence that NKA activity is vital for normal brain development and loss of NKA activity is associated with cognitive impairment, neurological and developmental disorders [14,15,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86]. Indeed, loss of NKA activity represents an interconnected molecular function in neurodevelopmental and neuropsychiatric and neurodegenerative disorders including; Down syndrome, Alzheimer’s, Parkinson’s and Huntington’s disease, as well as epilepsy, autism, schizophrenia, mood and depressive disorders. Furthermore, evidence has been presented that loss of NKA activity is also associated with allergic diseases, blood diseases, autoimmune diseases, metabolic disorders, male infertility and cardiovascular disease. Therefore, it is plausible that F-induced loss of NKA activity could lead to pathological states or further contribute to the severity of a diverse range of inflammatory diseases/disorders associated with loss of enzyme activity. Of particular note, while loss of NKA activity has been shown to be associated with autism spectrum disorder’s, research has also shown that inhibition of NKA activity can ultimately lead to a leaky and dysfunctional epithelium associated with chronic inflammation [558]. Accumulating evidence demonstrates that gastrointestinal inflammation and increased permeability of the intestinal tract, referred to as a “leaky gut” is a hallmark of ASD and the severity of gastrointestinal symptoms relate to the severity of ASD [559]. This suggests that a potential adverse effect of chronic F exposure may include contributing to the burden and severity of ASD. In this study, I have also elucidated how loss of NKA leads to downregulation of AMPA receptor, which leads to synaptic transmission defects, and consequently cognitive impairment [97]. I have further described how loss of AMPA receptors have been found to result in early-onset motor deficits, hyperactivity, cognitive defects and behavioural seizures [105]. I have further elucidated that these findings suggest a possible causal mechanism explaining how loss of NKA activity is associated with childhood neurodevelopmental disorders such as ADHD and ASD. Consistent with this, several studies have already demonstrated an association between cognitive impairment and loss of NKA activity and between loss of NKA and ASD. Importantly, these findings may also explain why exposure to fluoridated water has been found to be associated with increased prevalence of ADHD in the USA [560]. Interestingly, one of the most common difficulties in children with epilepsy is ADHD. Indeed, in children with epilepsy (seizures), ADHD has been found to be present in 20–50% of patients [561]. These findings further support the hypothesis that downregulation of AMPA receptors which results from loss of NKA activity is a factor in the pathogenesis of ADHD disorders. Furthermore, these findings may elucidate a key mechanism by which prenatal exposure to F has recently been found to be associated with cognitive impairment and increased risk of ADHD in offspring [562,563].
Increasing evidence also suggests that maternal iodine deficiency and hypothyroidism is associated with increased risk of cognitive impairment, neurodevelopmental and neuropsychiatric disorders in offspring including ADHD [511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530,531,532,533,534,535,536,537,538,539,540,541,542,543,544,545,546,547,548,549,550,551,552,553,554,555,556,557,558,559,560,561,562,563,564,565], ASD [566,567,568], behavioural seizures [517] and schizophrenia [516]. Moreover, maternal iodine deficiency and hypothyroidism is also associated with increased risk of asthma [518] and hypertension [569] in offspring. As elucidated in this study, loss of NKA activity appears to be a critical contributor to the pathophysiological underpinnings of these disorders. These findings suggest that loss of NKA activity is associated with iodine deficiency disorders. Consistent with this, I have previously elucidated that NKA is essential for NIS functionality, iodine uptake and metabolism. Indeed, I recently reported that inhibition of NKA contributes to iodine deficiency disorders [110]. As highlighted above, there is also an association between hypothyroidism and loss of NKA activity, suggesting a negative feedback mechanism that may further decrease enzyme activity. As elucidated in this current study, this mechanism appears to be driven by increased TRH secretion and DA release which leads to inhibition of enzyme activity.

Additional Perspectives

Reflecting on the established link between loss of NKA activity and increased risk of cancer, metabolic, pulmonary and cardiovascular disease as well as neuropsychiatric and neurodegenerative disorders, the indisputable fact that F has consistently been found to inhibit NKA activity suggests the possibility that populations with increased F intake may be susceptible to diseases associated with loss of NKA activity. In considering this hypothesis, the population on the island of Ireland offers an ideal model system for investigating the relationship between F exposure and adverse health effects associated with loss of NKA activity.
As previously discussed, drinking water is artificially fluoridated in the Republic of Ireland (RoI) and non-fluoridated in Northern Ireland (NI). The island of Ireland consists of an area of 84,421 km2 of which the RoI covers five sixths of the island or 70,273 km2, with NI constituting the remainder. The similarities in populations are reflected in 2011 census reports, which showed that the majority of people living on the island of Ireland were of a White ethnic background, which accounted for 98 per cent of those usually resident in Northern Ireland and 94 per cent of those in the Republic of Ireland [570]. Moreover, the median age of the population in the RoI is 34, compared to 37 in NI. The rates of young, working age and older age dependency for NI and the RoI are also similar at 52 and 49 per cent respectively. In addition, working age groups (aged between 19 and 64 years) made up 60 per cent of the population in NI, compared with 62 per cent in the RoI [570].
It is therefore pertinent to note that there is now considerable direct evidence derived from epidemiological studies that cancer incidence and mortality from inflammatory diseases is notably higher in the RoI than in NI. Notably, a previous study by the Institute of Public Health in Ireland examined mortality from leading causes of death for the whole island, NI and the RoI inclusive between 1989 and 1998 [571]. While the report recommends caution in the interpretation of findings highly significant difference were observed. For example, the directly standardised mortality rate (DSRRs) for diabetes mellitus was 371% higher in the RoI compared to NI. In addition, significant differences in the DSRRs were observed for endocrine, nutritional and metabolic diseases (245% higher); sudden infant death syndrome (210% higher); rheumatoid arthritis and osteoarthrosis (166%); diseases of the blood and blood-forming organs, immunological disorders (148% higher); heart diseases including acute pericarditis, acute and subacute endocarditis, acute myocarditis, cardiomyopathy, conduction disorders, cardiac dysrhythmias and heart failure (88% higher); mental and behavioural disorders (53% higher), chronic lower respiratory disease (44% higher), asthma (34%), diseases of the kidney and ureter (27% higher); diseases of the skin and subcutaneous tissue (26% higher) and cancer, including malignant neoplasms of the ovary (23% higher), prostate (19% higher); pancreas (18% higher); uterus (18% higher); skin (16% higher); oesophagus (15% higher); lymph/haematopoietic tissue (12% higher); colon (10% higher); breast (8% higher); cervix uteri (6% higher); and stomach (4% higher) [571].
More, recently, the National Cancer Registry Ireland and the Northern Ireland Cancer Registry published the findings of the All-Ireland cancer incidence for the period 1994 to 2004 [572]. In this report, statistically significant differences in incidence rates (EASIR) were found to exist with significantly lower incidence rates for cancer in NI compared to the RoI. Incidence rates in RoI were higher for cancer of the pancreas, bladder, brain, colorectal, prostate, cervical, breast, stomach, skin, oesophagus kidney and leukaemia [572]. A subsequent publication on cancer data from the island of Ireland, examining cancer incidence in NI and RoI provided similar disturbing findings [573]. According to the All-Ireland Cancer Registry (2011) the risk of developing prostate, bladder, pancreatic, oesophageal, ovarian, cervical, blood and bone cancers, non-melanoma and melanoma skin cancers and brain/central nervous system cancers was significantly higher in RoI compared to Northern Ireland [573]. Taken together these studies provide compelling evidence linking diseases associated with loss of NKA activity to the increased exposure of the population of the RoI to F from AFDW. Moreover, the observations from these studies reveal astonishing similarity to the findings of Takahashi et al. [574]. In this ecological study, the prevalence and geographic variation of a large number of cancers in the United States were found to be associated with water fluoridation. It is also pertinent to note that that the RoI has one of the highest rates of mental health illness in Europe with almost one in four of the population recorded as having a mental health disorder with a total cost to the Irish economy over €8.2 billion a year [575]. Interestingly, it has previously been reported that among the general population in the RoI the prevalence of schizophrenia is among the highest in the world [576,577]. It has recently been reported that among general practitioners in the RoI, seventy-three percent have between one and ten patients with schizophrenia on their list, and a further 27% have over ten [578]. According to the Central Statistics Office, the both men and women the highest cause of admission to psychiatric units in the RoI is for depressive disorders followed by schizophrenia [579]. It is also important to note that the United States has one of the highest prevalence’s of schizophrenia in the world with prevalence’s rates several fold higher than other developed countries [580]. Interestingly, Golder et al. also reported that the lowest prevalence reported in literature was found in Christchurch, New Zealand [580]. Notable, Christchurch, New Zealand is the largest urban population center in New Zealand where drinking water is non fluoridated. As previously elucidated loss of NKA is associated with schizophrenia, depressive and bipolar disorders. Taken together, the advances in understanding the molecular mechanisms by which F inhibits NKA activity and the role of loss of NKA activity in the etiology and pathophysiology of disease provides a plausible explanation for elucidating the reasons driving health inequalities in the island of Ireland and other countries with water fluoridation policies. Clearly, these associations are significant enough to warrant further research.
In this study I have elucidated that dephosphorylation of NKA is mediated by Cn and that inhibition of Cn activity leads to enhanced phosphorylation, which in turn leads to inhibition of enzyme activity. I have further described how F inhibits CN activity and elucidated the molecular mechanisms of inhibition including the contributory effect of F reducing manganese bioavailability. In addition, I have described how manganese is required for structural stability and full activity of Cn in addition to manganese being a crucial activator of Cn. To further our understanding of the molecular mechanisms by which F can induce neurotoxicity it is important to note that Cn is also thought to play a role in aspects of learning and memory by regulating synaptic plasticity and suppression of long-term depression (LPD) in the hippocampus [581,582] Studies have also found that inhibition of Cn causes impaired working memory [583] and inhibition of Cn has been implicated in the pathogenesis of Alzheimer’s disease [584]. Moreover, it has been shown that a reduction in function of Cn can lead to a spectrum of abnormalities related to schizophrenia, including defects in working/episodic like memory, hyperactive movement, social withdrawal, and defects in latent and pre-pulse inhibition in mice [585,586]. Of note, these abnormalities are also associated with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) [587,588,589,590,591,592]. Based on these findings, further studies are also warranted to provide objective evidence to evaluate adequately the association between F exposure, Cn expression, NKA activity and cognitive impairment, Alzheimer’s disease, schizophrenia, autism and ADHD.
In this study, I have also elucidated how F contributes to magnesium deficiency. It is important to note that magnesium deficiency is highly prevalent in many countries including the United States. where up to thirty per cent of the population have been reported to have subclinical magnesium deficiency, based on serum magnesium levels [591]. A previous study reported that among hospitalised patients in the United States the prevalence of hypomagnesaemia was identified in 47% of patients [592]. Although low magnesium status may not be a direct cause of inflammatory diseases, insufficient magnesium has consistently been shown across multiple laboratories to increase chronic low-grade inflammation, which is thought to play a major role in chronic disease etiology.
Furthermore, a growing body of literature from animal, epidemiologic, and clinical studies has demonstrated a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders; osteoporosis; hypertension; cardio-vascular diseases; metabolic syndrome; and diabetes [591]. As described in this study magnesium is required for ATP binding to NKA, thus, magnesium deficiency contributes to lower NKA activity. This elucidation may in part explain why magnesium deficiency is associated with pathologic conditions of the human nervous, metabolic, cardiovascular and muscular system that are also associated with loss of NKA activity.

6. Conclusions

In this study, several lines of evidence are provided to show that NKA activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that F inhibits NKA activity by altering biological pathways through modifying the expression of genes, glycolytic enzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and NKA enzyme activity resulting in loss of enzyme activity. Further, evidence from human studies show that inhibition of NKA activity occurs at biological relevant doses and the inhibitory effect increases as serum F levels rise in a dose dependent manner. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits NKA activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme activity. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may influence NKA activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.

Funding

The author did not receive payment or benefit for this work. This work was undertaken without funding for the benefit of public health and the advancement of scientific education in the fields of health promotion and disease prevention.

Conflicts of Interest

The author declares no conflict of interest.

Abbreviations

AAArachidonic Acid
ATPAdenosine-triphosphate
ALPAlkaline phosphatase
cAMPcyclic adenosine-monophosphate monophosphate
CaMCalmodulin
cGMPCyclic guanosine monophosphate
CnCalcineurin
COPDChronic obstructive pulmonary disease
CTCalcitonin
FFluoride
MnMagnesium
NKA:Na+, K+-ATPase
NONitric oxide
PKCProtein kinase C
PiInorganic phosphate
PGE2:Prostaglandin E2
PTHParathyroid hormone
PLA2Phospholipase A2
RAGEReceptors for advanced glycation end products
TGF-β1Transforming growth factor β 1
TSHThyroid-stimulating-hormone, also called Thyrotropin
αAlpha
βBeta
U.S.AUnited States of America

References

  1. Skou, J.C. The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim. Biophys. Acta 1957, 23, 394–401. [Google Scholar] [CrossRef]
  2. Jorgensen, P.L.; Hakansson, K.O.; Karlish, S.J. Structure and mechanism of Na, K-ATPase: Functional sites and their interactions. Annu. Rev. Physiol. 2003, 65, 817–849. [Google Scholar] [CrossRef]
  3. De Lores Arnaiz, G.R.; López Ordieres, M.G. Brain Na+, K+-ATPase Activity in Aging and Disease. Int. J. Biomed. Sci. 2014, 10, 85–102. [Google Scholar]
  4. Kristensen, A.S.; Andersen, J.; Jørgensen, T.N.; Sørensen, L.; Eriksen, J.; Loland, C.J.; Strømgaard, K.; Gether, U. SLC6 neurotransmitter transporters: Structure, function, and regulation. Pharmacol. Rev. 2011, 63, 585–640. [Google Scholar] [CrossRef] [PubMed]
  5. Mobasheri, A.; Avila, J.; Cózar-Castellano, I.; Brownleader, M.D.; Trevan, M.; Francis, M.J.; Lamb, J.F.; Martín-Vasallo, P. Na+, K+-ATPase isozyme diversity: Comparative biochemistry and physiological implications of novel functional interactions. Biosci. Rep. 2000, 20, 51–91. [Google Scholar] [CrossRef] [PubMed]
  6. Bartlett, D.E.; Miller, R.B.; Thiesfeldt, S.; Lakhani, H.V.; Shapiro, J.I.; Sodhi, K. The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Aging: Implications in Obesity and Cardiovascular Disease. Int. J. Mol. Sci. 2018, 19, 2139. [Google Scholar] [CrossRef] [PubMed]
  7. Clausen, M.V.; Hilbers, F.; Poulsen, H. The Structure and Function of the Na, K-ATPase Isoforms in Health and Disease. Front. Physiol. 2017, 8, 371. [Google Scholar] [CrossRef] [PubMed]
  8. Yan, Y.; Shapiro, J.I. The physiological and clinical importance of sodium potassium ATPase in cardiovascular diseases. Curr. Opin. Pharmacol. 2016, 27, 43–49. [Google Scholar] [CrossRef] [PubMed][Green Version]
  9. Srikanthan, K.; Shapiro, J.I.; Sodhi, K. The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Obesity and Cardiovascular Disease. Molecules 2016, 21, 1172. [Google Scholar] [CrossRef]
  10. Kinoshita, P.F.; Leite, J.A.; Orellana, A.M.; Vasconcelos, A.R.; Quintas, L.E.; Kawamoto, E.M.; Scavone, C. The Influence of Na(+), K(+)-ATPase on Glutamate Signaling in Neurodegenerative Diseases and Senescence. Front. Physiol. 2016, 7, 195. [Google Scholar] [CrossRef] [PubMed]
  11. Iannello, S.; Milazzo, P.; Belfiore, F. Animal and human tissue Na,K-ATPase in normal and insulin-resistant states: Regulation, behaviour and interpretative hypothesis on NEFA effects. Obes. Rev. 2007, 8, 231–251. [Google Scholar] [CrossRef]
  12. Suhail, M. Na+, K+-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions. J. Clin. Med. Res. 2010, 2, 1–17. [Google Scholar] [CrossRef]
  13. Rose, A.M.; Valdes, R., Jr. Understanding the sodium pump and its relevance to disease. Clin. Chem. 1994, 40, 1674–1685. [Google Scholar] [PubMed]
  14. Lichtstein, D.; Ilani, A.; Rosen, H.; Horesh, N.; Singh, S.V.; Buzaglo, N.; Hodes, A. Na+, K+-ATPase Signaling and Bipolar Disorder. Int. J. Mol. Sci. 2018, 19, 2314. [Google Scholar] [CrossRef] [PubMed]
  15. Li, Q.; Pogwizd, S.M.; Prabhu, S.D.; Zhou, L. Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes. PLoS ONE 2014, 9, e93928. [Google Scholar] [CrossRef]
  16. Roy, S.; Dasgupta, A.; Banerjee, U.; Chowdhury, P.; Mukhopadhyay, A.; Saha, G.; Singh, O. Role of membrane cholesterol and lipid peroxidation in regulating the Na+/K+-ATPase activity in schizophrenia. Indian J. Psychiatry 2016, 58, 317–325. [Google Scholar] [PubMed]
  17. Yan, Y.; Haller, S.; Shapiro, A.; Malhotra, N.; Tian, J.; Xie, Z.; Malhotra, D.; Shapiro, J.I.; Liu, J. Ouabain-stimulated trafficking regulation of the Na/K-ATPase and NHE3 in renal proximal tubule cells. Mol. Cell. Biochem. 2012, 367, 175–183. [Google Scholar] [CrossRef]
  18. Gentile, D.A.; Skoner, D.P. The relationship between airway hyperreactivity (AHR) and sodium, potassium adenosine triphosphatase (Na+,K+ATPase) enzyme inhibition. J. Allergy Clin. Immunol. 1997, 99, 367–373. [Google Scholar] [CrossRef]
  19. Chhabra, S.K.; Khanduja, A.; Jain, D. Decreased sodium-potassium and calcium adenosine triphosphatase activity in asthma: Modulation by inhaled and oral corticosteroids. Indian J. Chest Dis. Allied Sci. 1999, 41, 15–26. [Google Scholar]
  20. Chhabra, S.K.; Khanduja, A.; Jain, D. Increased intracellular calcium and decreased activities of leucocyte Na+, K+-ATPase and Ca2+-ATPase in asthma. Clin. Sci. 1999, 97, 595–601. [Google Scholar] [CrossRef] [PubMed]
  21. Bukowska, B.; Sicińska, P.; Pająk, A.; Koceva-Chyla, A.; Pietras, T.; Pszczółkowska, A.; Górski, P.; Koter-Michalak, M. Oxidative stress and damage to erythrocytes in patients with chronic obstructive pulmonary disease—Changes in ATPase and acetylcholinesterase activity. Biochem. Cell. Biol. 2015, 93, 574–580. [Google Scholar] [CrossRef] [PubMed]
  22. Skoner, D.P.; Gentile, D.; Evans, R. Decreased activity of the platelet Na+, K(+)-adenosine triphosphatase enzyme in allergic subjects. J. Lab. Clin. Med. 1990, 115, 535–540. [Google Scholar] [PubMed]
  23. Skoner, D.P.; Gentile, D.; Evans, R.W. A circulating inhibitor of the platelet Na+, K+ adenosine triphosphatase (ATPase) enzyme in allergy. J. Allergy Clin. Immunol. 1991, 87, 476–482. [Google Scholar] [CrossRef]
  24. Van Deusen, M.A.; Gentile, D.A.; Skoner, D.P. Inhibition of the sodium, potassium adenosine triphosphatase enzyme in peripheral blood mononuclear cells of subjects with allergic rhinitis. Ann. Allergy Asthma Immunol. 1997, 78, 259–264. [Google Scholar] [CrossRef]
  25. Omar, A.K.; Ahmed, K.A.; Helmi, N.M.; Abdullah, K.T.; Qarii, M.H.; Hasan, H.E.; Ashwag, A.; Nabil, A.M.; Abdu, A.L.G.M.; Salama, M.S. The sensitivity of Na+, K+ ATPase as an indicator of blood diseases. Afr. Health Sci. 2017, 17, 262–269. [Google Scholar] [CrossRef]
  26. Woo, A.L.; James, P.F.; Lingrel, J.B. Sperm Motility Is Dependent on a Unique Isoform of the Na, K-ATPase. J. Biol. Chem. 2000, 275, 20693–20699. [Google Scholar] [CrossRef] [PubMed]
  27. Newton, L.D.; Krishnakumar, S.; Menon, A.G.; Kastelic, J.P.; van der Thundathil, J.C. Na+/K+ATPase regulates sperm capacitation through a mechanism involving kinases and redistribution of its testis-specific isoform. Mol. Reprod. Dev. 2009, 77, 136–148. [Google Scholar] [CrossRef] [PubMed]
  28. Jimenez, T.; McDermott, J.P.; Sánchez, G.; Blanco, G. Na, K-ATPase α4 isoform is essential for sperm fertility. Proc. Natl. Acad. Sci. USA 2011, 108, 644–649. [Google Scholar] [CrossRef]
  29. Meskalo, О.I.; Fafula, R.V.; Lychkovskyj, E.I.; Vorobets, Z.D. Na+, K+-ATPase and Ca2+, Mg2+-ATPase Activity in Spermatozoa of Infertile Men with Different Forms of Pathospermia. Biol. Stud. 2017, 11, 5–12. [Google Scholar] [CrossRef]
  30. Testa, I.; Rabini, R.A.; Corvetta, A.; Danieli, G. Decreased NA+, K+-ATPase activity in erythrocyte membrane from rheumatoid arthritis patients. Scand. J. Rheumatol. 1987, 16, 301–305. [Google Scholar] [CrossRef]
  31. Kiziltunc, A.; Cogalgil, S.; Ugur, M.; Avci, B.; Akcay, F. Sialic acid, transketolase and Na+, K+, ATPase in patients with rheumatoid arthritis. Clin. Chem. Lab. Med. 1998, 36, 289–293. [Google Scholar] [CrossRef] [PubMed]
  32. Chibalin, A.V. Regulation of the Na, K-ATPase: Special implications for cardiovascular complications of metabolic syndrome. Pathophysiology 2007, 14, 153–158. [Google Scholar] [CrossRef] [PubMed]
  33. Vásárhelyi, B.; Sallay, P.; Balog, E.; Reusz, G.; Tulassay, T. Altered Na(+)-K+ ATPase activity in uraemic adolescents. Acta Paediatr. 1996, 85, 919–922. [Google Scholar] [CrossRef]
  34. Kaji, D.; Thomas, K. Na+-K+ pump in chronic renal failure. Am. J. Physiol. 1987, 252, F785–F793. [Google Scholar] [CrossRef]
  35. Welt, L.G.; Sachs, J.R.; McManus, T.J. An ion transport defect in erythrocytes from uremic patients. Trans. Assoc. Am. Phys. 1964, 77, 169–181. [Google Scholar] [PubMed]
  36. Finotti, P.; Palatini, P. Reduction of erythrocyte (Na-K1)ATPase activity in typeI (insulin dependent) diabetic subjects and its activation by homologous plasma. Diabetologia 1986, 29, 623–628. [Google Scholar] [CrossRef] [PubMed]
  37. Tsimarato, M.; Coste, T.C.; Djemli-Shipkolye, A.; Daniel, L.; Shipkolye, F.; Vague, P.; Raccah, D. Evidence of time-dependent changes in renal medullary Na,K-ATPase activity and expression in diabetic rats. Cell. Mol. Biol. 2001, 47, 239–245. [Google Scholar]
  38. Vague, P.; Coste, T.C.; Jannot, M.F.; Raccah, D.; Tsimaratos, M. C-peptide, Na+,K(+)-ATPase, and diabetes. Exp. Diabesity Res. 2004, 5, 37–50. [Google Scholar] [CrossRef]
  39. Djemli-Shipkolye, A.; Gallice, P.; Coste, T.; Jannot, M.F.; Tsimaratos, M.; Raccah, D.; Vague, P. The effects ex vivo and in vitro of insulin and C-peptide on Na/K adenosine triphosphatase activity in red blood cell membranes of type 1 diabetic patients. Metabolism 2000, 49, 868–872. [Google Scholar] [CrossRef]
  40. Mimura, M.; Makino, H.; Kanatsuka, A.; Asai, T.; Yoshida, S. Reduction of erythrocyte (Na(+)-K+)ATPase activity in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria. Horm. Metab. Res. 1994, 26, 33–38. [Google Scholar] [CrossRef] [PubMed]
  41. Schwinger, R.H.; Bundgaard, H.; Muller-Ehmsen, J.; Kjeldsen, K. The Na, K-ATPase in the failing human heart. Cardiovasc. Res. 2003, 57, 913–920. [Google Scholar] [CrossRef][Green Version]
  42. Muller-Ehmsen, J.; McDonough, A.A.; Farley, R.A.; Schwinger, R.H. Sodium pump isoform expression in heart failure: Implication for treatment. Basic Res. Cardiol. 2002, 97, I25–I30. [Google Scholar] [CrossRef]
  43. Stefanon, I.; Cade, J.R.; Fernandes, A.A.; Ribeiro Junior, R.F.; Targueta, G.P.; Mill, J.G.; Vassallo, D.V. Ventricular performance and Na+-K+ ATPase activity are reduced early and late after myocardial infarction in rats. Braz. J. Med. Biol. Res. 2009, 42, 902–911. [Google Scholar] [CrossRef] [PubMed]
  44. Ringel, R.E.; Hamlyn, J.M.; Hamilton, B.P.; Pinkas, G.A.; Chalew, S.A.; Berman, M.A. Red blood cell Na1, K1-ATPase in men with newly diagnosed or previously treated essential hypertension. Hypertension 1987, 9, 437–443. [Google Scholar] [CrossRef]
  45. Weiler, E.W.J.; Tuck, M.; Gonick, H.C. Observations on the “cascade” of Na-K-ATPase inhibitory and digoxin-like immunoreactive material in human urine: Possible relevance to essential hypertension. Clin. Exp. Hypertens. Theory Prac. 1985, A7, 809–836. [Google Scholar] [CrossRef]
  46. Tranquilli, A.L.; Mazzanti, L.; Ancona, A.; Brandi, S.; Bertoli, E.; Romanini, C. Inhibition of Na/K ATPase Activity in Maternal and Neonatal Erythrocyte Ghosts in Pregnancy-Induced Hypertension. Clin. Exp. Hypertens. Part B Hypertens. Pregnancy 1987, 6, 321–326. [Google Scholar] [CrossRef]
  47. Gonick, H.C.; Weiler, E.; Khalil-Manesh, F. Pattern of Na-K-ATPase inhibitors in plasma and urine of hypertensive patients: A preliminary report. Klin. Wochenschr. 1987, 65, 139–145. [Google Scholar] [PubMed]
  48. Vasdev, S.; Fernandez, P.G.; Longerich, L.; Gault, H. Higher plasma Na+, K+-ATPase inhibitory activity in essential hypertensive patients. Can. J. Cardiol. 1989, 5, 249–254. [Google Scholar]
  49. Miyagi, H.; Higuchi, M.; Nakayama, M.; Moromizato, H.; Sakanashi, M. Ouabain-like Na+, K(+)-ATPase inhibitory activity of a plasma extract in normal pregnancy and pregnancy induced hypertension. Jpn. J. Pharmacol. 1991, 57, 571–581. [Google Scholar] [CrossRef]
  50. Gonick, H.C.; Weiler, E.W.; Khalil-Manesh, F.; Weber, M.A. Predominance of high molecular weight plasma Na(+)-K(+)-ATPase inhibitor in essential hypertension. Am. J. Hypertens. 1993, 6, 680–687. [Google Scholar] [CrossRef]
  51. Kaplan, J.H. The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase. Proc. Natl. Acad. Sci. USA 2005, 102, 15723–15724. [Google Scholar] [CrossRef][Green Version]
  52. Jaitovich, A.; Bertorello, A.M. Salt, Na+, K+-ATPase and hypertension. Life Sci. 2010, 86, 73–78. [Google Scholar] [CrossRef] [PubMed]
  53. Waugh, D.T. The Contribution of Fluoride to the Pathogenesis of Eye Diseases: Molecular Mechanisms and Implications for Public Health. Int. J. Environ. Res. Public Health 2019, 16, 856. [Google Scholar] [CrossRef]
  54. Rajasekaran, S.A.; Huynh, T.P.; Wolle, D.G.; Espineda, C.E.; Inge, L.J.; Skay, A.; Lassman, C.; Nicholas, S.B.; Harper, J.F.; Reeves, A.E.; et al. Na, K-ATPase subunits as markers for epithelial-mesenchymal transition in cancer and fibrosis. Mol. Cancer Ther. 2010, 9, 1515–1524. [Google Scholar] [CrossRef][Green Version]
  55. Blok, L.J.; Chang, G.T.; Steenbeek-Slotboom, M.; van Weerden, W.M.; Swarts, H.G.; De Pont, J.J.; van Steenbrugge, G.J.; Brinkmann, A.O. Regulation of expression of Na+, K+-ATPase in androgen-dependent and androgen-independent prostate cancer. Br. J. Cancer 1999, 81, 28–36. [Google Scholar] [CrossRef]
  56. Espineda, C.; Seligson, D.B.; James Ball, W., Jr.; Rao, J.; Palotie, A.; Horvath, S.; Huang, Y.; Shi, T.; Rajasekaran, A.K. Analysis of the Na, K-ATPase alpha- and beta-subunit expression profiles of bladder cancer using tissue microarrays. Cancer 2003, 97, 1859–1868. [Google Scholar] [CrossRef] [PubMed]
  57. Espineda, C.E.; Chang, J.H.; Twiss, J.; Rajasekaran, S.A.; Rajasekaran, A.K. Repression of Na,K-ATPase beta1-subunit by the transcription factor snail in carcinoma. Mol. Biol. Cell 2004, 15, 1364–1373. [Google Scholar] [CrossRef]
  58. Inge, L.J.; Rajasekaran, S.A.; Yoshimoto, K.; Mischel, P.S.; McBride, W.; Landaw, E.; Rajasekaran, A.K. Evidence for a potential tumor suppressor role for the Na, K-ATPase beta1-subunit. Histol. Histopathol. 2008, 23, 459–467. [Google Scholar]
  59. Rajasekaran, S.A.; Ball, W.J., Jr.; Bander, N.H.; Liu, H.; Pardee, J.D.; Rajasekaran, A.K. (Reduced expression of beta-subunit of Na,K-ATPase in human clear-cell renal cell carcinoma. J. Urol. 1999, 162, 574–580. [Google Scholar] [CrossRef]
  60. Sun, M.Z.; Kim, J.M.; Oh, M.C.; Safaee, M.; Kaur, G.; Clark, A.J.; Bloch, O.; Ivan, M.E.; Kaur, R.; Oh, T.; et al. Na+/K+-ATPase β2-subunit (AMOG) expression abrogates invasion of glioblastoma-derived brain tumor-initiating cells. Neuro Oncol. 2013, 15, 1518–1531. [Google Scholar] [CrossRef]
  61. Sakai, H.; Suzuki, T.; Maeda, M.; Takahashi, Y.; Horikawa, N.; Minamimura, T.; Tsukada, K.; Takeguchi, N. Up-regulation of Na(+), K(+)-ATPase alpha 3-isoform and down-regulation of the alpha1-isoform in human colorectal cancer. FEBS Lett. 2004, 563, 151–154. [Google Scholar] [CrossRef]
  62. Lees, G.J. Contributory mechanisms in the causation of neurodegenerative disorders. Neuroscience 1993, 54, 287–322. [Google Scholar] [CrossRef]
  63. Lees, G.J. Inhibition of sodium-potassium-ATPase: A potentially ubiquitous mechanism contributing to central nervous system neuropathology. Brain Res. Rev. 1991, 16, 283–300. [Google Scholar] [CrossRef]
  64. Bolotta, A.; Visconti, P.; Fedrizzi, G.; Ghezzo, A.; Marini, M.; Manunta, P.; Messaggio, E.; Posar, A.; Vignini, A.; Abruzzo, P.M. Na+, K+ -ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells. Autism Res. 2018, 11, 1388–1403. [Google Scholar] [CrossRef] [PubMed]
  65. Ghezzo, A.; Visconti, P.; Abruzzo, P.M.; Bolotta, A.; Ferreri, C.; Gobbi, G.; Mazzanti, L. Oxidative stress and erythrocyte membrane alterations in children with autism: Correlation with clinical features. PLoS ONE 2013, 8, e66418. [Google Scholar] [CrossRef] [PubMed]
  66. Zhang, L.N.; Sun, Y.J.; Pan, S.; Li, J.X.; Qu, Y.E.; Li, Y.; Wang, Y.L.; Gao, Z.B. Na+, K+-ATPase, a potent neuroprotective modulator against Alzheimer disease. Fundam. Clin. Pharmacol. 2013, 27, 96–103. [Google Scholar] [CrossRef] [PubMed]
  67. Abruzzo, P.M.; Ghezzo, A.; Bolotta, A.; Ferreri, C.; Minguzzi, R.; Vignini, A.; Marini, M. Perspective biological markers for autism spectrum disorders: Advantages of the use of receiver operating characteristic curves in evaluating marker sensitivity and specificity. Dis. Markers 2015, 2015, 329607. [Google Scholar] [CrossRef]
  68. Kurup, R.K.; Kurup, P.A. A hypothalamic digoxin-mediated model for autism. Int. J. Neurosci. 2003, 113, 1537–1559. [Google Scholar] [CrossRef]
  69. Kumar, A.R.; Kurup, P.A. Endogenous sodium-potassium ATPase inhibition related biochemical cascade in trisomy 21 and Huntington’s disease: Neural regulation of genomic function. Neurol. India 2002, 50, 174–180. [Google Scholar]
  70. Ellis, D.Z.; Rabe, J.; Sweadner, K.J. Global loss of Na,K-ATPase and its nitric oxide-mediated regulation in a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurosci. 2003, 23, 43–51. [Google Scholar] [CrossRef] [PubMed]
  71. Naylor, G.J.; Smith, A.H.; Dick, E.G.; Dick, D.A.; McHarg, A.M.; Chambers, C.A. Erythrocyte membrane cation carrier in manic-depressive psychosis. Psycol. Med. 1980, 10, 521–525. [Google Scholar] [CrossRef]
  72. Hokin-Neaverson, M.; Jefferson, J.W. Deficient erythrocyte NaK-ATPase activity in different affective states in bipolar affective disorder and normalization by lithium therapy. Neuropsychobiology 1989, 22, 18–25. [Google Scholar] [CrossRef]
  73. Wood, A.J.; Smith, C.E.; Clarke, E.E.; Cowen, P.J.; Aronson, J.K.; Grahame-Smith, D.G. Altered in vitro adaptive responses of lymphocyte Na(+), K(+)-ATPase in patients with manic depressive psychosis. J. Affect. Disord. 1991, 21, 199–206. [Google Scholar] [CrossRef]
  74. Tochigi, M.; Iwamoto, K.; Bundo, M.; Sasaki, T.; Kato, N.; Kato, T. Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains. Neurosci. Res. 2008, 60, 184–191. [Google Scholar] [CrossRef] [PubMed]
  75. El-Mallakh, R.S.; Wyatt, R.J. The Na, K-ATPase hypothesis for bipolar illness. BiolPsychiatry 1995, 37, 235–244. [Google Scholar] [CrossRef]
  76. Bagrov, A.Y.; Bagrov, Y.Y.; Fedorova, O.V.; Kashkin, V.A.; Patkina, N.A.; Zvartau, E.E. Endogenous digitalis-like ligands of the sodium pump: Possible involvement in mood control and ethanol addiction. Eur. Neuropsychopharmacol. 2002, 12, 1–12. [Google Scholar] [CrossRef]
  77. Yao, J.K.; van Kammen, D.P. Red blood cell membrane dynamics in schizophrenia. I. Membrane fluidity. Schizophr. Res. 1994, 11, 209–216. [Google Scholar] [CrossRef]
  78. Kurup, R.K.; Kurup, P.A. Schizoid neurochemical pathology-induced membrane Na(+)-K+ ATPase inhibition in relation to neurological disorders. Int. J. Neurosci. 2003, 113, 1705–1717. [Google Scholar] [CrossRef]
  79. Corti, C.; Xuereb, J.H.; Crepaldi, L.; Corsi, M.; Michielin, F.; Ferraguti, F. Altered levels of glutamatergic receptors and Na+/K+ ATPase-alpha1 in the prefrontal cortex of subjects with schizophrenia. Schizophr. Res. 2011, 128, 7–14. [Google Scholar] [CrossRef]
  80. Chauhan, N.B.; Lee, J.M.; Siegel, G.J. Na, K-ATPase mRNA levels and plaque load in Alzheimer’s disease. J. Mol. Neurosci. 1997, 9, 151–166. [Google Scholar] [CrossRef]
  81. Hattori, N.; Kitagawa, K.; Higashida, T.; Yagyu, K.; Shimohama, S.; Wataya, T.; Perry, G.; Smith, M.A.; Inagaki, C. CI-ATPase and Na+/K(+)-ATPase activities in Alzheimer’s disease brains. Neurosci. Lett. 1998, 254, 141–144. [Google Scholar] [CrossRef]
  82. Sadanand, A.; Janardhanan, A.; Sankaradoss, A.; Vanisree, A.J.; Arulnambi, T.; Bhanu, K. Erythrocyte membrane in the evaluation of neurodegenerative disorders. Degener. Neurol. Neuromuscul. Dis. 2017, 7, 127–134. [Google Scholar] [CrossRef] [PubMed][Green Version]
  83. Gamaro, G.D.; Streck, E.L.; Matte, C.; Prediger, M.E.; Wyse, A.T. Reduction of hippocampal Na+, K+-ATPase activity in rats subjected to an experimental model of depression. Neurochem. Res. 2003, 28, 1339–1344. [Google Scholar] [CrossRef] [PubMed]
  84. De Vasconcellos, A.P.; Zugno, A.I.; Dos Santos, A.H.; Nietto, F.B.; Crema, L.M.; Gonçalves, M.; Franzon, R.; de Souza Wyse, A.T.; da Rocha, E.R.; Dalmaz, C. Na+, K+-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: Effect of chronic lithium treatment and possible involvement in learning deficits. Neurobiol. Learn. Mem. 2005, 84, 102–110. [Google Scholar] [CrossRef] [PubMed]
  85. Bedin, M.; Estrella, C.H.; Ponzi, D.; Duarte, D.V.; Dutra-Filho, C.S.; Wyse, A.T.; Wajner, M.; Wannmacher, C.M. Reduced Na(+), K(+)-ATPase activity in erythrocyte membranes from patients with phenylketonuria. Pediatr. Res. 2001, 50, 56–60. [Google Scholar] [CrossRef] [PubMed]
  86. Renkawek, K.; Renier, W.O.; de Pont, J.J.; Vogels, O.J.; Gabreels, F.J. Neonatal status convulsivus, spongiform encephalopathy, and low activity of Na+, K+-ATPase in the brain. Epilepsia 1992, 33, 58–64. [Google Scholar] [CrossRef] [PubMed]
  87. Rapport, R.L.; Harris, A.B.; Friel, P.N.; Ojemann, G.A. Human epileptic brain Na, K ATPase activity and phenytoin concentrations. Arch. Neurol. 1975, 32, 549–554. [Google Scholar] [CrossRef] [PubMed]
  88. Wyse, A.T.S.; Streck, E.L.; Worm, P.; Wajner, A.; Ritter, F.; Netto, C.A. Preconditioning prevents the inhibition of Na+, K+-ATPase activity after brain ischemia. Neurochem. Res. 2000, 25, 971–975. [Google Scholar] [CrossRef]
  89. Carletti, J.V.; Deniz, B.F.; Miguel, P.M.; Rojas, J.J.; Kolling, J.; Scherer, E.B.; de Souza Wyse, A.T.; Netto, C.A.; Pereira, L.O. Folic Acid Prevents Behavioral Impairment and Na+, K+-ATPase Inhibition Caused by Neonatal Hypoxia–Ischemia. Neurochem. Res. 2012, 37, 1624–1630. [Google Scholar] [CrossRef] [PubMed]
  90. Desfrere, L.; Karlsson, M.; Hiyoshi, H.; Malmerjö, S.; Nanou, E.; Estrada, M.; Miyakawa, A.; Lagercrantz, H.; El Manira, A.; Lal, M.; et al. Na, K-ATPase signal transduction triggers CREB activation and dendritic growth. Proc. Natl. Acad. Sci. USA 2009, 106, 2212–2217. [Google Scholar] [CrossRef]
  91. Lees, G.J.; Leong, W. The sodium-potassium-ATPase inhibitor ouabain is neurotoxic in the rat substantia nigra and striatum. Neurosci. Lett. 1995, 188, 113–116. [Google Scholar] [CrossRef]
  92. Lees, G.J.; Leong, W. Brain lesions induced by specific and non-specific inhibitors of sodium-potassium ATPase. Brain Res. 1994, 649, 225–233. [Google Scholar] [CrossRef]
  93. Clapcote, S.J.; Duffy, S.; Xie, G.; Kirshenbaum, G.; Bechard, A.R.; Rodacker Schack, V.; Petersen, J.; Sinai, L.; Saab, B.J.; Lerch, J.P.; et al. Mutation I810N in the alpha3 isoform of Na+, K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. Proc. Natl. Acad. Sci. USA 2009, 106, 14085–14090. [Google Scholar] [CrossRef]
  94. Kirshenbaum, G.S.; Dawson, N.; Mullins, J.G.; Johnston, T.H.; Drinkhill, M.J.; Edwards, I.J.; Fox, S.H.; Pratt, J.A.; Brotchie, J.M.; Order, J.C.; et al. Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+, K+-ATPase α3 missense mutant mice. PLoS ONE 2013, 8, e60141. [Google Scholar] [CrossRef] [PubMed]
  95. Lees, G.J.; Lehmann, A.; Sandberg, M.; Hamberger, A. The neurotoxicity of ouabain, a sodium-potassium ATPase inhibitor, in the rat hippocampus. Neurosci. Lett. 1990, 120, 159–162. [Google Scholar] [CrossRef]
  96. Brines, M.L.; Robbins, R.J. Inhibition of alpha 2/alpha 3 sodium pump isoforms potentiates glutamate neurotoxicity. Brain Res. 1992, 591, 94–102. [Google Scholar] [CrossRef]
  97. Zhang, D.; Hou, Q.; Wang, M.; Lin, A.; Jarzylo, L.; Navis, A.; Raissi, A.; Liu, F.; Man, H.Y. Na, K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis. J. Neurosci. 2009, 29, 4498–4511. [Google Scholar] [CrossRef] [PubMed][Green Version]
  98. Murrough, J.W.; Abdallah, C.G.; Mathew, S.J. Targeting glutamate signalling in depression: Progress and prospects. Nat. Rev. Drug Discov. 2017, 16, 472–486. [Google Scholar] [CrossRef]
  99. De Berardis, D.; Fornaro, M.; Valchera, A.; Cavuto, M.; Perna, G.; Di Nicola, M.; Serafini, G.; Carano, A.; Pompili, M.; Vellante, F.; et al. Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors. Int. J. Mol. Sci. 2018, 19, 2888. [Google Scholar] [CrossRef]
  100. Tomasetti, C.; Iasevoli, F.; Buonaguro, E.F.; De Berardis, D.; Fornaro, M.; Fiengo, A.L.; Martinotti, G.; Orsolini, L.; Valchera, A.; Di Giannantonio, M.; et al. Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. Int. J. Mol. Sci. 2017, 18, 135. [Google Scholar] [CrossRef] [PubMed]
  101. Plitman, E.; Nakajima, S.; de la Fuente-Sandoval, C.; Gerretsen, P.; Chakravarty, M.M.; Kobylianskii, J.; Chung, J.K.; Caravaggio, F.; Iwata, Y.; Remington, G.; et al. Glutamate-mediated excitotoxicity in schizophrenia: A review. Eur. Neuropsychopharmacol. 2014, 24, 1591–1605. [Google Scholar] [CrossRef] [PubMed][Green Version]
  102. Lewerenz, J.; Maher, P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? Front. Neurosci. 2015, 9, 469. [Google Scholar] [CrossRef]
  103. Pastural, E.; Ritchie, S.; Lu, Y.; Jin, W.; Kavianpour, A.; Khine Su-Myat, K.; Heath, D.; Wood, P.L.; Fisk, M.; Goodenowe, D.B. Novel plasma phospholipid biomarkers of autism: Mitochondrial dysfunction as a putative causative mechanism. Prostaglandins Leukot Essent Fat. Acids 2009, 81, 253–264. [Google Scholar] [CrossRef]
  104. Ghanizadeh, A. Targeting of glycine site on NMDA receptor as a possible new strategy for autism treatment. Neurochem. Res. 2012, 36, 922–923. [Google Scholar] [CrossRef] [PubMed]
  105. Stewart, M.; Lau, P.; Banks, G.; Bains, R.S.; Castroflorio, E.; Oliver, P.L.; Dixon, C.L.; Kruer, M.C.; Kullmann, D.M.; Acevedo-Arozena, A.; et al. Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities. Dis. Models Mech. 2019, 12. [Google Scholar] [CrossRef]
  106. Dalsgaard, S.; Mortensen, P.B.; Frydenberg, M.; Maibing, C.M.; Nordentoft, M.; Thomsen, P.H. Association between Attention-Deficit Hyperactivity Disorder in childhood and schizophrenia later in adulthood. Eur. Psychiatry 2014, 29, 259–263. [Google Scholar] [CrossRef]
  107. Adisetiyo, V.; Tabesh, A.; Di Martino, A.; Falangola, M.F.; Castellanos, F.X.; Jensen, J.H.; Helpern, J.A. Attention-deficit/hyperactivity disorder without comorbidity is associated with distinct atypical patterns of cerebral microstructural development. Hum. Brain Mapp. 2014, 35, 2148–2162. [Google Scholar] [CrossRef] [PubMed]
  108. Paire, A.; Bernier-Valentin, F.; Rabilloud, R.; Watrin, C.; Selmi-Ruby, S.; Rousset, B. Expression of alpha- and beta-subunits and activity of Na+K+ ATPase in pig thyroid cells in primary culture: Modulation by thyrotropin and thyroid hormones. Mol. Cell. Endocrinol. 1998, 146, 93–101. [Google Scholar] [CrossRef]
  109. Hingorani, M.; Spitzweg, C.; Vassaux, G.; Newbold, K.; Melcher, A.; Pandha, H.; Vile, R.; Harrington, K. The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery. Curr. Cancer Drug Targets 2010, 10, 242–267. [Google Scholar] [CrossRef]
  110. Waugh, D.T. Fluoride Exposure Induces Inhibition of Sodium/Iodide Symporter (NIS) Contributing to Impaired Iodine Absorption and Iodine Deficiency: Molecular Mechanisms of Inhibition and Implications for Public Health. Int. J. Environ. Res. Public Health 2019, 16, 1086. [Google Scholar] [CrossRef]
  111. Zimmermann, M.B. Iodine deficiency. Endocr. Rev. 2009, 30, 376–408. [Google Scholar] [CrossRef] [PubMed]
  112. Delange, F. The disorders induced by iodine deficiency. Thyroid 1994, 4, 107–128. [Google Scholar] [CrossRef] [PubMed]
  113. Valcana, T.; Timiras, P.S. Effect of hypothyroidism on ionic metabolism and Na-K activated ATP phosphohydrolase activity in the developing rat brain. J. Neurochem. 1969, 16, 935–943. [Google Scholar] [CrossRef] [PubMed]
  114. Schmitt, C.A.; MacDonough, A.A. Thyroid hormone regulates and isoforms of Na+, K+-ATPase during development in neonatal rat brain. J. Biol. Chem. 1988, 263, 17643–17649. [Google Scholar]
  115. Ahmed, O.M.; Abd El-Tawab, S.M.; Ahmed, R.G. Effects of experimentally induced maternal hypothyroidism and hyperthyroidism on the development of rat offspring: I. The development of the thyroid hormones-neurotransmitters and adenosinergic system interactions. Int. J. Dev. Neurosci. 2010, 28, 437–454. [Google Scholar] [CrossRef]
  116. Eayrs, J.T. The development of cerebral cortex in hypothyroid and starved rats. Anat. Rec. 1955, 121, 53–61. [Google Scholar] [CrossRef]
  117. Opit, L.J.; Potter, H.; Charnock, J.S. The effect of anions on (Na+ + K+)-activated. ATPase. Biochim. Biophys. Acta 1966, 120, 159–161. [Google Scholar] [CrossRef]
  118. Yoshida, H.; Nagai, K.; Kamei, M.; Nakagawa, Y. Irreversible inactivation of (Na+-K+)-dependent ATPase and K+-dependent phosphatase by fluoride. Biochim. Biophys. Acta 1968, 150, 162–164. [Google Scholar] [CrossRef]
  119. Millman, M.S.; Omachi, A. The Role of Oxidized Nicotinamide Adenine Dinucleotide in Fluoride Inhibition of Active Sodium Transport in Human Erythrocytes. J. Gen. Physiol. 1972, 60, 337–350. [Google Scholar] [CrossRef] [PubMed][Green Version]
  120. Iukhnovets, R.A.; Bachinskiĭ, P.P. Effect of fluoride and insulin on cation-dependent ATPase activity of the enterocytes during threonine absorption. Vopr. Med. Khim. 1982, 28, 46–50. [Google Scholar] [PubMed]
  121. Robinson, J.D.; Davis, R.L.; Steinberg, M. Fluoride and beryllium interact with the (Na + Kbdependent ATPase as analogs of phosphate. J. Bioenerg. Biomembr. 1986, 18, 521–531. [Google Scholar] [CrossRef] [PubMed]
  122. Swann, A.C. Inhibition of (Na+, K+)-ATPase by fluoride: Evidence for a membrane adaptation to ethanol. Alcohol 1990, 7, 91–95. [Google Scholar] [CrossRef]
  123. Murphy, A.J.; Hoover, J.C. Inhibition of the Na/K-ATPase by fluoride. Parallels with its inhibition of the sarcoplasmic reticulum CaATPase. J. Biol. Chem. 1992, 267, 16995–17000. [Google Scholar]
  124. Façanha, A.R.; de Meis, L. Inhibition of Maize Root H+-ATPase by Fluoride and Fluoroaluminate Complexes. Plant. Physiol. 1995, 108, 241–246. [Google Scholar] [CrossRef] [PubMed][Green Version]
  125. Suketa, Y.; Suzuki, K.; Taki, T.; Itoh, Y.; Yamaguchi, M.; Sakurai, T.; Tanishita, Y. Effect of fluoride on the activities of the Na+/glucose cotransporter and Na+/K(+)-ATPase in brush border and basolateral membranes of rat kidney (in vitro and in vivo). Biol. Pharm. Bull. 1995, 18, 273–278. [Google Scholar] [CrossRef]
  126. Liu, G.Y.; Chai, C.Y.; Kang, S.L. Effects of Fluoride on the Activity of ATPase on Erythrocytic membrane in Chicks. Heilongjinag J. Anim Sci. Vet. Med. 2002, 8. Available online: http://en.cnki.com.cn/Article_en/CJFDTOTAL-HLJX200208001.htm (accessed on 28 February 2019). [Google Scholar]
  127. Ekambaram, P.; Paul, V. Modulation of fluoride toxicity in rats by calcium carbonate and by withdrawal of fluoride exposure. Pharmacol. Toxicol. 2002, 90, 53–58. [Google Scholar] [CrossRef]
  128. Cittanova, M.L.; Estepa, L.; Bourbouze, R.; Blanc, O.; Verpont, M.C.; Wahbe, E.; Coriat, P.; Daudon, M.; Ronco, P.M. Fluoride ion toxicity in rabbit kidney thick ascending limb cells. Eur. J. Anaesthesiol. 2002, 19, 341–349. [Google Scholar] [CrossRef]
  129. Kravtsova, V.V.; Kravtsov, O.V. Inactivation of Na+, K+-ATPase from cattle brain by sodium fluoride. Ukr. Biokhim. Zhurnal 2004, 76, 39–47. [Google Scholar]
  130. Zhan, X.A.; Li, J.X.; Wang, M.; Xu, Z.R. Effects of Fluoride on Growth and Thyroid Function in Young Pigs. Fluoride 2006, 39, 95–100. [Google Scholar]
  131. Agalakova, N.I.; Gusev, G.P. Diverse effects of fluoride on Na+ and K+ transport across the rat erythrocyte membrane. Fluoride 2008, 41, 28–39. [Google Scholar]
  132. Agalakova, N.I.; Gusev, G.P. Fluoride-induced death of rat erythrocytes in vitro. Toxicol. In Vitro 2011, 25, 1609–1618. [Google Scholar] [CrossRef]
  133. Agalakova, N.I.; Gusev, G.P. Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride. ISRN Cell Biol. 2012, 2012, 403835. [Google Scholar] [CrossRef]
  134. Sarkar, C.; Pal, S. Ameliorative effect of resveratrol against fluoride-induced alteration of thyroid function in male wistar rats. Biol. Trace Elem. Res. 2014, 162, 278–287. [Google Scholar] [CrossRef] [PubMed]
  135. Sarkar, C.; Pal, S. Effects of sub-acute fluoride exposure on discrete regions of rat brain associated with thyroid dysfunction: A comparative study. Int. J. Biomed. Res. 2015, 6, 647–660. [Google Scholar] [CrossRef]
  136. Mondragão, M.A.; Schmidt, H.; Kleinhans, C.; Langer, J.; Kafitz, K.W.; Rose, C.R. Extrusion versus diffusion: Mechanisms for recovery from sodium loads in mouse CA1 pyramidal neurons. J. Physiol. 2016, 594, 5507–5527. [Google Scholar] [CrossRef]
  137. Arulkumar, M.; Vijayan, R.; Penislusshiyan, S.; Sathishkumar, P.; Angayarkanni, J.; Palvannan, T. Alteration of paraoxonase, arylesterase and lactonase activities in people around fluoride endemic area of Tamil Nadu, India. Clin. Chim. Acta 2017, 471, 206–215. [Google Scholar] [CrossRef]
  138. Shashi, A.; Meenakshi, G. Inhibitory Effect of Fluoride on Na+, K+ ATPase Activity in Human Erythrocyte Membrane. Biol. Trace Elem. Res. 2015, 168, 340–348. [Google Scholar]
  139. Peckham, S.; Lowery, D.; Spencer, S. Are fluoride levels in drinking water associated with hypothyroidism prevalence in England? A large observational study of GP practice data and fluoride levels in drinking water. J. Epidemiol. Community Health 2015, 69, 619–624. [Google Scholar] [CrossRef][Green Version]
  140. Kheradpisheh, Z.; Mirzaei, M.; Mahvi, A.H.; Mokhtari, M.; Azizi, R.; Fallahzadeh, H.; Ehrampoush, M.H. Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case—Control Study. Sci. Rep. 2018, 8, 2674. [Google Scholar] [CrossRef]
  141. EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion on Dietary Reference Values for fluoride. EFSA J. 2013, 11, 3332. [Google Scholar] [CrossRef][Green Version]
  142. Recommendations for Using Fluoride to Prevent and Control Dental Caries in the United States; MMWR; Centers for Disease Control and Prevention: Atlanta, GA, USA, 2001; Volume 50, pp. 1–42.
  143. Ten Cate, J.M. In vitro studies on the effects of fluoride on de- and remineralization. J. Dent. Res. 1990, 69, 614–619. [Google Scholar] [CrossRef]
  144. Water Fluoridation for the Prevention of Dental Caries (Review); The Cochrane Library: Hoboken, NJ, USA, 2015; Available online: https://www.cochrane.org/CD010856/ORAL_water-fluoridation-prevent-tooth-decay (accessed on 15 February 2019).
  145. Opinion of the Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers Concerning the Safety of Fluorine Compounds in Oral Hygiene Products for Children under the Age of 6 Years. June 2003. SCCNFP/0653/03: Final. Available online: https://ec.europa.eu/health/phrisk/committees/04sccp/docs/sccpo024.pdf (accessed on 15 February 2019).
  146. Sutton, S.V.; Bender, G.R.; Marquis, R.E. Fluoride Inhibition of Proton-Translocating ATPases of Oral Bacteria. Infect. Immun. 1987, 55, 2597–2603. [Google Scholar] [PubMed]
  147. Sturr, M.G.; Marquis, R.E. Inhibition of proton-translocating ATPases of Streptococcus mutans and Lactobacillus casei by fluoride and aluminum. Arch. Microbiol. 1990, 155, 22–27. [Google Scholar] [CrossRef]
  148. Marquis, R.E. Diminished acid tolerance of plaque bacteria caused by fluoride. J. Dent. Res. 1990, 69, 672–675. [Google Scholar] [CrossRef] [PubMed]
  149. Hamilton, I.R. Biochemical effects of fluoride on oral bacteria. J. Dent. Res. 1990, 69, 660–667. [Google Scholar] [CrossRef]
  150. National Research Council. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards; The National Academies Press: Washington, DC, USA, 2006. [Google Scholar]
  151. Chan, L.; Mehra, A.; Saikat, S.; Lynch, P. Human exposure assessment of fluoride from tea (Camellia sinensis L.). Food Res. Int. 2013, 51, 564–570. [Google Scholar] [CrossRef]
  152. Waugh, D.T.; Potter, W.; Limeback, H.; Godfrey, M. Risk assessment of fluoride intake from tea in the republic of Ireland and its implications for public health and water fluoridation. Int. J. Environ. Res. Public Health 2016, 13, 259. [Google Scholar] [CrossRef] [PubMed]
  153. Waugh, D.T.; Godfrey, M.; Limeback, H.; Potter, W. Black Tea Source, Production, and Consumption: Assessment of Health Risks of Fluoride Intake in New Zealand. J. Environ. Public Health 2017, 2017, 5120504. [Google Scholar] [CrossRef] [PubMed]
  154. Dabeka, R.W.; Karpinski, K.; McKenzie, A.; Bajdik, C. Survey of lead, cadmium and fluoride in human milk and correlation of levels with environmental and food factors. Food Chem. Toxicol. 1986, 24, 913–921. [Google Scholar] [CrossRef]
  155. Fomon, S.J.; Ekstrand, J. Fluoride Intake by Infants. J. Public Health Dentristry 1999, 59, 229–234. [Google Scholar] [CrossRef]
  156. Gupta, P.; Gupta, N.; Meena, K.; Moon, N.J.; Kumar, P.; Kaur, R. Concentration of Fluoride in Cow’s and Buffalo’s Milk in Relation to Varying Levels of Fluoride Concentration in Drinking Water of Mathura City in India—A Pilot Study. J. Clin. Diagn Res. 2015, 9, LC05–LC07. [Google Scholar] [CrossRef]
  157. Zohoori, V.; Maguire, A. Database of the Fluoride (F)content of Selected Drinks and Foods in the UK; Newscastle University: Newcastle upon Tyne, UK; Teeside University: Middlesbrough, UK, 2015; Available online: https://www.tees.ac.uk/docs/docrepo/research/finalfluoridedatabase.pdf (accessed on 15 March 2019).
  158. Suttie, J.W.; Miller, R.F.; Phillips, P.H. Effects of dietary sodium fluoride on dairy cows. 1. The physiological effects and the development symptoms of fluorosis. J. Nutr. 1957, 63, 211–224. [Google Scholar] [CrossRef]
  159. Zohoori, F.V.; Moynihan, P.J.; Omid, N.; Abuhaloob, L.; Maguire, A. Impact of water fluoride concentration on the fluoride content of infant foods and drinks requiring preparation with liquids before feeding. Community Dent. Oral Epidemiol. 2012, 40, 432–440. [Google Scholar] [CrossRef]
  160. Johnson, J., Jr.; Bawden, J.W. The fluoride content of infant formulas available in 1985. Pediatr. Dent. 1987, 9, 33–37. [Google Scholar]
  161. Siew, C.; Strock, S.; Ristic, H.; Kang, P.; Chou, H.; Chen, J.; Frantsve-Hawley, J.; Meyer, D.M. Assessing a potential risk factor for enamel fluorosis: A preliminary evaluation of fluoride content in infant formulas. J. Am. Dent. Assoc. 2009, 140, 1228–1236. [Google Scholar] [CrossRef]
  162. McKnight-Hanes, M.C.; Leverett, D.H.; Adair, S.M.; Shields, C.P. Fluoride content of infant formulas: Soy-based formulas as a potential factor in dental fluorosis. Fluoride content of infant formulas: Soy-based formulas as a potential factor in dental fluorosis. Pediatr. Dent. 1988, 10, 189–194. [Google Scholar]
  163. Hossny, E.; Reda, S.; Marzouk, S.; Diab, D.; Fahmy, H. Serum fluoride levels in a group of Egyptian infants and children from Cairo city. Arch. Environ. Health. 2003, 58, 306–315. [Google Scholar] [CrossRef]
  164. Warady, B.A.; Koch, M.; O’Neal, D.W.; Higginbotham, M.; Harris, D.J.; Hellerstein, S. Plasma fluoride concentration in infants receiving long-term peritoneal dialysis. J. Pediatr. 1989, 115, 436–439. [Google Scholar] [CrossRef]
  165. Anderson, W.A.; Pratt, I.; Ryan, M.R.; Flynn, A. A probabilistic estimation of fluoride intake by infants up to the age of 4 months from infant formula reconstituted with tap water in the fluoridated regions of Ireland. Caries Res. 2004, 38, 421–429. [Google Scholar] [CrossRef]
  166. Harriehausen, C.X.; Dosani, F.Z.; Chiquet, B.T.; Barratt, M.S.; Quock, R.L. Fluoride Intake of Infants from Formula. J. Clin. Pediatr. Dent. 2019, 43, 34–41. [Google Scholar] [CrossRef] [PubMed]
  167. Aperia, A.; Broberger, O.; Herin, P.; Thodenius, K.; Zetterström, R. Postnatal control of water and electrolyte homeostasis in pre-term and full-term infants. Acta Paediatr. Scand. Suppl. 1983, 305, 61–65. [Google Scholar] [CrossRef]
  168. Arant, B.S., Jr. Postnatal development of renal function during the first year of life. Pediatr. Nephrol. 1987, 1, 308–313. [Google Scholar] [CrossRef]
  169. Ekstrand, J.; Fomon, S.J.; Ziegler, E.E.; Nelson, S.E. Fluoride Pharmacokinetics in Infancy. Pediatr. Res. 1994, 35, 157–163. [Google Scholar] [CrossRef][Green Version]
  170. Ehrnebo, M.; Ekstrand, J. Occupational fluoride exposure and plasma fluoride levels in man. Int. Arch. Occup. Environ. Health 1986, 58, 179–190. [Google Scholar] [CrossRef]
  171. Kono, K.; Yoshisda, Y.; Watanabe, M.; Usada, K.; Nagaie, H.; Takahashi, Y. Serum and urine monitoring of fluoride exposed workers in aluminium smelting industry. J. Environ. Sci. 1996, 8, 242–248. [Google Scholar]
  172. Lobo, J.G.V.M.; Leite, A.L.; Pereira, H.A.B.S.; Fernandes, M.S.; Peres-Buzalaf, C.; Sumida, D.H.; Rigalli, A.; Buzalaf, M.A.R. Low-Level Fluoride Exposure Increases Insulin Sensitivity in Experimental Diabetes. J. Dent. Res. 2015, 94, 990–997. [Google Scholar] [CrossRef] [PubMed]
  173. Da Silva Pereira, H.A.; de Lima Leite, A.; Charone, S.; Lobo, J.G.; Cestari, T.M.; Peres-Buzalaf, C.; Buzalaf, M.A. Proteomic Analysis of Liver in Rats Chronically Exposed to Fluoride. PLoS ONE 2013, 8, e75343. [Google Scholar]
  174. Amaral, S.L.; Azevedo, L.B.; Buzalaf, M.A.; Fabricio, M.F.; Fernandes, M.S.; Valentine, R.A.; Maguire, A.; Zohoori, F.V. Effect of chronic exercise on fluoride metabolism in fluorosis-susceptible mice exposed to high fluoride. Sci. Rep. 2018, 8, 3211. [Google Scholar] [CrossRef]
  175. Trautner, K.; Siebert, G. An experimental study of bio-availability of fluoride from dietary sources in man. Arch. Oral Biol. 1986, 31, 223–228. [Google Scholar] [CrossRef]
  176. Toyota, S. Fluorine content in the urine and in the serum of hydrofluoric acid workers as an index of health administration. Sangyo Igaku 1979, 21, 335–348. [Google Scholar] [CrossRef] [PubMed]
  177. Ekstrand, J.; Alvan, G.; Boreus, L.; Norlin, A. Pharmacokinetics of fluoride in man after single and multiple oral doses. Eur. J. Clin. Pharmacol. 1977, 12, 311–317. [Google Scholar] [CrossRef]
  178. Ekstrand, J.; Ehrnebo, M.; Boreus, L. Fluoride bioavailability after intravenous and oral administration: Importance of renal clearance and urine flow. Clin. Pharmacol. Ther. 1978, 23, 329–371. [Google Scholar] [CrossRef] [PubMed]
  179. Ekstrand, J. Relationship between fluoride in the drinking water and the plasma fluoride concentration in man. Caries Res. 1978, 12, 123–127. [Google Scholar] [CrossRef]
  180. Reddy, P.V. Organofluorine Compounds in Biology and Medicine; Elsevier: Waltham, MA, USA, 2015; ISBN 978-0-444-53748-5. [Google Scholar]
  181. Skiles, J.L.; Imel, E.A.; Christenson, J.C.; Bell, J.E.; Hulbert, M.L. Fluorosis because of prolonged voriconazole therapy in a teenager with acute myelogenous leukemia. J. Clin. Oncol. 2011, 29, e779–e782. [Google Scholar] [CrossRef] [PubMed]
  182. Wermers, R.A.; Cooper, K.; Razonable, R.R.; Deziel, P.J.; Whitford, G.M.; Kremers, W.K.; Moyer, T.P. Fluoride Excess and Periostitis in Transplant Patients Receiving Long-Term Voriconazole Therapy. Clin. Infect. Dis. 2011, 52, 604–611. [Google Scholar] [CrossRef] [PubMed][Green Version]
  183. Perbet, S.; Salavert, M.; Amarger, S.; Constantin, J.M.; D’ Incan, M.; Bazin, J.E. Fluoroderma after exposure to sevoflurane. Br. J. Anaesth. 2011, 107, 106–107. [Google Scholar] [CrossRef][Green Version]
  184. Goldberg, M.E.; Cantillo, J.; Larijani, G.E.; Torjman, M.; Vekeman, D.; Schieren, H. Sevoflurane versus isoflurane for maintenance of anesthesia: Are serum inorganic fluoride ion concentrations of concern? Anesth. Analg. 1996, 82, 1268–1272. [Google Scholar]
  185. Ekstrand, J.; Koch, G. Systemic fluoride absorption following fluoride gel application. J. Dent. Res. 1980, 59, 1067. [Google Scholar] [CrossRef]
  186. Ekstrand, J.; Koch, G.; Lindgren, L.E.; Petersson, L.G. Pharmacokinetics of fluoride gels in children and adults. Caries Res. 1981, 15, 213–220. [Google Scholar] [CrossRef]
  187. Ekstrand, J.; Ehrnebo, M. Absorption of fluoride from fluoride dentifrices. Caries Res. 1980, 14, 96–102. [Google Scholar] [CrossRef]
  188. Zohoori, F.V.; Innerd, A.; Azevedo, L.B.; Whitford, G.M.; Maguire, A. Effect of exercise on fluoride metabolism in adult humans: A pilot study. Sci. Rep. 2015, 5, 16905. [Google Scholar] [CrossRef] [PubMed]
  189. Jacobson, A.P.M. Low Fluoride Concentrations: Their Relevance to the Inhibition of Dental Caries. Ph.D. Thesis, Faculty of Medicine, The University of Glasgow, Glasgow, UK, 1995. Available online: http://theses.gla.ac.uk/2479/1/1995jacobsonphd.pdf (accessed on 12 December 2018). [Google Scholar]
  190. Kurland, E.S.; Schulman, R.C.; Zerwekh, J.E.; Reinus, W.R.; Dempster, D.W.; Whyte, M.P. Recovery from skeletal fluorosis (an enigmatic, American case). J. Bone Min. Res. 2007, 22, 163–170. [Google Scholar] [CrossRef] [PubMed]
  191. European Academy of Paediatric Dentistry. Guidelines on the use of fluoride in children: An EAPD policy document. Eur. Arch. Paediatr. Dent. 2009, 10, 129–135. [Google Scholar] [CrossRef]
  192. Irish Oral Health Services Guideline Initiative. Topical Fluorides: Evidence-Based Guidance on the Use of Topical Fluorides for Caries Prevention in Children and Adolescents in Ireland. 2008. Available online: https://www.ucc.ie/en/media/research/ohsrc/TopicalFluoridesFull.pdf (accessed on 12 January 2019).
  193. American Academy of Pediatric Dentistry. Policy on early childhood caries (ECC): Classifications, consequences, and preventive strategies. Pediatr. Dent. 2008, 30, 40–42. [Google Scholar]
  194. Levy, S.M.; McGrady, J.A.; Bhuridej, P.; Warren, J.J.; Heilman, J.R.; Wefel, J.S. Factors affecting dentifrice use and ingestion among a sample of U.S. preschoolers. Pediatr. Dent. 2000, 22, 389–394. [Google Scholar]
  195. Hargreaves, J.A.; Ingram, G.S.; Wagg, B.J. A Gravimetric Study of the Ingestion of Toothpaste by Children. Caries Res. 1972, 6, 237–243. [Google Scholar] [CrossRef]
  196. Omid, N.; Maguire, A.; O’Hare, W.T.; Zohoori, F.V. Total daily fluoride intake and fractional urinary fluoride excretion in 4- to 6-year-old children living in a fluoridated area: Weekly variation? Community Dent. Oral Epidemiol. 2017, 45, 12–19. [Google Scholar] [CrossRef]
  197. Kaplan, J.H. Biochemistry of Na,K-ATPase. Annu. Rev. Biochem. 2002, 71, 511–535. [Google Scholar] [CrossRef] [PubMed]
  198. Sweadner, K.J. Isozymes of the Na+/K+-ATPase. Biochim. Biophys. Acta 1989, 988, 185–220. [Google Scholar] [CrossRef]
  199. Blanco, G.; Mercer, R.W. Isozymes of the Na-K-ATPase: Heterogeneity in structure, diversity in function. Am. J. Physiol. 1998, 275 Pt 2, F633–F650. [Google Scholar] [CrossRef]
  200. Skou, J.C.; Esmann, M. The Na, K-ATPase. J. Bioenerg. Biomembr. 1992, 24, 249–261. [Google Scholar] [PubMed]
  201. McDonough, A.A.; Geering, K.; Farley, R.A. The sodium pump needs its beta subunit. FASEB J. 1990, 4, 1598–1605. [Google Scholar] [CrossRef] [PubMed]
  202. Mercer, R.W. Structure of the Na, K-ATPase. Int. Rev. Cytol. 1993, 137C, 139–168. [Google Scholar] [PubMed]
  203. Scheiner-Bobis, G. The sodium pump. Its molecular properties and mechanics of ion transport. Eur. J. Biochem. 2002, 269, 2424–2433. [Google Scholar] [CrossRef] [PubMed]
  204. Bertorello, A.M.; Aperia, A.; Walaas, S.I.; Nairn, A.C.; Greengard, P. Phosphorylation of the catalytic subunit of Na+, K+-ATPase inhibits the activity of the enzyme. Proc. Natl. Acad. Sci. USA 1991, 88, 11359–11362. [Google Scholar] [CrossRef]
  205. Bertorello, A.; Aperia, A. Na+-K+-ATPase is an effector protein for protein kinase C in renal proximal tubule cells. Am. J. Physiol. 1989, 256 Pt 2, F370–F373. [Google Scholar] [CrossRef]
  206. Fukuda, Y.; Bertorello, A.; Aperia, A. Ontogeny of the regulation of Na+, K(+)-ATPase activity in the renal proximal tubule cell. Pediatr. Res. 1991, 30, 131–134. [Google Scholar] [CrossRef] [PubMed]
  207. Beguin, P.; Beggah, A.T.; Chibalin, A.V.; Burgener-Kairuz, P.; Jaisser, F.; Mathews, P.M.; Rossier, B.C.; Cotecchia, S.; Geering, K. Phosphorylation of the Na,K-ATPase alpha-subunit by protein kinase A and C in vitro and in intact cells. Identification of a novel motif for PKC-mediated phosphorylation. J. Biol. Chem. 1994, 269, 24437–24445. [Google Scholar]
  208. Marcaida, G.; Kosenko, E.; Miñana, M.D.; Grisolía, S.; Felipo, V. Glutamate induces a calcineurin-mediated dephosphorylation of Na+,K(+)-ATPase that results in its activation in cerebellar neurons in culture. J. Neurochem. 1996, 66, 99–104. [Google Scholar] [CrossRef]
  209. Cheng, X.J.; Höög, J.O.; Nairn, A.C.; Greengard, P.; Aperia, A. Regulation of rat Na(+)-K(+)-ATPase activity by PKC is modulated by state of phosphorylation of Ser-943 by PKA. Am. J. Physiol. 1997, 273 Pt 1, C1981–C1986. [Google Scholar] [CrossRef]
  210. Chibalin, A.V.; Pedemonte, C.H.; Katz, A.I.; Féraille, E.; Berggren, P.O.; Bertorello, A.M. Phosphorylation of the catalyic alpha-subunit constitutes a triggering signal for Na+, K+-ATPase endocytosis. J. Biol. Chem. 1998, 273, 8814–8819. [Google Scholar] [CrossRef] [PubMed]
  211. Nishi, A.; Fisone, G.; Snyder, G.L.; Dulubova, I.; Aperia, A.; Nairn, A.C.; Greengard, P. Regulation of Na+, K+-ATPase isoforms in rat neostriatum by dopamine and protein kinase C. J. Neurochem. 1999, 73, 1492–1501. [Google Scholar] [CrossRef]
  212. Taub, M.; Springate, J.E.; Cutuli, F. Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase. Biochem. Biophys. Res. Commun. 2010, 393, 339–344. [Google Scholar] [CrossRef]
  213. Liu, T.; Konkalmatt, P.R.; Yang, Y.; Jose, P.A. Gastrin decreases Na+, K+-ATPase activity via a PI3 kinase- and PKC-dependent pathway in human renal proximal tubule cells. Am. J. Physiol. Endocrinol. Metab. 2016, 310, E565–E571. [Google Scholar] [CrossRef]
  214. Saha, P.; Manoharan, P.; Arthur, S.; Sundaram, S.; Kekuda, R.; Sundaram, U. Molecular mechanism of regulation of villus cell Na-K-ATPase in the chronically inflamed mammalian small intestine. Biochim. Biophys. Acta 2015, 1848, 702–711. [Google Scholar] [CrossRef] [PubMed][Green Version]
  215. Zatyka, M.; Ricketts, C.; da Silva Xavier, G.; Minton, J.; Fenton, S.; Hofmann-Thiel, S.; Rutter, G.A.; Barrett, T.G. Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress. Hum. Mol. Genet. 2008, 17, 190–200. [Google Scholar] [CrossRef] [PubMed]
  216. Wang, Y.; Liu, X.; Xu, Z. Endoplasmic Reticulum Stress in Hearing Loss. J. Otorhinolaryngol. Hear. Balance Med. 2018, 1, 3. [Google Scholar] [CrossRef]
  217. Kobayashi, C.A.; Leite, A.L.; Peres-Buzalaf, C.; Carvalho, J.G.; Whitford, G.M.; Everett, E.T.; Siqueira, W.L.; Buzalaf, M.A. Bone response to fluoride exposure is influenced by genetics. PLoS ONE 2014, 11, e114343. [Google Scholar] [CrossRef]
  218. Poulsen, H.; Morth, P.; Egebjerg, J.; Nissen, P. Phosphorylation of the Na+, K+-ATPase and the H+, K+-ATPase. FEBS Lett. 2010, 584, 2589–2595. [Google Scholar] [CrossRef] [PubMed]
  219. Krasilnikova, O.A.; Kavok, N.S.; Babenko, N.A. Drug-induced and postnatal hypothyroidism impairs the accumulation of diacylglycerol in liver and liver cell plasma membranes. BMC Physiol. 2002, 2, 12. [Google Scholar] [CrossRef]
  220. Hermenegildo, C.; Felipo, V.; Miñana, M.D.; Grisolía, S. Inhibition of protein kinase C restores Na+, K+-ATPase activity in sciatic nerve of diabetic mice. J. Neurochem. 1992, 58, 1246–1249. [Google Scholar] [CrossRef] [PubMed]
  221. Hermenegildo, C.; Felipo, V.; Miñana, M.D.; Romero, F.J.; Grisolía, S. Sustained recovery of Na(+)-K(+)-ATPase activity in the sciatic nerve of diabetic mice by administration of H7 or calphostin C, inhibitors of PKC. Diabetes 1993, 42, 257–262. [Google Scholar] [CrossRef] [PubMed]
  222. Bocanera, L.V.; Krawiec, L.; Nocetti, G.; Juvenal, G.J.; Silberschmidt, D.; Pisarev, M.A. The protein kinase C pathway inhibits iodide uptake by calf thyroid cells via sodium potassium-adenosine triphosphatase. Thyroid 2001, 11, 813–817. [Google Scholar] [CrossRef] [PubMed]
  223. Rybin, V.; Steinberg, S.F. Thyroid hormone represses protein kinase C isoform expression and activity in rat cardiac myocytes. Circ. Res. 1996, 79, 388–398. [Google Scholar] [CrossRef] [PubMed]
  224. Meier, C.A.; Fabbro, D.; Meyhack, I.; Hemmings, B.; Olbrecht, U.; Jakob, A.; Walter, P. Effect of hypothyroidism and thyroid hormone replacement on the level of protein kinase C and protein kinase A in rat liver. FEBS Lett. 1991, 282, 397–400. [Google Scholar] [CrossRef][Green Version]
  225. Agalakova, N.I.; Gusev, G.P. Transient activation of protein kinase C contributes to fluoride-induced apoptosis of rat erythrocytes. Toxicol. In Vitro 2013, 27, 2335–2341. [Google Scholar] [CrossRef]
  226. Refsnes, M.; Kersten, H.; Schwarze, P.E.; Lag, M. Involvement of protein kinase C in fluoride-induced apoptosis in different types of lung cells. Ann. N. Y. Acad. Sci. 2002, 973, 218–220. [Google Scholar] [CrossRef] [PubMed]
  227. Chirumari, K.; Reddy, P.K. Dose-Dependent Effects of Fluoride on Neurochemical Milieu in the Hippocampus and Neocortex of Rat Brain. Fluoride 2007, 40, 101–110. [Google Scholar]
  228. Refsnes, M.; Schwarze, P.E.; Holme, J.A.; Låg, M. Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): Role of different G protein-linked signal systems. Hum. Exp. Toxicol. 2003, 22, 111–123. [Google Scholar] [CrossRef]
  229. Hauschildt, S.; Hirt, W.; Bessler, W. Modulation of protein kinase C activity by NaF in bone marrow derived macrophages. FEBS Lett. 1988, 230, 121–124. [Google Scholar] [CrossRef][Green Version]
  230. Murthy, K.S.; Makhlouf, G.M. Fluoride activates G protein-dependent and -independent pathways in dispersed intestinal smooth muscle cells. Biochem. Biophys. Res. Commun. 1994, 202, 1681–1687. [Google Scholar] [CrossRef] [PubMed]
  231. Bertorello, A.; Aperia, A. Short-term regulation of Na+, K+-ATPase activity by dopamine. Am. J. Hypertension. 1990, 3, 51S–54S. [Google Scholar] [CrossRef]
  232. Aperia, A.; Holtback, U.; Syren, M.L.; Svensson, L.B.; Fryckstedt, J.; Greengard, P. Activation/deactivation of renal Na-K ATPase: A final common pathway for regulation of natriuresis. FASEB J. 1994, 8, 436–439. [Google Scholar] [CrossRef] [PubMed]
  233. Delamere, N.A.; King, K.L. The Influence of Cyclic AMP Upon Na,K-ATPase Activity in Rabbit Ciliary Epithelium. Investig. Ophthalmol. Vis. Sci. 1992, 33, 430–435. [Google Scholar]
  234. Tipsmark, C.K.; Madsen, S.S. Rapid Modulation of Na+/K+-ATPase Activity in Osmoregulatory Tissues of a Salmonid Fish. J. Exp. Biol. 2001, 204, 701–709. [Google Scholar] [PubMed]
  235. Chiba, F.Y.; Garbin, C.A.S.; Sumida, D.H. Effect of Fluoride intake on Carbohydrate Metabolism, Glucose Tolerance, and Insulin Signaling. Fluoride 2012, 45, 236–241. [Google Scholar]
  236. Preedy, V.R. Fluorine: Chemistry, Analysis, Function and Effects; The Royal Society of Chemistry: Cambridge, UK, 2015. [Google Scholar]
  237. Mornstad, H.; Sundstrom, B.; Hedner, R. Increased Urinary Excretion of cAMP Following Administration of Sodium Fluoride. J. Dent. Res. 1975, 54. AbstractL39. [Google Scholar]
  238. Kornegay, D.; Pennington, S. A Review of the Effect of Fluoride ion on Adenyl Cyclase. Fluoride 1973, 6, 19–32. [Google Scholar]
  239. Isenberg, K.; Allmann, D.W. Effect of Inorganic Fluoride on Urinary Excretion of 35-Cyclic AMP. Clin. Res. 1976, 24, 601. [Google Scholar]
  240. Edgar, W.; Jenkins, G.N.; Prudhoe, P. Urinary cAMP Excretion in Human Subjects Following Single and Divided Doses of Sodium Fluoride. J. Dent. Res. 1979, 58, 1229. [Google Scholar]
  241. Mornstad, H.; Van Dijken, J. Caries Preventive Doses of Fluoride and Cyclic AMP Levels in Human Plasma. Caries Res. 1982, 16, 277–281. [Google Scholar] [CrossRef] [PubMed]
  242. Shashi, A.; Bhardwaj, M. Study on blood biochemical diagnostic indices for hepatic function biomarkers in endemic skeletal fluorosis. Biol. Trace Elem. Res. 2011, 143, 803–814. [Google Scholar] [CrossRef]
  243. Mörnstad, H.; van Dijken, J. The Effect of Low Doses of Fluoride on the Content of Cyclic AMP and Amylase in Human Parotid Saliva. Caries Res. 1985, 19, 433–438. [Google Scholar] [CrossRef]
  244. Kleiner, H.S.; Allmann, D.W. The effects of fluoridated water on rat urine and tissue cAMP levels. Arch. Oral Biol. 1982, 27, 107–112. [Google Scholar] [CrossRef]
  245. Allmann, D.W.; Dunipace, A.; Curro, F.A. Stimulation of cAMP production by NaF in isolated rat aorta. J. Dent. Res. 1982, 61, 321. [Google Scholar]
  246. Kleiner, H.S.; Miller, A.; Allmann, D.W. Effect of dietary fluoride on rat tissue 3′,5′ cyclic AMP levels. J. Dent. Res. 1979, 58, 1920. [Google Scholar] [CrossRef] [PubMed]
  247. Susheela, A.K.; Singh, M. Adenyl cyclase activity following fluoride ingestion. Toxicol. Lett. 1982, 10, 209–212. [Google Scholar] [CrossRef]
  248. Singh, M.; Sushella, A.K. Adenyl Cyclase activity and cyclic AMP levels following F-ingestion in rabbits and human subjects. Fluoride 1982, 15, 202–208. [Google Scholar]
  249. Gutowska, I.; Baranowska-Bosiacka, I.; Siennicka, A.; Telesiński, A.; Stańczyk-Dunaj, M.; Wesołowska, T.; Gąssowska, M.; Kłos, P.; Zakrzewska, H.; Machaliński, B.; et al. Activation of phospholipase A2 by low levels of fluoride in THP1 macrophages via altered Ca2+ and cAMP concentration. Prostaglandins Leukot Essent Fatty Acids 2012, 86, 99–105. [Google Scholar] [CrossRef]
  250. Bidey, S.B.; Marshall, M.J.; Ekins, R.P. Cyclic AMP release from normal human thyroid slices in response to thyrotrophin. Acta Endocrinol. 1980, 95, 335–340. [Google Scholar] [CrossRef] [PubMed]
  251. DeRubertis, F.; Yamashita, K.; Dekker, A.; Larsen, P.R.; Field, J.B. Effects of thyroid-stimulating hormone on adenyl cyclase activity and intermediary metabolism of “cold” thyroid nodules and normal human thyroid tissue. J. Clin. Investig. 1972, 51, 1109–1117. [Google Scholar] [CrossRef][Green Version]
  252. Wolff, J.; Jones, A.B. The Purification of Bovine Thyroid Plasma Membranes and the Properties of Membrane-bound Adenyl Cyclase. J. Biol. Chem. 1971, 246, 3939–3947. [Google Scholar] [PubMed]
  253. Burke, G. Comparison of thyrotropin and sodium fluoride effects on thyroid adenyl cyclase. Endocrinology 1970, 86, 346–352. [Google Scholar] [CrossRef]
  254. Bech, K.; Madsen, S.N. Human thyroid adenylate cyclase in non-toxic goitre: Sensitivity to TSH, fluoride and thyroid stimulating immunoglobulins. Clin. Endocrinol. 1978, 8, 457–466. [Google Scholar] [CrossRef]
  255. Zhang, S.; Zhang, X.; Liu, H.; Qu, W.; Guan, Z.; Zeng, Q.; Jiang, C.; Gao, H.; Zhang, C.; Lei, R.; et al. Modifying Effect of COMT Gene Polymorphism and a Predictive Role for Proteomics Analysis in Children’s Intelligence in Endemic Fluorosis Area in Tianjin, China. Toxicol. Sci. 2015, 144, 238–245. [Google Scholar] [CrossRef][Green Version]
  256. Singh, N.; Verma, K.G.; Verma, P.; Sidhu, G.K.; Sachdeva, S. A comparative study of fluoride ingestion levels, serum thyroid hormone & TSH level derangements, dental fluorosis status among school children from endemic and non-endemic fluorosis areas. Springerplus 2014, 3, 7. [Google Scholar] [CrossRef] [PubMed][Green Version]
  257. Yasmin, S.; Ranjan, S.; D’Souza, D.; D’Souza, H. Effect of excess fluoride ingestion on human thyroid function in Gaya region, Bihar, India. Toxicol. Environ. Chem. 2013, 95, 1235–1243. [Google Scholar] [CrossRef]
  258. Shashi, A.; Singla, S. Syndrome of Low Triiodothyronine in Chronic Fluorosis. Int. J. Appl. Basic Med. Res. 2013, 3, 152–160. [Google Scholar]
  259. Hosur, M.B.; Puranik, R.S.; Vanaki, S.; Puranik, S. Study of thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in subjects with dental fluorosis. Eur. J. Dent. 2012, 6, 184–190. [Google Scholar]
  260. Karademir, S.; Mustafa, A.; Kuybulu, A.E.; Olgar, S.; Öktem, F. Effects of fluorosis on QT dispersion, heart rate variability and echocardiographic parameters in children. Anadolu Kardiyol. Derg. 2011, 1, 150–155. [Google Scholar] [CrossRef] [PubMed]
  261. Xiang, Q.; Chen, L.; Miang, Y.; Wu, M.; Chen, B. Fluoride and thyroid function in children in two villages in China. J. Toxicol. Environ. Health Sci. 2009, 1, 54–59. [Google Scholar]
  262. Bahijri, S.M.; Al-Fares, A.; Al-Khateeb, T.; Mufti, A.B. Hyperparathyroidism and Hypothyroidism in Individuals Consuming High Fluoride Intake in Jeddah-Saudi Arabia. Syr. Clin. Lab. Assoc. 2008, 4, 1428–1436. [Google Scholar]
  263. Ruiz-Payan, A. Chronic Effects of Fluoride on Growth, Blood Chemistry and Thyroid Hormones in Adolescents Residing in Three Communities in Northern Mexico; AAI3214004; ETD Collection for University of Texas: El Paso, TX, USA, 2006. [Google Scholar]
  264. Suskeela, A.K.; Bhatnagar, M.; Vig, K.; Monda, N.K. Excess fluoride ingestion and thyroid hormone derangements in children living in Delhi, India. Fluoride 2005, 38, 98–108. [Google Scholar]
  265. Wang, X.; Wang, L.; Hu, P.; Guo, X.; Luo, X. Effects of high iodine and high fluorine on children’s intelligence and thyroid function. Chin. J. Endemiol. 2001, 20, 288–290. [Google Scholar]
  266. Xiaoli, L.; Zhongxue, F.; Jili, H.; Qinlan, W.; Hongyin, W. The Detection of Children’s T3, T4 and TSH Contents in Endemic Fluorosis Area. Endem. Dis. Bull. 1999, 14, 16–17. [Google Scholar]
  267. Yao, Y.; Qicheng, C.; Fengyan, L. Analysis on TSH and intelligence level of children with dental Fluorosis in a high fluoride area. Lit. Inf. Prev. Med. 1996, 2, 26–27. [Google Scholar]
  268. Lin, F.; Aihaiti, H.X.; Zhao, H.X.; Jin, L.; Ji-Yong, J.; Maimaiti, A. The relationship of a low-iodine and high-fluoride environment to subclinical cretinism in Xinjiang. Endem. Dis. Bull. 1991, 6, 62–67. [Google Scholar]
  269. Bachinskii, P.P.; Gutsalenko, O.A.; Naryzhniuk, N.D.; Sidora, V.D.; Shliakhta, A.I. Action of the body fluorine of healthy persons and thyroidopathy patients on the function of hypophyseal-thyroid the system. Probl. Endokrinol. 1985, 31, 25–29. [Google Scholar]
  270. Gutowska, I.; Baranowska-Bosiacka, I.; Baśkiewicz, M.; Milo, B.; Siennicka, A.; Marchlewicz, M.; Wiszniewska, B.; Machaliński, B.; Stachowska, E. Fluoride as a pro-inflammatory factor and inhibitor of ATP bioavailability in differentiated human THP1 monocytic cells. Toxicol. Lett. 2010, 196, 74–79. [Google Scholar] [CrossRef]
  271. Agalakova, N.I.; Gusev, G.P. Fluoride induces oxidative stress and ATP depletion in the rat erythrocytes in vitro. Environ. Toxicol. Pharmacol. 2012, 34, 334–337. [Google Scholar] [CrossRef] [PubMed]
  272. Cooper, G.M. The Cell: A Molecular Approach, 2nd ed.; Sinauer Associates: Sunderland, MA, USA, 2000. Available online: https://www.ncbi.nlm.nih.gov/books/NBK9903/ (accessed on 20 February 2019).
  273. Engelking, L.R. Intermediate Reactions in Anaerobic Glycolysis. In Textbook of Veterinary Physiological Chemistry, 3rd ed.; Academic Press, Elsevier: Waltham, MA, USA, 2015; Chapter 26; pp. 164–168. [Google Scholar]
  274. Shephard, E.G.; Anderson, R.; Rosen, O.; Fridkin, M. C-reactive protein (CRP) peptides inactivate enolase in human neutrophils leading to depletion of intracellular ATP and inhibition of superoxide generation. Immunology 1992, 76, 79–85. [Google Scholar] [PubMed]
  275. Warburg, O.; Christian, W. Isolation and crystallization of enolase. Biochem. Z. 1942, 310, 384–421. [Google Scholar]
  276. Cimasoni, G. The Inhibition of Enolase by Fluoride in vitro. Caries Res. 1972, 6, 93–102. [Google Scholar] [CrossRef] [PubMed]
  277. Qin, J.; Chai, G.; Brewer, J.M.; Lovelace, L.L.; Lebioda, L. Fluoride inhibition of enolase: Crystal structure and thermodynamics. Biochemistry 2006, 45, 793–800. [Google Scholar] [CrossRef] [PubMed]
  278. Wang, T.; Himoe, A. Kinetics of the rabbit muscle enolase-catalyzed dehydration of 2-phosphoglycerate. J. Biol. Chem. 1974, 249, 3895–3902. [Google Scholar] [PubMed]
  279. Kiroytcheva, M.; Cheval, L.; Carranza, M.L.; Martin, P.Y.; Favre, H.; Doucet, A.; Féraille, E. Effect of cAMP on the activity and the phosphorylation of Na+,K(+)-ATPase in rat thick ascending limb of Henle. Kidney Int. 1999, 55, 1819–1831. [Google Scholar] [CrossRef] [PubMed]
  280. Wacker, W.E.; Parisi, A.F. Magnesium metabolism. N. Engl. J. Med. 1968, 278, 658–663. [Google Scholar] [CrossRef] [PubMed]
  281. Martyka, Z.; Kotela, I.; Blady-Kotela, A. Clinical use of magnesium. Przegl. Lek. 1996, 53, 155–158. [Google Scholar]
  282. Vormann, J. Magnesium: Nutrition and metabolism. Mol. Asp. Med. 2003, 24, 27–37. [Google Scholar] [CrossRef]
  283. Cerklewski, F.L. Influence of dietary magnesium on fluoride bioavailability in the rat. J. Nutr. 1987, 117, 496–500. [Google Scholar] [CrossRef]
  284. Ophaug, R.H.; Singer, L. Effect of fluoride on the mobilization of skeletal magnesium and soft-tissue calcinosis during acute magnesium deficiency in the rat. J. Nutr. 1976, 106, 771–777. [Google Scholar] [CrossRef]
  285. Chen, P.; Yun, Z.; Li, T.; Gao, H.; Hao, J.; Qin, Y. Relations between endemic fluorosis and chemicalelements in environment. Zhongguo Gonggong Weisheng Xuebo 2002, 18, 433–434. [Google Scholar]
  286. Meral, I.; Demir, H.; Gunduz, H.; Mert, N.; Dogan, I.; Turkey, V. Serum copper, zinc, manganese, and magnesium status of subjects with chronic fluorosis. Fluoride 2004, 37, 102–106. [Google Scholar]
  287. Ersoy, I.H.; Koroglu, B.K.; Varol, S.; Ersoy, S.; Varol, E.; Aylak, F.; Tamer, M.N. Serum copper, zinc, and magnesium levels in patients with chronic fluorosis. Biol. Trace Elem. Res. 2011, 143, 619–624. [Google Scholar] [CrossRef] [PubMed]
  288. Kessabi, M.; Khouzaimi, M.; Braun, J.P.; Hamliri, A. Serum Biochemical Effects of Fluoride on Cattle in the Darmous Area. Vet. Hum. Toxicol. 1983, 25, 403–406. [Google Scholar] [PubMed]
  289. Rajendraprasad, U.S. Bovine Fluorosis in Central East India: Monitoring and Treatment Strategies. Master’s Thesis, Indira Gandhi Agriculture University, Raipur, India, 2002. [Google Scholar]
  290. Singh, J.L.; Swarup, D. Biochemical changes in serum and urine bovine fluorosis. Indian J. Anim. Sci. 1999, 69, 776–778. [Google Scholar]
  291. Wu, Z.J.; Ding, J.Y.; Qi, D.S.; Yu, Y.H. Biochemical indexes of buffalo with fluorosis and their significance for diagnosis. J. Huazhong Agric. Univ. 1995, 14, 369–373. [Google Scholar]
  292. Altuğ, N.; Arslan, S.; Yüksek, N.; Keles, I.; Yörük, H.I.; Başbuğan, Y.; Aytekin, I. The levels of trace elements and selected vitamins in goats with chronic fluorosis. Turk. J. Vet. Anim. Sci. 2013, 37, 529–534. [Google Scholar] [CrossRef]
  293. Aperia, A.; Ibarra, F.; Svensson, L.B.; Klee, C.; Greengard, P. Calcineurin mediates alpha-adrenergic stimulation of Na+, K(+)-ATPase activity in renal tubule cells. Proc. Natl. Acad. Sci. USA 1992, 89, 7394–7397. [Google Scholar] [CrossRef]
  294. Pallen, C.J.; Valentine, K.A.; Wang, J.H.; Hollenberg, M.D. Calcineurin-Mediated Dephosphorylation of the Human Placental Membrane Receptor for Epidermal Growth Factor Urogastrone1. Biochemistry 1985, 24, 4727–4730. [Google Scholar] [CrossRef] [PubMed]
  295. Tallant, E.A.; Cheung, W.Y. Characterization of bovine brain calmodulin-dependent protein phosphatase. Arch. Biochem. Biophys. 1984, 232, 260–279. [Google Scholar] [CrossRef]
  296. Klee, C.; Wang, X.; Ren, H. Calcium-Regulated Protein Dephosphorylation. In Calcium as a Cellular Regulator; Oxford University Press: Oxford, UK, 1999; pp. 344–370. [Google Scholar]
  297. King, M.M.; Huang, C.Y. The Calmodulin-dependent Activation and Deactivation of the Phosphoprotein Phosphatase, Calcineurin, and the Effect of Nucleotides, Pyrophosphate, and Divalent Metal Ions. J. Biol. Chem. 1984, 259, 8847–8856. [Google Scholar]
  298. Gupta, R.C.; Khandelwal, R.L.; Sulakhe, P.V. Divalent cation effects on calcineurin phosphatase: Differential involvement of hydrophobic and metal binding domains in the regulation of the enzyme activity. Mol. Cell. Biochem. 1990, 97, 53–66. [Google Scholar] [CrossRef] [PubMed]
  299. Ping, L.; Ke, Z.; Benqiong, X.; Qun, W. Effect of metal ions on the activity of the catalytic domain of calcineurin. Biometals 2004, 17, 157–165. [Google Scholar] [CrossRef]
  300. Amiranoff, B.M.; Laburthe, M.C.; Rouyer-Fessard, C.M.; Demaille, J.G.; Rosselin, G.E. Calmodulin Stimulation of Adenylate Cyclase of Intestinal Epithelium. Eur. J. Biochem. 1983, 130, 33–37. [Google Scholar] [CrossRef]
  301. Margaret, L.R.; Israels, S.J. Molecular Basis of Platelet Function, 7th ed.; Hematology: Fort Worth, TX, USA, 2018; Chapter 125; pp. 1870–1884.e2. [Google Scholar]
  302. Yingst, D.R.; Ye-Hu, J.; Chen, H.; Barrett, V. Calmodulin increases Ca-dependent inhibition of the Na,K-ATPase in human red blood cells. Arch. Biochem. Biophys. 1992, 295, 49–54. [Google Scholar] [CrossRef]
  303. Smilowitz, H.; Hadjian, R.A.; Dwyer, J.; Feinstein, M.B. Regulation of acetylcholine receptor phosphorylation by calcium and calmodulin. Proc. Natl. Acad. Sci. USA 1981, 78, 4708–4712. [Google Scholar] [CrossRef]
  304. Yorio, T.; Sinclair, R.; Henry, S. Fluoride inhibition of the hydro-osmotic response of the toad urinary bladder to antidiuretic hormone. J. Pharmacol. Exp. Ther. 1981, 219, 459–463. [Google Scholar]
  305. Feneck, R. Phosphodiesterase inhibitors and the cardiovascular system. Contin. Educ. Anaesth. Crit. Care Pain 2007, 6, 203–207. [Google Scholar] [CrossRef]
  306. Wang, Z.; Li, X.D.; Li, M.Q.; Wang, Q.P. Changes in basic metabolic elements associated with the degeneration and ossification of ligamenta flava. J. Spinal Med. 2008, 31, 279–284. [Google Scholar] [CrossRef]
  307. Tao, X.; Xu, Z.R.; Wang, Y.Z. Effect of excessive dietary fluoride on nutrient digestibility and retention of iron, copper, zinc and manganese in growing pigs. Biol. Trace Elem. Res. 2005, 107, 141–151. [Google Scholar] [CrossRef]
  308. Karademir, B. Effect of fluoride ingestion on serum levels of the trace minerals Co, Mo, Cr, Mn and Li in adult male mice. Fluoride 2010, 43, 174–178. [Google Scholar]
  309. Singh, M. Biochemical and cytochemical alterations in liver and kidney following experimental fluorosis. Fluoride 1984, 17, 81–93. [Google Scholar]
  310. Ranjan, R.; Swarup, D.; Patra, R.C. Changes in levels of zinc, copper, cobalt, and manganese in soft tissues of fluoride-exposed rabbits. Fluoride 2011, 44, 83–88. [Google Scholar]
  311. Birkner, E.; Grucka-Mamczar, E.; Machoy, Z.; Tamawski, R.; Polaniak, R. Disturbance of protein metabolism in rats after acute poisoning with sodium fluoride. Fluoride 2000, 33, 182–186. [Google Scholar]
  312. Smita, P.B.; Pawar, S.S. Effect of fluoride ingestion on trace elements on brain and liver of Rat Rattus rattus (Wistar). Int. J. Life Sci. 2017, A8, 125–128. [Google Scholar]
  313. McKee, M.; Scavone, C.; Nathanson, J.A. Nitric oxide, cGMP, and hormone regulation of active sodium transport. Proc. Natl. Acad. Sci. USA 1994, 91, 12056–12060. [Google Scholar] [CrossRef]
  314. Scavone, C.; Scanlon, C.; McKee, M.; Nathanson, J.A. Atrial natriuretic peptide modulates sodium and potassium-activated adenosine triphosphatase through a mechanism involving cyclic GMP and cyclic GMP-dependent protein kinase. J. Pharmacol. Exp. Ther. 1995, 272, 1036–1043. [Google Scholar]
  315. De Oliveira Elias, M.; Tavares de Lima, W.; Vannuchi, Y.B.; Marcourakis, T.; da Silva, Z.L.; Trezena, A.G.; Scavone, C. Nitric oxide modulates Na+, K+-ATPase activity through cyclic GMP pathway in proximal rat trachea. Eur. J. Pharmacol. 1999, 367, 307–314. [Google Scholar] [CrossRef]
  316. Liang, M.; Knox, F.G. Nitric oxide reduces the molecular activity of Na+, K+-ATPase in opossum kidney cells. Kidney Int. 1999, 56, 627–634. [Google Scholar] [CrossRef]
  317. Liang, M.; Knox, F.G. Nitric oxide activates PKCalpha and inhibits Na+-K+-ATPase in opossum kidney cells. Am. J. Physiol. 1999, 277, F859–F865. [Google Scholar] [PubMed]
  318. Linas, S.L.; Repine, J.E. Endothelial cells regulate proximal tubule epithelial cell sodium transport. Kidney Int. 1999, 55, 1251–1258. [Google Scholar] [CrossRef][Green Version]
  319. Bełtowski, J.; Marciniak, A.; Wójcicka, G.; Górny, D. Nitric oxide decreases renal medullary Na+, K+-ATPase activity through cyclic GMP-protein kinase G dependent mechanism. J. Physiol. Pharmacol. 2003, 54, 191–210. [Google Scholar] [PubMed]
  320. Bhatnagar, M.; Sukhwal, P.; Suhalka, P.; Jain, A.; Joshi, C.; Sharma, D. Effects of Fluoride in Drinking Water on Nadphdiaphorase Neurons in the Forebrain of Mice: A possible mechanism of fluoride neurotoxicity. Fluoride 2011, 44, 195–209. [Google Scholar]
  321. Shanmugam, T.; Abdulla, S.; Yakulasamy, V.; Selvaraj, M.; Mathan, R. A mechanism underlying the neurotoxicity induced by sodium fluoride and its reversal by epigallocatechin gallate in the rat hippocampus: Involvement of NrF2/Keap-1 signaling pathway. J. Basic Appl. Zool. 2018, 79, 17. [Google Scholar] [CrossRef]
  322. Liu, G.; Chai, C.; Cui, L. Fluoride causing abnormally elevated serum nitric oxide levels in chicks. Environ. Toxicol. Pharmacol. 2003, 13, 199–204. [Google Scholar] [CrossRef]
  323. Guoyan, L.; Chunyan, C.; Shiliang, K. Functions of nitric oxide in the mechanism of chick fluorosis. Chin. J. Vet. Sci. 2000, 20, 588–590. [Google Scholar]
  324. Zhan, X.; Xu, Z.; Li, J.; Wang, M. Effects of fluorosis on lipid peroxidation and antioxidant systems in young pigs. Fluoride 2005, 38, 157–161. [Google Scholar]
  325. Panneerselvam, L.; Subbiah, K.; Arumugum, A.; Senapathy, J.G. Ferulic acid modulates fluoride induced oxidative hepatotoxicity in male Wistar rats. Biol. Trace Elem. Res. 2013, 151, 85–91. [Google Scholar] [CrossRef] [PubMed]
  326. Hassan, H.A.; Yousef, M.I. Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats. Food Chem. Toxicol. 2009, 47, 2332–2337. [Google Scholar] [CrossRef] [PubMed]
  327. White, A.A.; Aurbach, G.D. Detection of guanyl cyclase in mammalian tissues. Biochim. Biophys. Acta 1969, 191, 686–697. [Google Scholar] [CrossRef]
  328. Yamashita, K.; Field, J.B. Elevation of Cyclic Guanosine 3′,5′-Monophosphate Levels in Dog Thyroid Slices Caused by Acetylcholine and Sodium Fluoride. J. Biol. Chem. 1972, 247, 7062–7066. [Google Scholar] [PubMed]
  329. Zhao, Y.; Li, Y.; Gao, Y.; Yuan, M.; Manthari, R.K.; Wang, J.; Wang, J. TGF-β1 acts as mediator in fluoride-induced autophagy in the mouse osteoblast cells. Food Chem. Toxicol. 2018, 115, 26–33. [Google Scholar] [CrossRef] [PubMed]
  330. Sakallioğlu, E.E.; Muğlali, M.; Baş, B.; Gulbahar, M.Y.; Lütfioğlu, M.; Aksoy, A. Effects of Excessive Fluoride intake on Bone Turnover in Mandible: An Immunohistochemical Study in Rabbits. Fluoride 2014, 47, 23–30. [Google Scholar]
  331. Gao, Y.H.; Fu, S.B.; Sun, H.; Zhou, L.W.; Yu, J.; Li, Y.; Wang, Y.; Sun, D.J. Expression of the transforming growth factor-β superfamily in bone turnover of fluorosis. Chin. J. Endemiol. 2006, 25, 374–378. [Google Scholar]
  332. Yang, C.; Wang, Y.; Xu, H. Fluoride Regulate Osteoblastic Transforming Growth Factor-β1 Signaling by Mediating Recycling of the Type I Receptor ALK5. PLoS ONE 2017, 12, e0170674. [Google Scholar]
  333. Liu, X.L.; Song, J.; Liu, K.J.; Wang, W.P.; Xu, C.; Zhang, Y.Z.; Liu, Y. Role of inhibition of osteogenesis function by Sema4D/Plexin-B1 signaling pathway in skeletal fluorosis in vitro. J. Huazhong Univ. Sci. Technol. Med. Sci. 2015, 35, 712–715. [Google Scholar] [CrossRef]
  334. Wang, Y.Q.; Yuan, R.; Sun, Y.P.; Lee, T.J.; Shah, G.V. Antiproliferative action of calcitonin on lactotrophs of the rat anterior pituitary gland: Evidence for the involvement of transforming growth factor beta 1 in calcitonin action. Endocrinology 2003, 144, 2164–2171. [Google Scholar] [CrossRef] [PubMed]
  335. Krishnamachari, K.A.V.R.; Sivakumar, B. Endemic genu valgum. A new dimension to the fluorosis problem in India. Fluoride 1976, 9, 185–200. [Google Scholar]
  336. Teotia, S.P.S.; Teotia, M.; Singh, R.K.; Teotia, N.P.S.; Taves, D.R.; Heels, S. Plasma fluoride, 25-hydroxycholecalciferol, immunoreactive parathyroid Hormone and calcitonin in patients with endemic skeletal fluorosis. Fluoride 1978, 11, 115–119. [Google Scholar]
  337. Ma, J.; Li, M.; Song, Y.; Tu, J.; Liu, F.; Liu, K. Serum Osteocalcin and Calcitonin in adult males with different fluoride exposures. Fluoride 2009, 42, 133–136. [Google Scholar]
  338. Chen, S.; Li, B.; Lin, S.; Huang, Y.; Zhao, X.; Zhang, M.; Xia, Y.; Fang, X.; Wang, J.; Hwang, S.A.; et al. Change of urinary fluoride and bone metabolism indicators in the endemic fluorosis areas of southern china after supplying low fluoride public water. BMC Public Health 2013, 13, 156. [Google Scholar] [CrossRef]
  339. Shashi, A.; Singla, S. Parathyroid Function in Osteofluorosis. World J. Med. Sci. 2013, 8, 67–73. [Google Scholar]
  340. Ba, Y.; Zhu, J.; Yang, Y.; Yu, B.; Huang, H.; Wang, G.; Ren, L.; Cheng, X.; Cui, L.; Zhang, Y. Serum calciotropic hormone levels, and dental fluorosis in children exposed to different concentrations of fluoride and iodine in drinking water. Chin. Med. J. 2010, 123, 675–679. [Google Scholar]
  341. Apell, H.J.; Roudna, M.; Corrie, J.E.; Trentham, D.R. Kinetics of the phosphorylation of Na,K-ATPase by inorganic phosphate detected by a fluorescence method. Biochemistry 1996, 35, 10922–10930. [Google Scholar] [CrossRef] [PubMed]
  342. Huang, W.H.; Askari, A. Regulation of (Na++K+)-ATPase by inorganic phosphate: pH dependence and physiological implications. Biochem. Biophys. Res. Commun. 1984, 123, 438–443. [Google Scholar] [CrossRef]
  343. Martin, B.L.; Graves, D.J. Mechanistic aspects of the low-molecular-weight phosphatase activity of the calmodulin-activated phosphatase, calcineurin. J. Biol. Chem. 1986, 261, 14545–14550. [Google Scholar] [PubMed]
  344. Li, J.W.; Xu, C.; Fan, Y.; Wang, Y.; Xiao, Y.B. Can serum levels of alkaline phosphatase and phosphate predict cardiovascular diseases and total mortality in individuals with preserved renal function? A systemic review and meta-analysis. PLoS ONE 2014, 9, e102276. [Google Scholar] [CrossRef] [PubMed]
  345. Penido, M.G.M.G.; Alon, U.S. Phosphate homeostasis and its role in bone health. Pediatr. Nephrol. 2012, 27, 2039–2048. [Google Scholar] [CrossRef][Green Version]
  346. Liu, H.L.; Cheng, X.M.; Fan, Q.T.Q. Water fluoride concentration and human health effect. Chin. J. Endemiol. 1993, 12, 21–23. [Google Scholar]
  347. Ravula, S.; Harinarayan, C.V.; Prasad, U.V.; Ramalakshmi, T.; Rupungudi, A.; Madrol, V. Effect of Fluoride on Reactive Oxygen Species and Bone Metabolism in Postmenopausal Women. Fluoride 2012, 45, 108–115. [Google Scholar]
  348. Lavanya, R.; Devadoss, Y. Study of bone markers and fluoride levels in adult men with skeletal fluorosis. IOSR J. Dent. Med. Sci. 2018, 17, 78–80. [Google Scholar]
  349. Raghuramula, N.; Krishnamachari, K.A.V.R.; Rao, B.S. Serum 25-Hydroxy Vitamin D3 in Endemic fluorosis Genu ValGum and Fluorosis. Fluoride 1997, 30, 147–152. [Google Scholar]
  350. Jackson, R.; Kelly, S.; Noblitt, T.; Zhang, W.; Dunipace, A.; Li, Y.; Stookey, G.; Katz, B.; Brizendine, E.; Farley, S.; et al. The effect of fluoride therapy on blood chemistry parameters in osteoporotic females. Bone Miner. 1994, 27, 13–23. [Google Scholar] [CrossRef]
  351. Murugan, A.; Subramanian, A. Studies on the Biological Effects of Fluoride Intoxication in Dental Fluorosis Cases. Aust. J. Basic Appl. Sci. 2011, 5, 1362–1367. [Google Scholar]
  352. Pan, L.; Shib, X.; Liua, S.; Guo, X.; Zhao, M.; Cai, R.; Sun, G. Fluoride promotes osteoblastic differentiation through canonicalWnt/β-catenin signaling pathway. Toxicol. Lett. 2014, 225, 34–42. [Google Scholar] [CrossRef] [PubMed]
  353. Farley, J.R.; Wergedal, J.E.; Hall, S.L.; Herring, S.; Tarbaux, N.M. Calcitonin has direct effects on 3[H]-thymidine incorporation and alkaline phosphatase activity in human osteoblast-line cells. Calcif. Tissue Int. 1991, 48, 297–301. [Google Scholar] [CrossRef] [PubMed]
  354. Potts, J.T. Parathyroid hormone: Past and present. J. Endocrinol. 2005, 187, 311–325. [Google Scholar] [CrossRef]
  355. Torres, P.A.; De Brauwere, D.P. Three feedback loops precisely regulating serum phosphate concentration. Kidney Int. 2011, 80, 443–445. [Google Scholar] [CrossRef][Green Version]
  356. Gupta, A.; Guo, X.L.; Alvarez, U.M.; Hruska, K.A. Regulation of sodium-dependent phosphate transport in osteoclasts. J. Clin. Investig. 1997, 100, 538–549. [Google Scholar] [CrossRef] [PubMed]
  357. Liu, Q.; Liu, H.; Yu, X.; Wang, Y.; Yang, C.; Xu, H. Analysis of the Role of Insulin Signaling in Bone Turnover Induced by Fluoride. Biol. Trace Elem. Res. 2016, 171, 380–390. [Google Scholar] [CrossRef]
  358. Santoyo-Sanchez, M.P.; del Carmen Silva-Lucero, M.; Arreola-Mendoza, L.; Barbier, O.C. Effects of acute sodium fluoride exposure on kidney function, water homeostasis, and renal handling of calcium and inorganic phosphate. Biol. Trace Elem. Res. 2013, 152, 367–372. [Google Scholar] [CrossRef]
  359. Monsour, P.A.; Kruger, B.J.; Smid, J.R. Effects of a single intravenous dose of sodium fluoride on plasma electrolytes and metabolites in rats, rabbits, and cockerels. J. Dent. Res. 1985, 64, 1281–1285. [Google Scholar] [CrossRef]
  360. Di Loreto, V.; Rigalli, A.; Puche, R. Effect of sodium fluoride administration to rats on bone phosphorous content and phosphatemia. Arzneimittelforschung 2006, 56, 760–766. [Google Scholar] [CrossRef]
  361. Dandona, P.; Coumar, A.; Gill, D.S.; Bell, J.; Thomas, M. Sodium Fluoride Stimulates Osteocalcin in Normal Subjects. Clin. Endocrinol. 1988, 29, 437–441. [Google Scholar] [CrossRef]
  362. Nabavi, S.M.; Habtemariam, S.; Nabavi, S.F.; Sureda, A.; Daglia, M.; Moghaddam, A.H.; Amani, M.A. Protective effect of gallic acid isolated from Peltiphyllum peltatum against sodium fluoride-induced oxidative stress in rat’s kidney. Mol. Cell. Biochem. 2013, 372, 233–239. [Google Scholar] [CrossRef]
  363. Shanthakumari, D.; Subramanian, S. Effect of Fluoride Intoxication on Bone Tissue of Experimental Rats. Res. J. Environ. Sci. 2007, 1, 82–92. [Google Scholar]
  364. Gupta, A.R.; Dey, S.; Saini, M.; Swarup, D. Toxic effect of sodium fluoride on hydroxyproline level and expression of collagen-1 gene in rat bone and its amelioration by Tamrindus indica L. fruit pulp extract. Interdiscip. Toxicol. 2017, 9, 12–16. [Google Scholar] [CrossRef] [PubMed]
  365. Ranjan, R.; Swarup, D.; Patra, R.C.; Chandra, V. Tamarindus indica L. and Moringa oleifera M. extract administration ameliorate fluoride toxicity in rabbits. Indian J. Exp. Biol. 2009, 47, 900–905. [Google Scholar]
  366. Gupta, A.R.; Dey, S.; Swarup, D.; Saini, M.; Saxena, A.; Dan, A. Ameliorative effect of Tamarindus indica L. on biochemical parameters of serum and urine in cattle from fluoride endemic area. Vet. Arhiv. 2013, 83, 487–496. [Google Scholar]
  367. Gupta, A.R.; Dey, S.; Saini, M.; Swarup, D. Toxic effect of fluoride on biochemical parameters and collagen metabolism in osseous and non-osseous tissues of rats. Proc. Natl. Acad. Sci. India Sect. B Biol. Sci. 2015, 85, 719–724. [Google Scholar] [CrossRef]
  368. de Lores, R.; Arnaiz, G. Neuronal Na+-K+-ATPase and its regulation by catecholamines. Intern. Brain Res. Org. Monogr. Ser. 1983, 10, 147–158. [Google Scholar]
  369. Seri, I.; Kone, B.C.; Gullans, S.R.; Aperia, A.; Brenner, B.M.; Ballermann, B.J. Locally formed dopamine inhibits Na+-K+-ATPase activity in rat renal cortical tubule cells. Am. J. Physiol. 1988, 255, F666–F673. [Google Scholar] [CrossRef]
  370. Seri, I.; Kone, B.C.; Gullans, S.R.; Aperia, A.; Brenner, B.M.; Ballermann, B.J. Influence of Na+ intake on dopamine-induced inhibition of renal cortical Na(+)-K(+)-ATPase. Am. J. Physiol. 1990, 258, F52–F60. [Google Scholar] [CrossRef]
  371. Satoh, T.; Cohen, H.T.; Katz, A.I. Intracellular signaling in the regulation of renal Na-K-ATPase. I. Role of cyclic AMP and phospholipase A2. J. Clin. Investig. 1992, 89, 1496–1500. [Google Scholar] [CrossRef] [PubMed]
  372. Shahedi, M.; Laborde, K.; Azimi, S.; Hamdani, S.; Sachs, C. Mechanisms of dopamine effects on Na-K-ATPase activity in Madin-Darby canine kidney (MDCK) epithelial cells. Pflug. Arch. 1995, 429, 832–840. [Google Scholar] [CrossRef]
  373. Pinto-do-O, P.C.; Chibalin, A.V.; Katz, A.I.; Soares-da-Silva, P.; Bertorello, A.M. Short term vs. sustained inhibition of proximal tubule Na-K ATPase activity by dopamine: Cellular mechanisms. Clin. Exp. Hypertens. 1997, 19, 73–86. [Google Scholar] [CrossRef]
  374. Khundmiri, S.J.; Lederer, E. PTH and DA regulate Na-K ATPase through divergent pathways. Am. J. Physiol. Ren. Physiol. 2002, 282, F512–F522. [Google Scholar] [CrossRef] [PubMed]
  375. Khan, F.H.; Sen, T.; Chakrabarti, S. Dopamine oxidation products inhibit Na+, K+-ATPase activity in crude synaptosomal-mitochondrial fraction from rat brain. Free Radic. Res. 2003, 37, 597–601. [Google Scholar] [CrossRef] [PubMed]
  376. Gagnon, F.; Hamet, P.; Orlov, S.N. Na+, K+ pump and Na+-coupled ion carriers in isolated mammalian kidney epithelial cells: Regulation by protein kinase C. Can. J. Physiol. Pharmacol. 1999, 77, 305–319. [Google Scholar] [CrossRef]
  377. Hatta, S.; Amemiya, N.; Takemura, H.; Ohshika, H. Effects of Dopamine on Adenylyl Cyclase Activity and Amylase Secretion in Rat Parotid Tissue. J. Dent. Res. 1995, 74, 1289–1294. [Google Scholar] [CrossRef] [PubMed]
  378. Vortherms, T.A.; Nguyen, C.H.; Bastepe, M.; Jüppner, H.; Watts, V.J. D2 dopamine receptor-induced sensitization of adenylyl cyclase type 1 is G alpha(s) independent. Neuropharmacology 2006, 50, 576–584. [Google Scholar] [CrossRef] [PubMed]
  379. Osborne, N.N. Effects of GTP, forskolin, sodium fluoride, serotonin, dopamine, and carbachol on adenylate cyclase in Teleost retina. Neurochem. Res. 1990, 15, 523–528. [Google Scholar] [CrossRef] [PubMed]
  380. Battaglia, G.; Norman, A.B.; Hess, E.J.; Creese, I. Forskolin potentiates the stimulation of rat striatal adenylate cyclase mediated by D-1 dopamine receptors, guanine nucleotides, and sodium fluoride. J. Neurochem. 1986, 46, 1180–1185. [Google Scholar] [CrossRef]
  381. Woodward, J.J.; Harms, J. Potentiation of N-methyl-D-aspartate-stimulated dopamine release from rat brain slices by aluminum fluoride and carbachol. J. Neurochem. 1992, 58, 1547–1554. [Google Scholar] [CrossRef]
  382. Tsunoda, M.; Aizawa, Y.; Nakano, K.; Liu, Y.; Horiuchi, T.; Itai, K.; Tsunoda, H. Changes in Fluoride Levels in the Liver, Kidney, and Brain and in Neurotransmitters of Mice after Subacute Administration of Fluoride. Fluoride 2005, 38, 284–292. [Google Scholar]
  383. Pereira, M.; Dombrowski, P.A.; Losso, E.M.; Chioca, L.R.; Da Cunha, C.; Andreatini, R. Memory impairment induced by sodium fluoride is associated with changes in brain monoamine levels. Neurotox. Res. 2011, 19, 55–62. [Google Scholar] [CrossRef]
  384. Hall, R.; Amos, J.; Garry, R.; Buxton, R.L. Thyroid-stimulating hormone response to synthetic thyrotropin releasing hormone in man. Br. Med. J. 1970, 2, 274–277. [Google Scholar] [CrossRef] [PubMed]
  385. Sergev, O.; Rácz, K.; Varga, I.; Kiss, R.; Futo, L.; Mohari, K.; Gláz, E. Thyrotropin-releasing hormone increases plasma atrial natriuretic peptide levels in human. J. Endocrinol. Investig. 1990, 13, 649–652. [Google Scholar] [CrossRef]
  386. Ikegami, H.; Spahn, S.A.; Prasad, C. Neuropeptide-dopamine interactions. IV. Effect of thyrotropin-releasing hormone on striatal dopaminergic neurons. Peptides 1989, 10, 681–685. [Google Scholar] [CrossRef]
  387. Prasad, C. Modulation of striatal dopamine system by thyrotropin-releasing hormone and cyclo(His-Pro). In Basal Ganglia: Structure and Function II; Carpenter, M.B., Jayara-Man, A., Eds.; Plenum Publishing Co.: New York, NY, USA, 1987; pp. 155–168. [Google Scholar]
  388. Narumi, S.; Nagai, Y.; Saji, Y.; Nagawa, Y. A possible mechanism of action of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on the release of dopamine from the nucleus accumbens and striatum in rats. Jpn. J. Pharmacol. 1985, 39, 425–435. [Google Scholar] [CrossRef]
  389. Crocker, A.D.; Overstreet, D.H.; Crocker, J.M. Hypothyroidism leads to increased dopamine receptor sensitivity and concentration. Pharmacol. Biochem. Behav. 1986, 24, 1593–1597. [Google Scholar] [CrossRef]
  390. Bunney, B.S.; Achajanian, G.K. d-Amphetamine-induced inhibition of central dopaminergic neurons: Mediation by a striato-nigral feedback pathway. Science 1976, 192, 391–393. [Google Scholar] [CrossRef] [PubMed]
  391. Mitnick, M.; Reichlin, S. Enzymatic Synthesis of Thyrotropin-Releasing Hormone (TRH) by Hypothalamic “TRH Synthetase”. Endocrinology 1972, 91, 1145–1153. [Google Scholar] [CrossRef] [PubMed]
  392. Yu, Y.; Yang, W.; Dong, Z.; Wan, C.; Zhang, J.; Liu, J.; Xiao, K.; Huang, Y. Neurotransmitter and Receptor Changes in the Brains of Fetuses from Areas of Endemic Fluorosis. Chin. J. Endemiol. 1996, 15, 257–259. [Google Scholar]
  393. Ribeiro, C.P.; Mandel, L.J. Parathyroid hormone inhibits proximal tubule Na(+)-K(+)-ATPase activity. Am. J. Physiol. 1992, 262, F209–F216. [Google Scholar] [CrossRef]
  394. Zhang, Y.; Norian, J.M.; Magyar, C.E.; Holstein-Rathlou, N.H.; Mircheff, A.K.; McDonough, A.A. In vivo PTH provokes apical NHE3 and NaPi-2 redistribution and Na-K ATPase inhibition. Am. J. Physiol. 1999, 276, F711–F719. [Google Scholar] [PubMed]
  395. Khundmiri, S.J.; Dean, W.L.; McLeish, K.R.; Lederer, E.D. Parathyroid hormone-mediated regulation of Na+-K+-ATPase requires ERK-dependent translocation of protein kinase Calpha. J. Biol. Chem. 2005, 280, 8705–8713. [Google Scholar] [CrossRef]
  396. Khundmiri, S.J.; Weinman, E.J.; Steplock, D.; Cole, J.; Ahmad, A.; Baumann, P.D.; Barati, M.; Rane, M.J.; Lederer, E. Parathyroid hormone regulation of NA+, K+-ATPase requires the PDZ 1 domain of sodium hydrogen exchanger regulatory factor-1 in opossum kidney cells. J. Am. Soc. Nephrol. 2005, 16, 2598–2607. [Google Scholar] [CrossRef]
  397. Derrickson, B.H.; Mandel, L.J. Parathyroid hormone inhibits Na-K ATPase through Gq/G11and the calcium independent phospholipase A2. Am. J. Physiol. Ren. Physiol. 1997, 272, F781–F788. [Google Scholar] [CrossRef] [PubMed]
  398. Ribeiro, C.P.; Dubay, G.R.; Falck, J.R.; Mandel, L.J. Parathyroid hormone inhibits Na-K-ATPase through a cytochrome P-450 pathway. Am. J. Physiol. Ren. Fluid Electrolyte Physiol. 1994, 266, F497–F505. [Google Scholar] [CrossRef]
  399. Koroglu, B.K.; Ersoy, I.H.; Koroglu, M.; Balkarli, A.; Ersoy, S.; Varol, S.; Tamer, M.N. Serum parathyroid hormone levels in chronic endemic fluorosis. Biol. Trace Elem. Res. 2011, 143, 79–86. [Google Scholar] [CrossRef]
  400. Schwartz, P.; Madsen, J.C.; Rasmussen, A.Q.; Transbol, I.B.; Brown, E.M. Evidence for a role of intracellular stored parathyroid hormone in producing hysteresis of the PTH-Calcium relationship in normal humans. Clin. Endo Crinol. 1998, 48, 725–732. [Google Scholar] [CrossRef]
  401. Greene, D.A.; Lattimer, S.A.; Sima, A.F. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetes complications. N. Engl. J. Med. 1987, 316, 599–606. [Google Scholar]
  402. Winegrad, A.I. Does a common mechanism induce the diverse complications of diabetes? Diabetes 1987, 36, 396–406. [Google Scholar] [CrossRef] [PubMed]
  403. MacGregor, L.C.; Matschinsky, F.M. Altered retinal metabolism in diabetes: II. measurement of sodium-potassium ATPase and total sodium and potassium in individual retinal layers. J. Biol. Chem. 1986, 261, 4052–4058. [Google Scholar]
  404. Owada, S.; Larsson, O.; Arkhammar, P.; Katz, A.I.; Chibalin, A.V.; Berggren, P.O.; Bertorello, A.M. Glucose decreases Na+, K+-ATPase activity in pancreatic beta-cells. An effect mediated via Ca2+-independent phospholipase A2 and protein kinase C-dependent phosphorylation of the alpha-subunit. J. Biol. Chem. 1999, 274, 2000–2008. [Google Scholar] [CrossRef] [PubMed]
  405. Rivelli, J.F.; Amaiden, M.R.; Monesterolo, N.E.; Previtali, G.; Santander, V.S.; Fernandez, A.; Arce, C.A.; Casale, C.H. High glucose levels induce inhibition of Na, K-ATPase via stimulation of aldose reductase, formation of microtubules and formation of an acetylated tubulin/Na,K-ATPase complex. Int. J. Biochem. Cell Biol. 2012, 44, 1203–1213. [Google Scholar] [CrossRef]
  406. Xia, P.; Kramer, R.M.; King, G.L. Identification of the mechanism for the inhibition of Na+, K(+)-adenosine triphosphatase by hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2. J. Clin. Investig. 1995, 96, 733–740. [Google Scholar] [CrossRef]
  407. Trivedi, N.; Mithal, A.; Gupta, S.K.; Godbole, M.M. Reversible impairment of glucose tolerance in patients with endemic fluorosis. Diabetologia 1993, 36, 826–828. [Google Scholar] [CrossRef] [PubMed]
  408. Guan, Z.; Yang, P.; Yu, N.; Zhuang, Z. An Experimental study of blood biochemical diagnostic indices for chronic fluorosis. Fluoride 1989, 22, 108–111. [Google Scholar]
  409. Suketa, Y.; Asao, Y.; Kanamoto, Y.; Shakashita, T.; Okada, S. Changes in adrenal function as a possible mechanism for elevation of serum glucose by single large dose of fluoride. Toxicol. Appl. Pharmacol. 1985, 80, 199–205. [Google Scholar] [CrossRef]
  410. Rigalli, A.; Ballina, J.C.; Roveri, E.; Puche, R.C. Inhibitory effect of fluoride on the secretion of Insulin. Calcif. Tissue Int. 1990, 46, 333–338. [Google Scholar] [CrossRef]
  411. Grucka-Mamczar, E.; Birkner, E.; Kasperczyk, S.; Kasperczyk, A.; Chlubek, D.; Samujto, D.; Cegłowska, A. Lipid Balance in rats with fluoride-induced hyperglycemia. Fluoride 2004, 37, 195–200. [Google Scholar]
  412. McGown, E.L.; Suttie, J.W. Mechanism of fluoride-induced hyperglycemia in the Rat. Toxicol. Appl. Pharmacol. 1977, 40, 83–90. [Google Scholar] [CrossRef]
  413. Allmann, D.W.; Kleiner, H.S. Effect of NaF on Rat Tissue cAMP levels in vivo. Pharmacol. Ther. Dent. 1980, 5, 73–78. [Google Scholar] [PubMed]
  414. Grucka-Mamczar, E.; Birkner, E.; Zalejska-Fiolka, J.; Machoy, Z. Disturbances of kidney function in rats with fluoride-induced hyperglycemia after acute poisoning by fluoride. Fluoride 2005, 38, 48–51. [Google Scholar]
  415. Szymafiska, H.; Mandat, A.; Jaroszewicz-Heigelmann, H.; Szymadski, Z.; Holicki, M.; Neuman, Z.; Ruszkowska, A. The results of assorted investigations carried out in workers exposed to Fluorine compounds. Metabolism of Fluorine. Soc. Sci. Stetin. PWN Warszawa Poznafi 1982, 96–102. [Google Scholar]
  416. Chlubek, D.; Grucka-Mamczar, E.; Birkner, E.; Polaniak, R.; Stawiarska-Pieta, B.; Duliban, H. Activity of pancreatic antioxidative enzymes and malondialdehyde concentrations in rats with hyperglycemia caused by fluoride intoxication. J. Trace Elem. Med. Biol. 2003, 17, 57–60. [Google Scholar] [CrossRef]
  417. Rupal, A.V.; Dhrutigna, R.K.; Krutika, L.B.; Narasimhacharya, A.V.R.L. Therapeutic benefits of glibenclamide in fluoride intoxicated diabetic rats. Fluoride 2010, 43, 141–149. [Google Scholar]
  418. García-Montalvo, E.A.; Reyes-Pérez, H.; Del Razo, L.M. Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. Toxicology 2009, 263, 75–83. [Google Scholar] [CrossRef] [PubMed]
  419. Grucka-Mamczar, E.; Birkner, E.; Zalejska-Fiolka, J.; Machoy, Z.; Kasperczyk, S.; Blaszczyk, I. Influence of extended exposure to sodium fluoride and caffeine on the activity of carbohydrate metabolism enzymes in rat blood serum and liver. Fluoride 2007, 40, 62–66. [Google Scholar]
  420. Sakurai, T.; Suzuki, K.; Taki, T.; Suketa, V.T. The mechanism of changes in metabolism and transport of glucose caused by fluoride administration to rats. Fluoride 1993, 26, 210. [Google Scholar]
  421. Al Alam, N.; Kreydiyyeh, S.I. FTY720P inhibits hepatic Na+–K+ ATPase via S1PR2 and PGE2. Biochem. Cell Biol. 2016, 94, 371–377. [Google Scholar] [CrossRef]
  422. Al Alam, N.; Kreydiyyeh, S.I. Signaling pathway involved in the inhibitory effect of FTY720P on the Na+/K+ ATPase in HepG2 cells. J. Cell Commun. Signal. 2017, 11, 309–316. [Google Scholar] [CrossRef] [PubMed]
  423. Gutowska, I.; Baranowska-Bosiacka, I.; Siennicka, A.; Bakiewicz, M.; Machaliński, B.; Stachowska, E.; Chlube, D. Fluoride and generation of pro-inflammatory factors in human macrophages. Fluoride 2011, 44, 125–134. [Google Scholar]
  424. Gutowska, I.; Baranowska-Bosiacka, I.; Goschorska, M.; Kolasa, A.; Łukomska, A.; Jakubczyk, K.; Dec, K.; Chlubek, D. Fluoride as a factor initiating and potentiating inflammation in THP1 differentiated monocytes/macrophages. Toxicol. In Vitro 2015, 29, 1661–1668. [Google Scholar] [CrossRef] [PubMed]
  425. Kitazawa, M.; Shibata, Y.; Hashimoto, S.; Ohizumi, Y.; Yamakuni, T. Proinsulin C-peptide stimulates a PKC/IkappaB/NF-kappaB signaling pathwayto activate COX-2 gene transcription in Swiss 3T3 fibroblasts. J. Biochem. 2006, 139, 1083–1088. [Google Scholar] [CrossRef] [PubMed]
  426. Ke, J.; Long, X.; Liu, Y.; Zhang, Y.F.; Li, J.; Fang, W.; Meng, Q.G. Role of NF-kappaB in TNF-alpha-induced COX-2 expression in synovial fibroblasts from human TMJ. J. Dent. Res. 2007, 86, 363–367. [Google Scholar] [CrossRef]
  427. Stachowska, E.; Baśkiewicz-Masiuk, M.; Machaliński, B.; Rybicka, M.; Gutowska, I.; Bober, J.; Grymula, K.; Dziedziejko, V.; Chlubek, D. Sodium fluoride enhancement of monocyte differentiation via nuclear factor κB mechanism. Fluoride 2005, 38, 297–306. [Google Scholar]
  428. Tian, Y.; Huo, M.; Li, G.; Wang, J. Regulation of LPS-induced mRNA expression of pro-inflammatory cytokines via alteration of NF-κB activity in mouse peritoneal macrophages exposed to fluoride. Chemosphere 2016, 161, 89–95. [Google Scholar] [CrossRef] [PubMed]
  429. Refsnes, M.; Skuland, T.; Låg, M.; Schwarze, P.E.; Øvrevik, J. Differential NF-κB and MAPK activation underlies fluoride- and TPA-mediated CXCL8 (IL-8) induction in lung epithelial cells. J. Inflamm. Res. 2014, 7, 169–185. [Google Scholar] [CrossRef] [PubMed][Green Version]
  430. Luo, Q.; Cui, H.; Deng, H.; Kuang, P.; Liu, H.; Lu, Y.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; et al. Sodium fluoride induces renal inflammatory responses by activating NF-κB signaling pathway and reducing anti-inflammatory cytokine expression in mice. Oncotarget 2017, 8, 80192–80207. [Google Scholar] [CrossRef] [PubMed][Green Version]
  431. Thangapandiyan, S.; Miltonprabu, S. Epigallocatechin gallate supplementation protects against renal injury induced by fluoride intoxication in rats: Role of Nrf2/HO-1 signaling. Toxicol. Rep. 2014, 1, 12–30. [Google Scholar] [CrossRef][Green Version]
  432. Deng, H.; Kuang, P.; Cui, H.; Luo, Q.; Liu, H.; Lu, Y.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; et al. Sodium fluoride induces apoptosis in mouse splenocytes by activating ROS-dependent NF-κB signalling. Oncotarget 2017, 8, 114428–114441. [Google Scholar] [CrossRef] [PubMed]
  433. Zhang, M.; Wang, A.; Xia, T.; He, P. Effects of fluoride on DNA damage, S-phase cell-cycle arrest and the expression of NF-kappaB in primary cultured rat hippocampal neurons. Toxicol. Lett. 2008, 179, 1–5. [Google Scholar] [CrossRef] [PubMed]
  434. Zhang, J.; Zhu, W.J.; Xu, X.H.; Zhang, Z.G. Effect of fluoride on calcium ion concentration and expression of nuclear transcription factor kappa-B ρ65 in rat hippocampus. Exp. Toxicol. Pathol. 2011, 63, 407–411. [Google Scholar] [CrossRef] [PubMed]
  435. Misra, U.K.; Gawdi, G.; Pizzo, S.V. Beryllium fluoride-induced cell proliferation: A process requiring P21(ras)-dependent activated signal transduction and NF-kappaB-dependent gene regulation. J. Leukoc. Biol. 2002, 71, 487–494. [Google Scholar]
  436. Abdulrazzaq, Y.M.; Osman, N.; Nagelkerke, N.; Kosanovic, M.; Adem, A. Trace element composition of plasma and breast milk of well-nourished women. J. Environ. Sci. Health A Toxicol. Hazard. Subst. Environ. Eng. 2008, 43, 329–334. [Google Scholar] [CrossRef]
  437. Ikem, A.; Nwankwoala, A.; Odueyungbo, S.; Nyavora, K.; Egiebora, N. Levels of 26 elements in infant formula from USA, UK, and Nigeria by microwave digestion and ICP–OES. Food Chem. 2002, 77, 439–447. [Google Scholar] [CrossRef]
  438. Combeau, C.; Carlier, M.F. Characterization of the Aluminum and Beryllium Fluoride Species Bound to F-actin and Microtubules at the Site of the y-Phosphate of the Nucleotide. J. Biol. Chem. 1989, 264, 1907–19021. [Google Scholar]
  439. Antonny, B.; Chabre, M. Characterization of the aluminum and beryllium fluoride species which activate transducin. Analysis of the binding and dissociation kinetics. J. Biol. Chem. 1992, 267, 6710–6718. [Google Scholar] [PubMed]
  440. Bigay, J.; Deterre, P.; Pfister, C.; Chabre, M. Fluoride complexes of aluminium or beryllium act on G-proteins as reversibly bound analogues of the gamma phosphate of GTP. EMBO J. 1987, 6, 2907–2913. [Google Scholar] [CrossRef] [PubMed]
  441. Chabre, M. Aluminofluoride and beryllofluoride complexes: A new phosphate analogs in enzymology. Trends Biochem. Sci. 1990, 15, 6–10. [Google Scholar] [CrossRef]
  442. Pietkiewicz, J.; Gamian, A.; Staniszewska, M.; Danielewicz, R. Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products. J. Enzyme Inhib. Med. Chem. 2009, 24, 356–364. [Google Scholar] [CrossRef] [PubMed][Green Version]
  443. Gallicchio, M.A.; Bach, L.A. Advanced glycation end products inhibit Na+ K+ ATPase in proximal tubule epithelial cells: Role of cytosolic phospholipase A2alpha and phosphatidylinositol 4-phosphate 5-kinase gamma. Biochim. Biophys. Acta 2010, 1803, 919–930. [Google Scholar] [CrossRef] [PubMed]
  444. Zhang, K.L.; Lou, D.D.; Guan, Z.Z. Activation of the AGE/RAGE system in the brains of rats and in SH-SY5Y cells exposed to high level of fluoride might connect to oxidative stress. Neurotoxicol. Teratol. 2015, 48, 49–55. [Google Scholar] [CrossRef] [PubMed]
  445. Hashemi, M.; Kordi-Tamandani, D.M.; Sharifi, N.; Moazeni-Roodi, A.; Kaykhaei, M.A.; Narouie, B.; Torkmanzehi, A. Serum paraoxonase and arylesterase activities in metabolic syndrome in Zahedan, southeast Iran. Eur. J. Endocrinol. 2011, 164, 219–222. [Google Scholar] [CrossRef][Green Version]
  446. Pavlov, V.A.; Ochani, M.; Gallowitsch-Puerta, M.; Ochani, K.; Huston, J.M.; Czura, C.J.; Al-Abed, Y.; Tracey, K.J. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc. Natl. Acad. Sci. USA 2006, 103, 5219–5223. [Google Scholar] [CrossRef][Green Version]
  447. Mabley, J.G.; Pacher, P.; Szabo, C. Activation of the cholinergic anti-inflammatory pathway reduces ricin-induced mortality and organ failure in mice. Mol. Med. 2009, 15, 166–172. [Google Scholar] [CrossRef]
  448. Søyseth, V.; Kongerud, J.; Broen, P.; Lilleng, P.; Boe, J. Bronchial responsiveness, eosinophilia, and short term exposure to air pollution. Arch. Dis. Child. 1995, 73, 418–422. [Google Scholar] [CrossRef]
  449. Søyseth, V.; Kongerud, J.; Ekstrand, J.; Boe, J. Relation between exposure to fluoride and bronchial responsiveness in aluminium potroom workers with work-related asthma-like symptoms. Thorax 1994, 49, 984–989. [Google Scholar] [CrossRef]
  450. Van Schoor, J.; Joos, G.F.; Pauwels, R.A. Indirect bronchial hyperresponsiveness in asthma:mechanisms, pharmacology and implications for clinical research. Eur. Respir. J. 2000, 16, 514–533. [Google Scholar] [CrossRef] [PubMed]
  451. Burrows, B.; Sears, M.R.; Flannery, E.M.; Herbison, G.P.; Holdaway, D. Relationships of bronchial responsiveness assessed by methacholine to serum IgE, lung function, symptoms, and diagnoses in 11-year-old New Zealand children. J. Allergy Clin. Immunol. 1992, 90, 376–385. [Google Scholar] [CrossRef]
  452. Joos, G.F.; O’Connor, B.; Anderson, S.D.; Chung, F.; Cockcoft, D.W.; Dahlen, B.; Di Maria, G.; Foresi, A.; Hargreave, F.E.; Holgate, S.T.; et al. Indirect airway challenges. Eur. Respir. J. 2003, 21, 1050–1068. [Google Scholar] [CrossRef] [PubMed][Green Version]
  453. Anderson, S.D.; Brannan, J.D. Methods for “indirect” challenge tests including exercise, eucapnic voluntary hyperpnes, and hypertonic aerolos. Clin. Rev. Allergy Immunol. 2003, 24, 27–54. [Google Scholar] [CrossRef]
  454. Nielson, K.G. Lung Function and bronchial responsiveness in young children. Dan Med. Bull. 2006, 53, 46–75. [Google Scholar]
  455. Rijchen, B.; Schouten, J.P.; Weiss, S.T.; Speizer, F.E.; Van der Lende, R. The relationship between airways responsiveness to histamine and pulmonary function level in a random population sample. Bull. Eur. Physiopathol. Respir. 1987, 23, 391–394. [Google Scholar] [CrossRef]
  456. Kongerud, J.; Soyseth, V. Methacholine responsiveness, respiratory symptoms and pulmonary function in aluminium potroom workers. Eur. Respir. J. 1991, 4, 159–166. [Google Scholar] [PubMed]
  457. Joseph-Bowen, J.; de Klerk, N.H.; Firth, M.J.; Kendall, G.E.; Holt, P.G.; Sly, P.D. Lung Function, Bronchial Responsiveness, and Asthma in a Community Cohort of 6-Year-Old Children. Am. J. Respir. Crit. Care Med. 2004, 169, 850–854. [Google Scholar] [CrossRef]
  458. Adinolfi, M. The development of the human blood-CSF-brain barrier. Dev. Med. Child Neurol. 1985, 27, 532–537. [Google Scholar] [CrossRef] [PubMed]
  459. Johanson, C.E. Permeability and vascularity of the developing brain: Cerebellum vs. cerebral cortex. Brain Res. 1980, 190, 3–16. [Google Scholar] [CrossRef]
  460. Sullivan, J.L.; Newton, R.B. Serum antioxidant activity in neonates. Arch. Dis. Child. 1988, 63, 748–750. [Google Scholar] [CrossRef]
  461. Gutteridge, J.M.C.; Stocks, J. Cacruloplasmin: Physiological and pathological perspectives. Crit. Rev. Clin. Lab. Sci. 1981, 14, 257–329. [Google Scholar] [CrossRef] [PubMed]
  462. National Research Council. Pesticides in the Diets of Infants and Children; National Academy Press: Washington, DC, USA, 1993. [Google Scholar]
  463. Dourson, M.; Charnley, G.; Scheuplein, R. Differential sensitivity of children and adults to chemical toxicity. II. Risk and regulation. Regul. Toxicol. Pharmacol. 2002, 35, 448–467. [Google Scholar] [CrossRef]
  464. Naik, U.S.; Gangadharan, C.; Abbagani, K.; Nagalla, B.; Dasari, N.; Manna, S.K. A study of nuclear transcription factor-kappa B in childhood autism. PLoS ONE 2011, 6, e19488. [Google Scholar] [CrossRef] [PubMed]
  465. Young, A.M.; Campbell, E.; Lynch, S.; Suckling, J.; Powis, S.J. Aberrant NF-kappaB expression in autism spectrum condition: A mechanism for neuroinflammation. Front. Psychiatry 2011, 2, 27. [Google Scholar] [CrossRef] [PubMed]
  466. Abdel-Salam, O.M.E.; Youness, E.R.; Mohammed, N.A.; Elhamed, W.A.A. Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children. Open J. Mol. Integr. Physiol. 2015, 5, 18–27. [Google Scholar] [CrossRef]
  467. Ghanizadeh, A. Nuclear factor kappa B may increase insight into the management of neuroinflammation and excitotoxicity in autism. Expert Opin. Ther. Targets 2011, 15, 781–783. [Google Scholar] [CrossRef] [PubMed]
  468. Feng, Y.; Li, X.; Zhou, W.; Lou, D.; Huang, D.; Li, Y.; Kang, Y.; Xiang, Y.; Li, T. Regulation of set gene expression by NF-κB. Mol. Neurobiol. 2016, 54, 4477–4485. [Google Scholar] [CrossRef]
  469. Lukiw, W.J.; Bazan, N.G. Strong nuclear factor-κB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer’s disease superior temporal lobe neocortex. J. Neurosci. Res. 1998, 53, 583–592. [Google Scholar] [CrossRef]
  470. Boissiere, F.; Hunot, S.; Faucheux, B.; Duyckaerts, C.; Hauw, J.J.; Agid, Y.; Hirsch, E.C. Nuclear translocation of NF-κB in cholinergic neurons of patients with Alzheimer’s disease. Neuroreport 1997, 8, 2849–2852. [Google Scholar] [CrossRef]
  471. Akiyama, H.; Nishimura, T.; Kondo, H.; Ikeda, K.; Hayashi, Y.; McGeer, P.L. Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upregulation in brains of patients with Alzheimer’s disease and amyotrophic lateral sclerosis. Brain Res. 1994, 639, 171–174. [Google Scholar] [CrossRef]
  472. Hunot, S.; Brugg, B.; Ricard, D.; Michel, P.P.; Muriel, M.P.; Ruberg, M.; Faucheux, B.A.; Agid, Y.; Hirsch, E.C. Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease. Proc. Natl. Acad. Sci. USA 1997, 94, 7531–7536. [Google Scholar] [CrossRef] [PubMed]
  473. Block, M.L.; Hong, J.S. Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Prog. Neurobiol. 2005, 76, 77–98. [Google Scholar] [CrossRef][Green Version]
  474. Edwards, M.R.; Bartlett, N.W.; Clarke, D.; Birrell, M.; Belvisi, M.; Johnston, S.L. Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol. Ther. 2009, 121, 1–13. [Google Scholar] [CrossRef] [PubMed]
  475. Barnes, P.J.; Karin, M. Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 1997, 336, 1066–1071. [Google Scholar] [CrossRef] [PubMed]
  476. ISSAC Steering Committee. Worldwide variations in the prevalence of asthma symptoms: The International Study of Asthma and Allergies in Childhood (ISAAC). Eur. Respir. J. 1998, 12, 315–335. [Google Scholar] [CrossRef]
  477. Lai, C.K.W.; Beasley, R.; Crane, J.; Foliaki, S.; Shah, J.; Weiland, S.; The ISAAC Phase Three Study Group. Global variation in the prevalence and severity of asthma symptoms: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2009, 64, 476–483. [Google Scholar] [CrossRef]
  478. Burney, P.G.J.; Luczynska, C.; Chinn, S.; Jarvis, D. The European Community Respiratory Health Survey. Eur. Respir. J. 1994, 7, 954–960. [Google Scholar] [CrossRef][Green Version]
  479. European Community Respiratory Health Survey (ECRHS). Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur. Respir. J. 1996, 9, 687–695. [Google Scholar] [CrossRef][Green Version]
  480. Australian Institute of Health and Welfare. Australian National Infant Feeding Survey: Indicator Results; Cat. no. PHE 156; AIHW: Canberra, Australia, 2010. Available online: http://www.aihw.gov.au/publication-detail/?id=10737420927 (accessed on 19 March 2019).
  481. The longitudinal Study of Australian Children 2006–2007 Annual Report. Available online: https://growingupinaustralia.gov.au/sites/default/files/annualreport2006-07.pdf (accessed on 19 March 2019).
  482. OECD Family Database, CO1.5: Breastfeeding Rates. 2009. Available online: https://www.oecd.org/els/family/43136964.pdf (accessed on 15 March 2019).
  483. O’Donovan, S.M.; Murray, D.M.; Hourihane, J.B.; Kenny, L.C.; Irvine, A.D.; Kiely, M. Adherence with early infant feeding and complementary feeding guidelines in the Cork BASELINE Birth Cohort Study. Public Health Nutr. 2015, 18, 2864–2873. [Google Scholar] [CrossRef][Green Version]
  484. New Zealand’s Breastfeeding Rates—Statistics from Breastfeeding: A Guide to Action; New Zealand Ministry of Health: Wellington, New Zealand, 2002. Available online: https://www.health.govt.nz/system/files/documents/publications/breastfeeding.pdf (accessed on 15 January 2019).
  485. Centers for Disease Control and Prevention. Racial and Ethnic Differences in Breastfeeding Initiation and Duration, by State National Immunization Survey, United States. 2004—2008. Available online: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5911a2.htm (accessed on 15 January 2019). [Google Scholar]
  486. Williams, H.; McNicol, K.N. Prevalence, natural history and relationship of wheezy bronchitis and asthma in children. An epidemiological study. Br. Med. J. 1969, 4, 321–325. [Google Scholar] [CrossRef] [PubMed]
  487. Akinbami, L.J.; Moorman, J.E.; Garbe, P.L.; Sondik, E.J. Status of Childhood Asthma in the United States, 1980–2007. Pediatrics 2009, 123, S131–S145. [Google Scholar] [CrossRef] [PubMed]
  488. Greally, P. Childhood Asthma: Prevalence and Presentation. Continuing Education Module 19: Child Health. WIN. 2012. Available online: https://www.inmo.ie/tempDocs/ChildHlth-Asthma%20PAGE41-42.pdf (accessed on 19 March 2019).
  489. Masoli, M.; Fabian, D.; Holt, S.; Beasley, R.; Global Initiative for Asthma (GINA) Program. The global burden of asthma: Executive summary of the GINA Dissemination Committee report. Allergy 2004, 59, 469–478. [Google Scholar] [CrossRef]
  490. Whelton, H.; Crowley, E.; O’Mullane, D.; Donaldson, M.; Kelleher, V.; Cronin, M. Dental caries and enamel fluorosis among the fluoridated and non-fluoridated populations in the Republic of Ireland in 2002. Community Dent. Health 2004, 21, 37–44. [Google Scholar]
  491. NCHS Data Brief Number 53, November 2010, Prevalence and Severity of Dental Fluorosis in the United States. 1999–2004. Available online: http://www.cdc.gov/nchs/data/databriefs/db53.htm (accessed on 19 January 2019).
  492. Do, L.G.; Spencer, A.J. Decline in the prevalence of dental fluorosis among South Australian children. Community Dent. Oral Epidemiol. 2007, 35, 282–291. [Google Scholar] [CrossRef]
  493. Obry-Musset, A.M. Epidemiology of dental caries in children. Arch. Pediatr. 1998, 5, 1145–1148. [Google Scholar] [CrossRef]
  494. Momeni, A.; Neuhäuser, A.; Renner, N.; Heinzel-Gutenbrunner, M.; Abou-Fidah, J.; Rasch, K.; Kröplin, M.; Fejerskov, O.; Pieper, K. Prevalence of dental fluorosis in German school children in areas with different preventive programmes. Caries Res. 2007, 41, 437–444. [Google Scholar] [CrossRef]
  495. Trabelsi, M.; Guermazi, F.; Zeghal, N. Effect of fluoride on thyroid function and cerebellar development in mice. Fluoride 2001, 34, 165–173. [Google Scholar]
  496. Bouaziz, H.; Ammar, E.; Ghorbel, H.; Ketata, S.; Jamoussi, K.; Ayadi, F.; Guermazi, F.; Zeghal, N. Effect of fluoride ingested by lactating mice on the thyroid function and bone maturation of their suckling pups. Fluoride 2004, 37, 133–142. [Google Scholar]
  497. Bouaziz, H.; Soussia, L.; Guermazi, F.; Zeghal, N. Fluoride-induced thyroid proliferative changes and their reversal in female mice and their pups. Fluoride 2005, 38, 185–192. [Google Scholar]
  498. Sun, Z.; Zhang, Y.; Xue, X.; Niu, R.; Wang, J. Maternal fluoride exposure during gestation and lactation decreased learning and memory ability, and glutamate receptor mRNA expressions of mouse pups. Hum. Exp. Toxicol. 2018, 37, 87–93. [Google Scholar] [CrossRef]
  499. Blaylock, R.L. Excitotoxicity: A possible central mechanism in fluoride neurotoxicity. Fluoride 2004, 37, 301–314. [Google Scholar]
  500. Dong, Y.T.; Wang, Y.; Wei, N.; Zhang, Q.F.; Guan, Z.Z. Deficit in learning and memory of rats with chronic fluorosis correlates with the decreased expressions of M1 and M3 muscarinic acetylcholine receptors. Arch. Toxicol. 2015, 89, 1981–1991. [Google Scholar] [CrossRef]
  501. Dong, Y.T.; Wei, N.; Qi, A.L.; Liu, X.H.; Chen, D.; Zeng, A.A.; Guan, Z.Z. Attenuating effect of Vitamin E on the deficit of learning and memory of rats with chronic fluorosis: The mechanism may involve Muscarinic Acetylcholine Receptors. Fluoride 2017, 50, 354–364. [Google Scholar]
  502. Raedler, T.J.; Bymaster, F.P.; Tandon, R.; Copolov, D.; Dean, B. Towards a muscarinic hypothesis of schizophrenia. Mol. Psychiatry 2007, 12, 232–246. [Google Scholar] [CrossRef]
  503. Gibbons, A.S.; Scarr, E.; McLean, C.; Sundram, S.; Dean, B. Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects. J. Affect. Disord. 2008, 116, 184–191. [Google Scholar] [CrossRef]
  504. Medeiros, R.; Kitazawa, M.; Caccamo, A.; Baglietto-Vargas, D.; Estrada-Hernandez, T.; Cribbs, D.H.; Fisher, A.; LaFerla, F.M. Loss of Muscarinic M1 Receptor Exacerbates Alzheimer’s Disease–Like Pathology and Cognitive Decline. Am. J. Pathol. 2011, 179, 980–991. [Google Scholar] [CrossRef]
  505. Miyakawa, T.; Yamada, M.; Duttaroy, A.; Wess, J. Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor. J. Neurosci. 2001, 21, 5239–5250. [Google Scholar] [CrossRef] [PubMed]
  506. Gautam, D.; Han, S.J.; Hamdan, F.F.; Jeon, J.; Li, B.; Li, J.H.; Cui, Y.; Mears, D.; Lu, H.; Deng, C.; et al. A critical role for β cell M3muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab. 2006, 3, 449–461. [Google Scholar] [CrossRef] [PubMed]
  507. Smit, B.J.; Kok, J.H.; Vulsma, T.; Briet, J.M.; Boer, K.; Wiersinga, W.M. Neurologic development of the newborn and young child in relation to maternal thyroid function. Acta Paediatr. 2000, 89, 291–295. [Google Scholar] [CrossRef] [PubMed]
  508. Glinoer, D.; Delange, F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid 2000, 10, 871–887. [Google Scholar] [CrossRef] [PubMed]
  509. Willoughby, K.A.; McAndrews, M.P.; Rovet, J.F. Effects of Maternal Hypothyroidism on Offspring Hippocampus and Memory. Thyroid 2014, 24, 576–584. [Google Scholar] [CrossRef] [PubMed]
  510. Gillberg, I.C.; Gillberg, C.; Kopp, S. Hypothyroidism and autism spectrum disorders. J. Child Psychol. Psychiatry 1992, 33, 531–542. [Google Scholar] [CrossRef]
  511. Vermiglio, F.; Lo Presti, V.P.; Moleti, M.; Sidoti, M.; Tortorella, G.; Scaffidi, G.; Castagna, M.G.; Mattina, F.; Violi, M.A.; Crisà, A.; et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: A possible novel iodine deficiency disorder in developed countries. J. Clin. Endocrinol. Metab. 2004, 89, 6054–6060. [Google Scholar] [CrossRef] [PubMed]
  512. Instanes, J.T.; Halmøy, A.; Engeland, A.; Haavik, J.; Furu, K.; Klungsøyr, K. Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers with Inflammatory and Immune System Diseases. Biol. Psychiatry 2017, 81, 452–459. [Google Scholar] [CrossRef] [PubMed]
  513. Abel, M.H.; Ystrom, E.; Caspersen, I.H.; Meltzer, H.M.; Aase, H.; Torheim, L.E.; Askeland, R.B.; Reichborn-Kjennerud, T.; Brantsæter, A.L. Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study. Nutrients 2017, 9, 1239. [Google Scholar] [CrossRef] [PubMed]
  514. Getahun, D.; Jacobsen, S.J.; Fassett, M.J.; Wing, D.A.; Xiang, A.H.; Chiu, V.Y.; Peltier, M.R. Association between maternal hypothyroidism and autism spectrum disorders in children. Pediatr. Res. 2018, 83, 580–588. [Google Scholar] [CrossRef] [PubMed]
  515. Andersen, S.L.; Laurberg, P.; Wu, C.S.; Olsen, J. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: A Danish nationwide cohort study. Int. J. Obstet. Gynaecol. 2014, 121, 1365–1374. [Google Scholar] [CrossRef]
  516. Gyllenberg, D.; Sourander, A.; Surcel, H.M.; Hinkka-Yli-Salomäki, S.; McKeague, I.W.; Brown, A.S. Hypothyroxinemia During Gestation and Offspring Schizophrenia in a National Birth Cohort. Biol. Psychiatry 2016, 79, 962–970. [Google Scholar] [CrossRef] [PubMed]
  517. Andersen, S.L.; Laurberg, P.; Wu, C.S.; Olsen, J. Maternal Thyroid Dysfunction and Risk of Seizure in the Child: A Danish Nationwide Cohort Study. J. Pregnancy 2013, 2013, 636705. [Google Scholar] [CrossRef]
  518. Liu, X.; Andersen, S.L.; Olsen, J.; Agerbo, E.; Schlünssen, V.; Dharmage, S.C.; Munk-Olsen, T. Maternal hypothyroidism in the perinatal period and childhood asthma in the offspring. Allergy 2018, 73, 932–939. [Google Scholar] [CrossRef]
  519. Aydin, G.; Ciçek, E.; Akdoğan, M.; Gökalp, O. Histopathological and biochemical changes in lung tissues of rats following administration of fluoride over several generations. J. Appl. Toxicol. 2003, 23, 437–446. [Google Scholar] [CrossRef] [PubMed]
  520. Karaoz, E.; Oncu, M.; Gulle, K.; Kanter, M.; Gultekin, F.; Karaoz, S.; Mumcu, E. Effect of chronic fluorosis on lipid peroxidation and histology of kidney tissues in first- and second-generation rats. Biol. Trace Elem. Res. 2004, 102, 199–208. [Google Scholar] [CrossRef]
  521. Oncu, M.; Gulle, K.; Karaoz, E.; Gultekin, F.; Karaoz, S.; Karakoyun, I.; Mumcu, E. Effect of chronic fluorosis on lipid peroxidation and histology of lung tissues in first and second generation rats. Toxicol. Ind. Health 2006, 22, 375–380. [Google Scholar] [CrossRef] [PubMed]
  522. Oncü, M.; Kocak, A.; Karaoz, E.; Darici, H.; Savik, E.; Gultekin, F. Effect of long-term fluoride exposure on lipid peroxidation and histology of testes in first- and second-generation rats. Biol. Trace Elem. Res. 2007, 118, 260–268. [Google Scholar] [CrossRef] [PubMed]
  523. Aluru, N.; Karchner, S.I.; Glazer, L. Early Life Exposure to Low Levels of AHR Agonist PCB126 (3,3′,4,4′,5-Pentachlorobiphenyl) Reprograms Gene Expression in Adult Brain. Toxicol. Sci. 2017, 160, 386–397. [Google Scholar] [CrossRef] [PubMed][Green Version]
  524. Stankiewicz, A.M.; Swiergiel, A.H.; Lisowski, P. Epigenetics of stress adaptations in the brain. Brain Res. Bull. 2013, 98, 76–92. [Google Scholar] [CrossRef][Green Version]
  525. Bravo, J.A.; Dinan, T.G.; Cryan, J.F. Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain. Front. Mol. Neurosci. 2014, 7, 24. [Google Scholar] [CrossRef]
  526. Mpofana, T.; Daniels, W.M.; Mabandla, M.V. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model. Parkinsons Dis. 2016, 2016, 6438783. [Google Scholar] [CrossRef]
  527. Cohen, S.; Janicki-Deverts, D.; Doyle, W.; Miller, G.E.; Frank, E.; Rabin, B.S.; Turner, R.B. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc. Natl. Acad. Sci. USA 2012, 109, 5995–5999. [Google Scholar] [CrossRef][Green Version]
  528. Liu, J.; Xia, T.; Zhang, M.; He, W.; He, P.; Chen, X.; Yang, K.; Wang, A. Screening of Environmental Response Genes Related to Dental Fluorosis. Fluoride 2006, 39, 195–201. [Google Scholar]
  529. Swift, R.G.; Polymeropoulos, M.H.; Torres, R.; Swift, M. Predisposition of Wolfram syndrome heterozygotes to psychiatric illness. Mol. Psychiatry 1998, 3, 86–91. [Google Scholar] [CrossRef] [PubMed][Green Version]
  530. Swift, M.; Swift, R.G. Psychiatric disorders and mutations at the Wolfram syndrome locus. Biol. Psychiatry 2000, 47, 787–793. [Google Scholar] [CrossRef]
  531. Swift, M.; Swift, R.G. Wolframin mutations and hospitalization for psychiatric illness. Mol. Psychiatry 2005, 10, 799–803. [Google Scholar] [CrossRef] [PubMed][Green Version]
  532. Harding, H.P.; Ron, D. Endoplasmic reticulum stress and the development of diabetes: A review. Diabetes 2002, 51, S455–S461. [Google Scholar] [CrossRef] [PubMed]
  533. Rohayem, J.; Ehlers, C.; Wiedemann, B.; Holl, R.; Oexle, K.; Kordonouri, O.; Salzano, G.; Meissner, T.; Burger, W.; Schober, E.; et al. Diabetes and neurodegeneration in Wolfram syndrome: A multicenter study of phenotype and genotype. Diabetes Care 2011, 34, 1503–1510. [Google Scholar] [CrossRef] [PubMed]
  534. Mayer-Davis, E.J.; Dabelea, D.; Lawrence, J.M. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002–2012. N. Engl. J. Med. 2017, 377, 301. [Google Scholar] [CrossRef] [PubMed]
  535. Neurath, C.; Limeback, H.; Osmunson, B.; Connett, M.; Kanter, V.; Wells, C.R. Dental Fluorosis Trends in US Oral Health Surveys: 1986 to 2012. JDR Clin. Transl. Res. 2019. [Google Scholar] [CrossRef] [PubMed]
  536. Wiener, R.C.; Shen, C.; Findley, P.; Tan, X.; Sambamoorthi, U. Dental Fluorosis over Time: A comparison of National Health and Nutrition Examination Survey data from 2001–2002 and 2011–2012. J. Dent. Hyg. 2018, 92, 23–29. [Google Scholar]
  537. Chafe, R.; Aslanov, R.; Sarkar, A.; Gregory, P.; Comeau, A.; Newhook, L.A. Association of type 1 diabetes and concentrations of drinking water components in Newfoundland and Labrador, Canada. BMJ Open Diabetes Res. Care 2018, 6, e000466. [Google Scholar] [CrossRef] [PubMed][Green Version]
  538. Fluegge, K. Community water fluoridation predicts increase in age-adjusted incidence and prevalence of diabetes in 22 states from 2005 and 2010. J. Water Health 2016, 14, 864–877. [Google Scholar] [CrossRef][Green Version]
  539. Harding, H.P.; Zeng, H.; Zhang, Y.; Jungries, R.; Chung, P.; Plesken, H.; Sabatini, D.D.; Ron, D. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/-mice reveals a role for translational control in secretory cell survival. Mol. Cell. 2001, 7, 1153–1163. [Google Scholar] [CrossRef]
  540. Mathers, C.; Loncar, D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006, 28, e442. [Google Scholar] [CrossRef] [PubMed]
  541. Jemal, A.; Ward, E.; Hao, Y.; Thun, M. Trends in the leading causes of death in the United States, 1970–2002. JAMA 2005, 294, 1255–1259. [Google Scholar] [CrossRef]
  542. OECD. Health at a Glance 2011; OECD Indicators, Ed.; OECD Publishing: Paris, France, 2011; Available online: https://www.oecd.org/els/health-systems/49105858.pdf (accessed on 22 January 2019).
  543. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed]
  544. Global Cancer Data by Country; World Cancer Research Fund, American Institute for Cancer Research: Washington, DC, USA, 2018; Available online: https://www.wcrf.org/dietandcancer/cancer-trends/data-cancer-frequency-country (accessed on 22 January 2019).
  545. Malfatti, C.R.; Burgos, L.T.; Rieger, A.; Rüdger, C.L.; Túrmina, J.A.; Pereira, R.A.; Pavlak, J.L.; Silva, L.A.; Osiecki, R. Decreased erythrocyte NA+, K+-ATPase activity and increased plasma TBARS in prehypertensive patients. Sci. World J. 2012, 2012, 348246. [Google Scholar] [CrossRef]
  546. Sun, L.; Gao, Y.; Liu, H.; Zhang, W.; Ding, Y.; Li, B.; Li, M.; Sun, D. An assessment of the relationship between excess fluoride intake from drinking water and essential hypertension in adults residing in fluoride endemic areas. Sci. Total Environ. 2013, 443, 864–869. [Google Scholar] [CrossRef]
  547. Haghighat, G.A.; Yunesian, M.; Amini, H. Hypertension and drinking water fluoride? Is there a relationship? Fluoride 2012, 45 Pt 1, 167. [Google Scholar]
  548. Tomar, S.; Mishra, S.; Choudhary, M.; Chauhan, D.S.; Yadav, P.; Singh, V.P.; Joshi, D.K.; Tripathi, S.; Tomar, S.; Tomar, A. Increased oxidative burden in hypertensive retinopathy patients and its association with fluoride exposure in population of Rajasthan India. Fluoride 2012, 45, 207–208. [Google Scholar]
  549. Amini, H.; Taghavi Shahri, S.M.; Amini, M.; Ramezani Mehrian, M.; Mokhayeri, Y.; Yunesian, M. Drinking water fluoride and blood pressure? An environmental study. Biol. Trace Elem. Res. 2011, 144, 157–163. [Google Scholar] [CrossRef]
  550. Singh, K.P.; Dash, R.J.; Varma, J.S.; Singh, M.; Gauba, K.; Dhillon, M.S. Incidence of cardiovascular abnormalities in endemic skeletal fluorosis. Fluoride 1998, 31, S22. [Google Scholar]
  551. Bera, I.; Sabatini, R.; Auteri, P.; Flace, P.; Sisto, G.; Montagnani, M.; Potenza, M.A.; Marasciulo, F.L.; Carratu, M.R.; Coluccia, A.; et al. Neurofunctional effects of developmental sodium fluoride exposure in rats. Eur. Rev. Med. Pharmacol. Sci. 2007, 11, 211–224. [Google Scholar] [PubMed]
  552. Omóbòwálé, T.O.; Oyagbemi, A.A.; Alaba, B.A.; Ola-Davies, O.E.; Adejumobi, O.A.; Asenuga, E.R.; Ajibade, T.O.; Adedapo, A.A.; Yakubu, M.A. Ameliorative effect of Azadirachta indica on sodium fluoride-induced hypertension through improvement of antioxidant defence system and upregulation of extracellular signal regulated kinase 1/2 signaling. J. Basic Clin. Physiol. Pharmacol. 2018, 29, 155–164. [Google Scholar] [CrossRef]
  553. Oyagbemi, A.A.; Omobowale, T.O.; Asenuga, E.R.; Adejumobi, A.O.; Ajibade, T.O.; Ige, T.M.; Ogunpolu, B.S.; Adedapo, A.A.; Yakubu, M.A. Sodium fluoride induces hypertension and cardiac complications through generation of reactive oxygen species and activation of nuclear factor kappa beta. Environ. Toxicol. 2017, 32, 1089–1101. [Google Scholar] [CrossRef] [PubMed]
  554. Oyagbemi, A.A.; Omobowale, T.O.; Ola-Davies, O.E.; Asenuga, E.R.; Ajibade, T.O.; Adejumobi, O.A.; Arojojoye, O.A.; Afolabi, J.M.; Ogunpolu, B.S.; Falayi, O.O.; et al. Quercetin attenuates hypertension induced by sodium fluoride via reduction in oxidative stress and modulation of HSP 70/ERK/PPARγ signaling pathways. Biofactors 2018, 44, 465–479. [Google Scholar] [CrossRef]
  555. Oyagbemi, A.A.; Omobowale, T.O.; Ola-Davies, O.E.; Asenuga, E.R.; Ajibade, T.O.; Adejumobi, O.A.; Afolabi, J.M.; Ogunpolu, B.S.; Falayi, O.O.; Saba, A.B.; et al. Luteolin-mediated Kim-1/NF-kB/Nrf2 signaling pathways protects sodium fluoride-induced hypertension and cardiovascular complications. Biofactors 2018, 44, 518–531. [Google Scholar] [CrossRef]
  556. Oyagbemi, A.A.; Omobowale, T.O.; Ola-Davies, O.E.; Asenuga, E.R.; Ajibade, T.O.; Adejumobi, O.A.; Afolabi, J.M.; Ogunpolu, B.S.; Falayi, O.O.; Ayodeji, F.; et al. Ameliorative effect of Rutin on sodium fluoride-induced hypertension through modulation of Kim-1/NF-κB/Nrf2 signaling pathway in rats. Environ. Toxicol. 2018, 33, 1284–1297. [Google Scholar] [CrossRef]
  557. Garcia, S.I.; Dabsys, S.M.; Martinez, V.N.; Delorenzi, A.; Santajuliana, D.; Nahmod, V.E.; Finkielman, S.; Pirola, C.J. Thyrotropin-releasing hormone hyperactivity in the preoptic area of spontaneously hypertensive rats. Hypertension 1995, 26, 1105–1110. [Google Scholar] [CrossRef]
  558. Sugi, K.; Much, M.W.; Field, M.; Chang, E.B. Inhibition of Na+, K+-ATPase by interferon gamma down-regulates intestinal epithelial transport and barrier function. Gastroenterology 2001, 120, 1393–1403. [Google Scholar] [CrossRef] [PubMed]
  559. Li, Q.; Han, Y.; Dy, A.B.C.; Hagerman, R.J. The Gut Microbiota and Autism Spectrum Disorders. Front. Cell. Neurosci. 2017, 11, 120. [Google Scholar] [CrossRef]
  560. Malin, A.J.; Till, C. Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: An ecological association. Environ. Health 2015, 14, 17. [Google Scholar] [CrossRef] [PubMed]
  561. Williams, A.E.; Giust, J.M.; Kronenberger, W.G.; Dunn, D.W. Epilepsy and attention-deficit hyperactivity disorder: Links, risks, and challenges. Neuropsychiatr. Dis. Treat. 2016, 12, 287–296. [Google Scholar]
  562. Bashash, M.; Thomas, D.; Hu, H.; Martinez-Mier, E.A.; Sanchez, B.N.; Basu, N.; Peterson, K.E.; Ettinger, A.S.; Wright, R.; Zhang, Z.; et al. Prenatal Fluoride Exposure and Cognitive Outcomes in Children at 4 and 6-12 Years of Age in Mexico. Environ. Health Perspect. 2017, 125, 097017. [Google Scholar] [CrossRef] [PubMed]
  563. Bashash, M.; Marchand, M.; Hu, H.; Till, C.; Martinez-Mier, E.A.; Sanchez, B.N.; Basu, N.; Peterson, K.E.; Green, R.; Schnaas, L.; et al. Prenatal fluoride exposure and attention deficit hyperactivity disorder (ADHD) symptoms in children at 6–12 years of age in Mexico City. Environ. Int. 2018, 121, 658–666. [Google Scholar] [CrossRef]
  564. Kanık Yüksek, S.; Aycan, Z.; Öner, Ö. Evaluation of Iodine Deficiency in Children with Attention Deficit/Hyperactivity Disorder. J. Clin. Res. Pediatr. Endocrinol. 2016, 8, 61–66. [Google Scholar] [CrossRef] [PubMed]
  565. Konikowska, K.; Regulska-Ilow, B.; Rózańska, D. The influence of components of diet on the symptoms of ADHD in children. Rocz. Panstw. Zakl. Hig. 2012, 63, 127–134. [Google Scholar] [PubMed]
  566. Błażewicz, A.; Makarewicz, A.; Korona-Glowniak, I.; Dolliver, W.; Kocjan, R. Iodine in autism spectrum disorders. J. Trace Elem. Med. Biol. 2016, 34, 32–37. [Google Scholar] [CrossRef]
  567. Hamza, R.T.; Hewedi, D.H.; Sallam, M.T. Iodine deficiency in Egyptian autistic children and their mothers: Relation to disease severity. Arch. Med. Res. 2013, 44, 555–561. [Google Scholar] [CrossRef]
  568. Sullivan, K.M. Iodine deficiency as a cause of autism. J. Neurol. Sci. 2009, 276, 202. [Google Scholar] [CrossRef] [PubMed]
  569. Rytter, D.; Andersen, S.L.; Bech, B.H.; Halldorsson, T.I.; Henriksen, T.B.; Laurberg, P.; Olsen, S.F. Maternal thyroid function in pregnancy may program offspring blood pressure, but not adiposity at 20 y of age. Pediatr. Res. 2016, 80, 7–13. [Google Scholar] [CrossRef] [PubMed]
  570. Census 2011 Ireland and Northern Ireland. Central Statistics Office and Northern Ireland Statistics Research Agency. June 2014. Available online: https://www.cso.ie/en/media/csoie/census/documents/north-south-spreadsheets/Census2011IrelandandNorthernIrelandwebversion1.pdf (accessed on 15 March 2019).
  571. Balanda, K.P.; Wilde, J. Inequalities in Mortality 1989–1998. A Report on All-Ireland Mortality Data; Institute of Public Health in Ireland: Dublin, Ireland, 2001. [Google Scholar]
  572. Donnelly, D.W.; Gavin, A.T.; Comber, H. Cancer in Ireland 1994–2004: A Summary Report; National Cancer Registry/Northern Ireland Cancer Registry: Cork/Belfast, UK, 2009; Available online: https://www.ncri.ie/sites/ncri/files/pubs/CancerinIreland1994-2004(SummaryReport).pdf (accessed on 15 March 2019).
  573. All Ireland Cancer Atlas 1995–2007; National Cancer Registry/Northern Ireland Cancer Registry: Cork/Belfast, UK, 2011; Available online: https://www.ncri.ie/publications/cancer-atlases-and-geographic-studies/all-ireland-cancer-atlas-1995-2007 (accessed on 15 March 2019).
  574. Takahashi, K.; Akiniwa, K.; Narita, K. Regression Analysis of Cancer Incidence Rates and Water Fluoride in the U.S.A. based on IACR/IARC (WHO) Data (1978–1992). J. Epidemiol. 2001, 11, 170–179. [Google Scholar] [CrossRef] [PubMed]
  575. OECD/EU. Health at a Glance: Europe 2018: State of Health in the EU Cycle; OECD Publishing: Paris, France, 2018; Available online: https://doi.org/10.1787/health_glance_eur-2018-en (accessed on 19 March 2019).
  576. Torrey, E.F.; McGuire, M.; O’Hare, A.; Walsh, D.; Spellman, M.P. Endemic psychosis in Western Ireland. Am. J. Psychiatry 1984, 141, 966–970. [Google Scholar] [PubMed]
  577. Torrey, E.F. Prevalence studies in schizophrenia. Br. J. Psychiatry 1987, 150, 598–608. [Google Scholar] [CrossRef] [PubMed]
  578. Behan, C.; Kennelly, B.; O’Callaghan, E. The economic cost of schizophrenia in Ireland: A cost of illness study. Ir. J. Psychol. Med. 2008, 25, 80–87. [Google Scholar] [CrossRef] [PubMed]
  579. Women and Men in Ireland 2013; Central Statistics Office: Blackrock, Ireland, 2013; Available online: https://www.cso.ie/en/releasesandpublications/ep/pwamii/womenandmeninireland2013/healthlist/health/ (accessed on 19 March 2019).
  580. Goldner, E.; Hsu, L.; Waraich, P.; Somers, J. Prevalence and incidence studies of schizophrenic disorders: A systematic review of the literature. Can. J. Psychiatry 2002, 47, 833–843. [Google Scholar] [CrossRef] [PubMed]
  581. Winder, D.G.; Sweatt, J.D. Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nat. Rev. Neurosci. 2001, 2, 461–474. [Google Scholar] [CrossRef]
  582. Macedoni-Lukšič, M.; Petrič, I.; Cestnik, B.; Urbančič, T. Developing a Deeper Understanding of Autism: Connecting Knowledge through Literature Mining. Autism Res. Treat. 2011, 2011, 307152. [Google Scholar] [CrossRef]
  583. Runyan, J.D.; Moore, A.N.; Dash, P.K. A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory. Learn. Mem. 2005, 12, 103–110. [Google Scholar] [CrossRef] [PubMed][Green Version]
  584. Lian, Q.; Ladner, C.J.; Magnuson, D.; Lee, J.M. Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer’s disease cerebral cortex. Exp. Neurol. 2001, 167, 158–165. [Google Scholar] [CrossRef] [PubMed]
  585. Zeng, H.; Chattarji, S.; Barbarosie, M.; Rondi-Reig, L.; Philpot, B.D.; Miyakawa, T.; Bear, M.F.; Tonegawa, S. Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 2001, 107, 617–629. [Google Scholar] [CrossRef]
  586. Miyakawa, T.; Leiter, L.M.; Gerber, D.J.; Gainetdinov, R.R.; Sotnikova, T.D.; Zeng, H.; Caron, M.G.; Tonegawa, S. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc. Natl. Acad. Sci. USA 2003, 100, 8987–8992. [Google Scholar] [CrossRef] [PubMed][Green Version]
  587. Mayes, S.D.; Calhoun, S.L.; Mayes, R.D.; Molitoris, S. Autism and ADHD: Overlapping and discriminating symptoms. Res. Autism Spectr. Disord. 2012, 6, 277–285. [Google Scholar] [CrossRef]
  588. Leitner, Y. The co-occurrence of autism and attention deficit hyperactivity disorder in children—What do we know? Front. Hum. Neurosci. 2014, 8, 268. [Google Scholar] [CrossRef] [PubMed]
  589. Miranda, A.; Berenguer, C.; Roselló, B.; Baixauli, I.; Colomer, C. Social Cognition in Children with High-Functioning Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. Associations with Executive Functions. Front. Psychol. 2017, 8, 1035. [Google Scholar] [CrossRef] [PubMed]
  590. Colombi, C.; Ghaziuddin, M. Neuropsychological Characteristics of Children with Mixed Autism and ADHD. Autism Res. Treat. 2017, 2017, 5781781. [Google Scholar] [CrossRef] [PubMed]
  591. Costello, R.B.; Elin, R.J.; Rosanoff, A.; Wallace, T.C.; Guerrero-Romero, F.; Hruby, A.; Lutsey, P.L.; Nielsen, F.H.; Rodriguez-Moran, M.; Song, Y.; et al. Perspective: The case for an evidence-based reference interval for serum magnesium: The time has come. Adv. Nutr. 2016, 7, 977–993. [Google Scholar] [CrossRef]
  592. Whang, R.; Ryder, K.W. Frequency of hypomagnesemia and hypermagnesemia. Requested vs routine. JAMA 1990, 263, 3063–3064. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Pathophysiological conditions and neurological disorders associated with loss of Na+, K+-ATPase activity.
Figure 1. Pathophysiological conditions and neurological disorders associated with loss of Na+, K+-ATPase activity.
Ijerph 16 01427 g001
Figure 2. Schematic representation of the molecular mechanisms and biological pathways by which fluoride inhibits Na+, K+-ATPase activity on plasma membranes and in thyroid follicular cells.
Figure 2. Schematic representation of the molecular mechanisms and biological pathways by which fluoride inhibits Na+, K+-ATPase activity on plasma membranes and in thyroid follicular cells.
Ijerph 16 01427 g002
Table 2. Key molecular mechanisms by which fluoride inhibits Na+, K+-ATPase activity. Arrows refer to increases (↑) or decreases (↓) in regulation or expression by fluoride.
Table 2. Key molecular mechanisms by which fluoride inhibits Na+, K+-ATPase activity. Arrows refer to increases (↑) or decreases (↓) in regulation or expression by fluoride.
FactorEffect of FEffect on Na+, K+-ATPase Activity
ATPATP is required for NKA homeostasis. Lower bioavailability of ATP leads to inhibition of enzyme activity
ENO1Enolase is necessary for glycolysis and ATP production. Inhibition of enolase leads to
loss of NKA activity
PKCPKC phosphorylates the α-1 subunit of NKA leading to inhibition of activity.
cAMPInhibits NKA activity by decreasing bioavailability of ATP and enhancing phosphorylation of the α-1 subunit of NKA
CnRegulates the dephosphorylation of NKA. Phosphorylation of NKA inhibits enzyme activity. Hence, inhibition or activation of Cn regulates enzymatic activity. Requires Calmodulin and Manganese for structural stability and full activity.
CaMInhibits Na+, K+-ATPase activity by enhancing phosphorylation
Mn2+Mn2+ is also an activator of Cn and its binding to Cn is required for functional stability and enzyme activity. Loss of Mn2+ inhibits Cn expression and impairs Cn activity leading to enhanced phosphorylation of NKA. Phosphorylation inhibits NKA activity.
Mg2+Mg2+ facilitates the binding of ATP to NKA thereby providing the chemical energy required for enzyme activity.
cGMPInhibits NKA activity
NOInhibits NKA activity
PiInhibits NKA activity directly as well as inhibiting the phosphatase activity of Cn.
RANKLInhibits NKA indirectly by increasing osteoclast number, bone resorption and Pi release
ALPALP regulates Pi release, thereby indirectly inhibiting NKA activity. ALP activity in turn stimulated by Calcitonin.
TGF-β1Inhibits NKA activity. Calcitonin has been found to be a potent stimulator of TGF-β1 protein synthesis as well as TGF-β1 mRNA expression.
CTInhibits NKA activity indirectly by upregulating TGF-β1 and ALP activity.
DAInhibits NKA activity. PKC and cAMP signalling further contribute to dopaminergic inhibition of NKA.
TRHInhibits NKA activity indirectly by inducing DA release.
PTHInhibits NKA activity directly. PTH also inhibits NKA activity indirectly through activation of PKC, cAMP, PLA2 and PKA dependent pathways.
PLA2Inhibits NKA activity.
PGE2Inhibits NKA activity.
BgLInhibits NKA activity, via activation of PKC, PLA2 and PGE2.
AGEsInhibits NKA activity.
TSHTSH induces cAMP production and cAMP inhibits NKA activity by reducing ATP bioavailability and enhancing phosphorylation of the alpha-1 subunit of NKA
Abbreviations: NKA: Na+, K+-ATPase; PKC: Protein kinase C; ATP: Adenosine-triphosphate; cAMP: cyclic adenosine-monophosphate monophosphate; Cn: Calcineurin; CaM: Calmodulin; Mn2+: Magnesium; cGMP: Cyclic guanosine monophosphate; ENO1: Enolase; NO: Nitric oxide; Pi: Inorganic phosphate; ALP: Alkaline phosphatase; TGF-β1: Transforming growth factor β 1; CT: Calcitonin; DA: Dopamine; PTH: Parathyroid hormone; PLA2: Phospholipase A2; AA: Arachidonic Acid; Prostaglandin E2; BgL: Blood glucose; Glc: Glucose; RAGE: Receptors for advanced glycation end products; OC: Osteocalcin; DA: Dopamine; PTH: Parathyroid hormone; INS: Insulin;. TSH: Thyroid stimulating hormone; TRH: Thyroid-releasing hormone.

© 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Int. J. Environ. Res. Public Health EISSN 1660-4601 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top