Environmental Factors That Affect Parathyroid Hormone and Calcitonin Levels

Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate homeostasis in the body. Therefore, an understanding of environmental and genetic factors influencing PTH and calcitonin levels is crucial. Genetic factors are estimated to account for 60% of variations in PTH levels, while the genetic background of interindividual calcitonin variations has not yet been studied. In this review, we analyzed the literature discussing the influence of environmental factors (lifestyle factors and pollutants) on PTH and calcitonin levels. Among lifestyle factors, smoking, body mass index (BMI), diet, alcohol, and exercise were analyzed; among pollutants, heavy metals and chemicals were analyzed. Lifestyle factors that showed the clearest association with PTH levels were smoking, BMI, exercise, and micronutrients taken from the diet (vitamin D and calcium). Smoking, vitamin D, and calcium intake led to a decrease in PTH levels, while higher BMI and exercise led to an increase in PTH levels. In terms of pollutants, exposure to cadmium led to a decrease in PTH levels, while exposure to lead increased PTH levels. Several studies have investigated the effect of chemicals on PTH levels in humans. Compared to PTH studies, a smaller number of studies analyzed the influence of environmental factors on calcitonin levels, which gives great variability in results. Only a few studies have analyzed the influence of pollutants on calcitonin levels in humans. The lifestyle factor with the clearest relationship with calcitonin was smoking (smokers had increased calcitonin levels). Given the importance of PTH and calcitonin in maintaining calcium and phosphate homeostasis and bone mineral metabolism, additional studies on the influence of environmental factors that could affect PTH and calcitonin levels are crucial.


Introduction
Maintenance of calcium homeostasis in the body is crucial since calcium regulates various physiological processes, including cellular signaling, protein and enzyme function, neurotransmission, contractility of the muscles, and blood coagulation [1]. Calcium homeostasis is regulated by parathyroid hormone (PTH), calcitonin, the active form of vitamin D (1α,25-dihydroxyvitamin D (1,25(OH)2D3)), and serum calcium and phosphate levels. Regulation of phosphate metabolism is also important as phosphate is involved in protein and enzyme function, cell signaling, and skeletal mineralization and is a component of cell membranes and nucleic acids [2,3]. The main factors that regulate phosphate homeostasis are PTH, fibroblast growth factor 23 (FGF-23), 1,25(OH)2D3, and Klotho [3]. Calcitonin is also involved in the regulation of phosphate levels [4,5]. PTH is released from the parathyroid glands [6], while calcitonin is released from thyroid C-cells [7]. Alternation of PTH levels can lead to the development of hyperparathyroidism and hypoparathyroidism. Changes in calcitonin levels have also been observed in pathological conditions (such as medullary thyroid carcinoma [8]). Therefore, variations in PTH and calcitonin levels may indicate that the normal functioning of parathyroid glands and thyroid is altered. Various pathological conditions (such as medullary thyroid carcinoma [8]). Therefore, variations in PTH and calcitonin levels may indicate that the normal functioning of parathyroid glands and thyroid is altered. Various factors can affect PTH and calcitonin levels, such as genetic factors [9][10][11], demographic factors (age [12][13][14], sex [15][16][17]), and environmental factors [18][19][20][21]. It is estimated that genetic factors account for 60% of variations in PTH levels [9], while the amount to which genetic factors contribute to interindividual variation in calcitonin levels has not been studied. This review aims to provide an insight into environmental factors (lifestyle factors and pollutants) that affect PTH and calcitonin levels ( Figure 1).

Involvement of PTH and Calcitonin in the Regulation of Calcium and Phosphate Levels
Calcium and phosphate levels in the body are regulated by the complex intestinebone-kidney-parathyroid axis [22]. Calcium homeostasis is regulated by PTH, calcitonin, 1,25(OH)2D3, and serum phosphate and calcium levels. PTH increases calcium levels in the body, and calcitonin decreases calcium levels in the body. PTH increases serum calcium levels by activating osteoclasts (cells involved in bone resorption) and absorbing calcium in the kidneys. Calcitonin lowers calcium levels by inhibiting osteoclasts [23]. Additionally, 1,25(OH)2D3 stimulates intestinal calcium absorption [24]. Increasing serum levels of 1,25(OH)2D3 and calcium decrease PTH secretion, while increasing serum phosphate levels increase PTH secretion [25]. In addition to PTH, phosphate levels are mainly regulated by FGF-23, 1,25(OH)2D3, Klotho, and dietary phosphate [3,22,26,27], while calcitonin also affects phosphate levels [4,5]. PTH, FGF-23, and Klotho decrease serum phosphate levels (by inhibiting renal phosphate reabsorption), while 1,25(OH)2D3 increases serum phosphate levels (by increasing renal phosphate reabsorption, phosphate absorption from the intestine, and phosphate release from the bones) [2,22]. It has been suggested that FGF-23 acts in a negative feedback loop with PTH [28]; PTH stimulates FGF-23 production [28], while FGF-23 has been shown to inhibit PTH secretion indirectly (by increasing urinary phosphate excretion) and directly (by acting directly on parathyroid glands) [29]. Additionally, a negative feedback mechanism was observed between FGF-23 and 1,25(OH)2D3; 1,25(OH)2D3 increases FGF-23 levels, and FGF-23 decreases 1,25(OH)2D3 levels (by suppressing the expression of 1α-hydroxylase-the enzyme responsible for the production of 1,25(OH)2D3) (reviewed in [22]). Most studies investigating the effect of smoking on calcitonin levels have found an increase in calcitonin levels in smokers (Table 2). A large population study by Song et al., involving 10,566 participants showed an increase in calcitonin levels in male smokers [17].

Environmental Factors That Affect PTH and Calcitonin Levels
Smoking affects the normal functioning of the thyroid gland [39]; however, the effect of smoking on calcitonin-producing C cells has not been elucidated [17]. The results of Tabassian et al. suggested that the lungs are the source of increased calcitonin in smokers rather than the thyroid. Specifically, smoking increases the release of calcitonin from neuroendocrine lung cells [40].

Body Mass Index
Many studies have investigated the influence of body mass index (BMI) on PTH levels. Most studies have shown that an increase in BMI is accompanied by an increase in PTH levels (Table 1). However, a study by Yuan et al., showed a positive correlation between BMI and PTH levels in subjects with lower PTH levels (below 65.8 pg/mL), while a negative correlation was observed between BMI and PTH levels in the group of patients with high PTH levels (above 147 pg/mL) [41]. There are several possible explanations for the positive correlation between BMI and PTH levels. The first possibility is that weight gain leads to an increase in PTH levels by sequestration of 25-hydroxyvitamin D (25(OH)D) in adipose tissue (since 25(OH)D is soluble in fat) [42,43]. Because PTH and 25(OH)D are inversely related, a decrease in 25(OH)D levels increases PTH levels. Another possibility is that an increase in PTH levels causes weight gain. Because PTH can activate 1α-hydroxylase (the enzyme responsible for the production of 1,25(OH)2D), an increase in PTH levels can lead to an increase in 1,25(OH)2D levels. Both PTH and 1,25(OH)2D increase calcium levels. Increased calcium levels in adipocytes result in increased lipid storage (by activation of phosphodiesterase 3β which reduces catecholamine-induced lipolysis [44,45]). A possible explanation of the negative correlation between PTH and BMI in patients with high PTH levels is that PTH in higher concentrations inhibits adipogenesis, consequently resulting in weight loss [46]. Additionally, high-dose PTH has been shown to increase the expression of thermogenesis genes, resulting in white adipose browning [47].
Several studies have investigated the association between BMI and calcitonin levels, reporting conflicting results ( Table 2). The largest study, which included 9340 people with type 2 diabetes, showed a positive correlation between BMI and calcitonin levels [48]. However, a study by Song et al., conducted on 4638 healthy individuals did not show an association between BMI and calcitonin [17]. Although the relationship between calcitonin levels and BMI in humans has not been fully elucidated, experimental studies have shown that salmon calcitonin intake causes weight loss (reviewed in [49]). These authors also described some additional compounds that target the calcitonin receptor and that could be used as an option in the treatment of obesity [49].

Diet
Different types of food can affect the level of PTH in the body (Table 1). A diet high in phosphorus and low in calcium has been shown to increase PTH levels [50,51]. This is logical because both high serum phosphate levels and low serum calcium levels are signals to increase PTH release [52]. Phosphorus is present in various types of food and food additives, while dairy products contain a large amount of calcium. Increased intake of dairy products and decreased intake of highly processed food should increase calcium levels and reduce phosphorus levels [51]. Processed foods such as sausages, salami, and white bread [21] and a proinflammatory diet (processed and red meat, refined carbohydrates, and fried food) [53] have been observed to increase PTH levels. Consumption of this type of food increases BMI, which is positively correlated with PTH levels ( Table 1). A decrease in PTH levels was observed in consumers of bran bread [21]. A low-protein diet was associated with an increase in PTH levels [54][55][56]. Interestingly, the consumption of plant foods also led to an increase in PTH levels [21,57]. Therefore, vegans [58] and vegetarians [59] had higher levels of PTH than controls. A possible explanation for this is that higher plant food intake increases serum phosphorus levels (due to pesticide treatment of plants) [60]. PTH levels either decreased [30,61] or did not change [32, 62,63] after coffee consumption.
The effect of different types of food on calcitonin levels has not been studied to date. Several studies have shown that food intake (without specifying the type of food) does not affect calcitonin levels [64,65]. Zayed et al., have shown that calcitonin levels increase after ingestion of food (without specifying the type of food) [66]. A study in pigs showed that a diet high in phosphorus increased calcitonin levels [67], while a study in rats showed that a diet high in fat increased calcitonin levels [68].

Micronutrients
Many studies have tested the effect of vitamin D on PTH levels because these two hormones act together. About 95% of vitamin D is synthesized in the skin after exposure to sunlight, while 5% of vitamin D comes from food [69]. Since PTH and the active form of vitamin D (1,25(OH)2D) are in an inverse relationship, it is not surprising that most of the studies have reported a decrease in PTH levels after vitamin D intake (Table 1). In some studies, however, there was no change in PTH levels after vitamin D intake (Table 1). On the other hand, a meta-analysis by Moslehi et al. confirmed that PTH levels are reduced by vitamin D intake [70]. Vitamin A intake decreased [63,71] or did not affect PTH levels [72]. In vitro studies in human [73] and bovine parathyroid cells [74] have shown that retinoic acid (a metabolite of vitamin A) directly suppresses PTH secretion.
No changes in calcitonin levels were observed after vitamin D intake [75]. While calcitonin stimulates 1,25(OH)2D synthesis, 1,25(OH)2D reduces the synthesis of calcitonin [76]. Therefore, it is necessary to conduct additional studies on the relationship between vitamin D and calcitonin.
Most studies have shown that calcium intake decreases PTH levels (Table 1), which is logical since PTH is released in hypocalcemia. Magnesium intake either increased [77,78] or did not affect [32,79] PTH levels. The relationship between PTH and magnesium is complex because PTH improves magnesium absorption [80], and magnesium reduces PTH secretion in a state of moderately low calcium concentration [81,82]. Zinc intake [83] did not affect PTH levels. However, a study in rats showed that a zinc-deficient diet increased PTH levels [84], while patients with primary hyperparathyroidism had decreased serum zinc levels [85].
Zinc intake decreased calcitonin levels [83,86], while copper intake [86] did not affect calcitonin levels. Intake of both zinc and copper resulted in inhibition of bone loss [87,88].

Alcohol
Studies investigating the influence of alcohol on PTH levels have yielded conflicting results. Some studies have found a decrease in PTH levels in alcoholics, while most studies have not reported a significant change in PTH levels due to alcohol consumption (Table 1). Moreover, the two largest studies involving more than 7000 participants yielded conflicting results; Jorde et al. observed a significant reduction in PTH levels in alcoholics [30], while Paik et al. did not notice a significant change in PTH levels in alcoholics [32]. Because alcohol inhibits bone regeneration [89], it has been suggested that alcohol intake reduces PTH levels [90][91][92] and increases calcitonin levels [93].
Several studies investigated calcitonin levels in alcoholics, and all yielded conflicting results ( Table 2) with calcitonin levels that were increased [94], decreased [95], or unchanged [96] in alcoholics. Schuster et al. suggested that the reduction in calcitonin in chronic alcoholism is due to lower calcium concentration at this stage of alcohol consumption [95]. Interestingly, animal studies have shown that salmon calcitonin intake reduces various alcohol-related behaviors [97,98].

Exercise
Most studies that have investigated the influence of exercise on PTH levels have reported an increase in PTH levels during and after exercise (Table 1). However, most of these studies involved a small number of participants (less than 50). In contrast to the results of these studies, two studies involving as many as 7561 [31] and 3427 [30] participants reported a decrease in PTH levels after exercise. Causes of inconsistencies between studies may be the physical status of the participants; the age and gender of the participants; and the type, duration, and intensity of the exercise [99]. PTH is thought to increase during highintensity exercise (reviewed in [100]). Although exercise is thought to be beneficial for BMD, some groups of professional athletes have had significant reductions in BMD [101,102]. It has been suggested that intense exercise leads to a decrease in calcium levels, resulting in an increase in PTH. Elevated PTH levels may contribute to bone resorption (reviewed in [103]). Moreover, Shea et al. suggested that calcium supplementation during exercise could reduce bone resorption [104]. However, other researchers have noticed an increase in PTH levels during exercise despite the stability of calcium levels (reviewed in [103]). Some other factors that can lead to an increase in PTH during exercise are increased catecholamine release (which stimulates PTH release) [105], increased aldosterone release (which increases PTH and calcitonin release) [80], and acidosis (stimulates PTH release) [106].

Heavy Metals
Various heavy metals, such as cadmium (Cd), arsenic (As), and lead (Pb), affect PTH levels. Most studies have shown that PTH levels decrease after cadmium exposure (Table 3). Schutte et al., explained the decrease in PTH levels after cadmium exposure as a consequence of the direct osteotoxic effect of cadmium [18]. Exposure to cadmium leads to a decrease in bone density, resulting in increased release of calcium from bone tissue. The result of increased calcium release is the decrease in PTH levels [18]. In addition, cadmium has been shown to have a toxic effect on parathyroid glands [237]. However, some studies did not observe any effect [238][239][240] or observed an increase [241,242] in PTH levels in subjects exposed to cadmium. Studies in experimental animals observed an increase in PTH levels after cadmium exposure [243]. Arsenic exposure did not affect PTH levels [244]. Most studies reported an increase in PTH levels in subjects exposed to lead (Table 3). Lead inhibits 1α-hydroxylase (the enzyme responsible for the production of 1,25(OH)2D) [245], and since PTH and 25(OH)D are in an inverse relationship, a decrease in 25(OH)D levels results in an increase in PTH levels. PTH levels were also measured in Gulf War I veterans who were exposed to uranium, and it was shown that uranium exposure led to a decrease in PTH levels [246].
We found only one study that analyzed the influence of heavy metals on calcitonin levels. Schutte et al., observed an increase in calcitonin levels after cadmium exposure [18]. A study in rats showed that exposure to cadmium and lead decreased calcitonin levels [243,247]. Exposure of laying hens to cadmium led to a decrease in calcitonin levels [248], while a study in goldfish found no changes in calcitonin levels after cadmium exposure (although exposure to methylmercury increased calcitonin levels) [249].

Chemicals
Only a few studies have investigated the effect of chemicals on PTH levels in humans (Table 3). Exposure to persistent organochlorine compounds (p,p -diphenyldichloroethene (p,p -DDE) and polychlorinated biphenyls (PCBs)) did not affect PTH levels [132,250].
Exposure to perfluoroalkyl substances (PFAS) led to an increase in PTH levels [251]. Di Nisio et al. suggested that perfluoro-octanoic acid (PFOA) binds to vitamin D receptors, causing reduced 1,25(OH)D activity, which in turn increases PTH levels [251]. Fluoride exposure increases PTH levels [252]. According to researchers, excess fluoride alters calcium metabolism and potentially leads to secondary hyperparathyroidism (reviewed in [253]). Exposure to perchlorate, thiocyanate, and nitrate has led to a decrease in PTH levels, but the underlying mechanism of this action is not yet clear [19].
Data on the effect of chemicals and pesticides on calcitonin levels in humans are scarce. A study on goldfish has shown that bisphenol A inhibits the release of calcitonin [249]. Aroclor 1254 (PCB) increased calcitonin expression in rat thyroid [254]. Because many chemicals have an endocrine disruptive effect [255], further studies are needed on the impact of chemicals and pesticides on PTH and calcitonin levels.

Conclusions
In this review, we gave an insight into environmental factors that affect the levels of PTH and calcitonin, two hormones that regulate calcium and phosphate homeostasis. We included literature discussing lifestyle factors (smoking, BMI, diet, alcohol, and exercise) and pollutants (heavy metals and chemicals) ( Figure 1). In terms of lifestyle factors, most studies have shown a decrease in PTH levels in smokers, a positive correlation between BMI and PTH, an increase in PTH levels during exercise, and a decrease in PTH levels after vitamin D and calcium intake ( Table 1). The results of studies on the impact of alcohol consumption and intake of different types of food and micronutrients (except for vitamin D and calcium) showed great variability (Table 1). Regarding studies that analyzed the effect of pollutants on PTH levels, the clearest relationship was between PTH and cadmium, with PTH levels decreasing after cadmium exposure (Table 3). While arsenic exposure did not affect PTH levels, lead exposure resulted in increased PTH levels (Table 3). Several studies have investigated the influence of chemicals on PTH levels in humans. Moreover, data on the effect of chemicals and heavy metals on calcitonin levels in humans are scarce, and most of the knowledge, to date, relies on studies in experimental animals. As for the relationship between lifestyle factors and calcitonin, several studies have been conducted on humans and have given great variability in results. The most consistent results were related to smoking (an increase in calcitonin levels was observed in smokers) ( Table 2). Given the important role that PTH and calcitonin play in maintaining calcium and phosphate homeostasis in the body, additional studies on the influence of environmental and genetic factors that could affect the levels of these two hormones are extremely important.