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Natural Products in Mitigation of Bisphenol A Toxicity: Future Therapeutic Use

Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Nilai 71800, Malaysia
Institute of Medical Science Technology, Universiti Kuala Lumpur, Kuala Lumpur 50250, Malaysia
Author to whom correspondence should be addressed.
Molecules 2022, 27(17), 5384;
Received: 29 June 2022 / Revised: 13 August 2022 / Accepted: 16 August 2022 / Published: 24 August 2022


Bisphenol A (BPA) is a ubiquitous environmental toxin with deleterious endocrine-disrupting effects. It is widely used in producing epoxy resins, polycarbonate plastics, and polyvinyl chloride plastics. Human beings are regularly exposed to BPA through inhalation, ingestion, and topical absorption routes. The prevalence of BPA exposure has considerably increased over the past decades. Previous research studies have found a plethora of evidence of BPA’s harmful effects. Interestingly, even at a lower concentration, this industrial product was found to be harmful at cellular and tissue levels, affecting various body functions. A noble and possible treatment could be made plausible by using natural products (NPs). In this review, we highlight existing experimental evidence of NPs against BPA exposure-induced adverse effects, which involve the body’s reproductive, neurological, hepatic, renal, cardiovascular, and endocrine systems. The review also focuses on the targeted signaling pathways of NPs involved in BPA-induced toxicity. Although potential molecular mechanisms underlying BPA-induced toxicity have been investigated, there is currently no specific targeted treatment for BPA-induced toxicity. Hence, natural products could be considered for future therapeutic use against adverse and harmful effects of BPA exposure.

1. Introduction

1.1. Bisphenol A

Bisphenol A (BPA) and its derivatives, bisphenol S, bisphenol AF, bisphenol E, and bisphenol B, consist of two phenyl rings connected by a small linking group. This synthetic carbon-based compound is widely used in various industries [1]. It was reported that the production of this compound was estimated to be 4.85 million tons [2]. Since the 1960s, BPA has been used in epoxy resins and polycarbonate plastics production, which are the main constituents of daily consumer products, including containers of food products and drinks, thermal receipts, medical equipment, toys, dental sealants, paints, CD/DVDs, etc. [3,4]. BPA biodegrades, leaches easily from consumer goods, and enters the environment. Its presence has been detected in soil, both drinking and wastewater, dust, food, and air [5].
BPA has a half-life of approximately 4.5 days in water and soil and less than one day in the air [6]. At room temperature, leaching of BPA from polycarbonate bottles into drinking water occurred at an observed rate of 0.20 to 0.79 ng/h. At boiling temperature, the leaching of BPA from the same polycarbonate bottles into water increases 55-fold [7]. Researchers also found that, along with temperature, repeated use of a bottle will influence the leaching of BPA [8]. BPA can also enter food stuff through the BPA epoxy resin films, which are used in the lining of food cans [9,10,11]. Other BPA exposure sources include thermal printing paper [12], medical equipment, and plastics used in medical devices [13], particularly polycarbonate equipment used in hemodialysis [14], and dental composites and sealants [15]. According to the European Food Safety Authority (EFSA), the daily tolerated intake of BPA was reported to be 4 μg/kg/day [16].
BPA may be exposed through several exposure routes, including the integumentary system, digestive system, respiratory system, and maternofetal transmission [17]. It is easily absorbed in the gastrointestinal tract, whereby it is metabolized and secreted within a few hours of exposure. In the liver, BPA is biotransformed into BPA-glucuronide after conjugating with the uridine diphosphate glucuronic acid. BPA is also known to form other conjugates, such as BPA diglucuronide and BPA sulfate conjugates. The conjugate formation and excretion of bisphenol glucuronide are rapid and take place with a half-life of 5.3 h [18,19]. BPA conjugates are excreted in the bile, urine, and feces. The developing fetus, as well as infants, are also exposed to BPA through placental transfer and milk, respectively [20]. The β-glucuronidase enzyme converts conjugated BPA into its active free form. A considerable amount of this enzyme has been detected in various tissues, including rodent livers, lungs, kidneys, and human and rodent placentas [21]. This could be one of the reasons that even though BPA is rapidly eliminated in more than 95% of individuals, considerable levels of BPA can still be observed [4,22]. Consequently, human fluids and tissues only contain very little non-conjugated BPA, often in the nanogram per milliliter range [23,24]. According to a study, the mean free BPA concentration in human serum ranged from 2.3 to 2.4 ng mL−1, 2.8 ng mL−1 in adolescents, and 4.3 ng mL−1 in children [25]. A BPA biomonitoring study has shown that the compound can be found in human blood, urine, and milk in nanomolar quantities [24]. Of great concern is that BPA could be found in various bodily fluids from vulnerable populations, including in the urine of children and healthy infants, pregnant women’s serum, fetal serum, follicular and amniotic fluid, cord blood, placenta tissue, breast milk, and saliva from patients who have undergone certain dental procedures [26]. BPA was found to accumulate more in fat compared to other tissues, such as kidneys, muscles, and others due to its high affinity with the fat [27]. In a study conducted by Geens et al., free BPA levels were detected highest in adipose tissues (1.12 to 12.28 ng/g), followed by the liver (0.77 to 3.35 ng/g), and brain (up to 2.36 ng/g). In breast milk, total BPA and unconjugated BPA were detected at concentrations of 1.1 and 0.4 ng/mL, respectively [28]. A study undertaken to determine the distribution of BPA in people revealed that BPA was found in almost all human tissues. Due to its tendency to bioaccumulate in human tissues, BPA can potentially pose long-term metabolic consequences.
Ever since the 1990s, BPA occurrence has been detected in the environment and continues to contaminate and pollute globally [29]. As a primary river pollutant, BPA’s presence has been observed in surface water and drinking water. A study from Malaysia reported a presence of BPA in the Bentong River at concentrations of 5.52 and 2.06 ng/L in colloidal and soluble phases, respectively [30]. In studies from India, Spain, Germany, and China, the BPA levels in the surface water were reported to be in the range of 6.63–136 ng/L, 87–126 ng/L, 28–560 ng/L, and 22–3360 ng/L, respectively [31,32,33,34]. In a recent study, in two different rivers in Romania, the BPA concentrations were found to be in the range of 22.1–35.8 ng/L and 74.5–135 ng/L, respectively [35]. BPA can reach the soil through sewage sludge from wastewater treatment plants, leachate from landfills, and soil amendments [36]. Studies from Asian countries, such as Korea, China, Japan, and India have reported BPA levels of 0.5–48.68 μg/kg, 2340 pg/m3, 1920 pg/m3, and 17,400 pg/m3, respectively [36]. In Mexico, BPA concentrations in agricultural soil irrigated with wastewater were found to be 1.6–30.2 μg/kg [37]. In European soils that were amended with biosolids, a median concentration of 0.24 μg/kg BPA was reported [38]. BPA can enter the air, and most of its sources are anthropogenic. The contamination of BPA into the atmosphere occurs through various routes including incineration of plastic materials, transportation of recyclable materials and environmental emissions, BPA-producing factories, waste treatment plants, and landfills [29,39]. The highest air levels of BPA were documented in China at a concentration of 1.1 × 106 pg/m3 [40].

1.2. Conventional Methods for BPA Degradation and Removal

BPA is potentially harmful at concentrations ranging from 5 to 200 n/L (nanoliters) in surface and ground waters [41]. BPA may be accumulated in aquatic organisms. Since BPA may accumulate in the water, better water treatment methods are essential. Biodegradation has several advantages, such as environment and economic protection, low costs, wider scopes of action, longer durations, and fewer problems with regard to space and equipment requirements [42]. White-rot fungi can produce extracellular lignin-producing enzymes, which are responsible for the biotransformation of many aromatic compounds and pollutants, such as BPA [43,44]. It was found that 80% of BPA was removed over a period of 12 days using white-rot basidiomycete Pleurotus ostreatus [45]. Many enzymes, such as lignin peroxidase (LiP), manganese-dependent peroxidase (MnP), and laccase may be beneficial in the degradation of BPA. MnP enzyme was reported to catalyze the oxidation of various phenols in the presence of H2O2 and Mn(II) [46]. MnP is a heme peroxidase enzyme and oxidizes phenolic compounds in the presence of Mn(II) and H2O2, while laccase is a multicopper oxidase enzyme and catalyzes one-electron oxidation of phenolic compounds by reducing oxygen to water [47]. Compared to MnP, laccase remains stable and high throughout the incubation period, suggesting that it may be a key enzyme in BPA degradation [48]. In the future, probiotics could be tried for BPA degradation.
Fly ash represents 80% of the coal combustion byproducts. Besides its utilization for building and construction purposes, fly ash has beneficial effects on environmental and economic applications [49]. Interestingly, fly ash has been used to degrade and remove phenol chemicals, such as the endocrine disrupter BPA [50]. A zeolite is prepared from fly ash and has a low absorption capacity of BPA. However, the absorption capacity of BPA by zeolites was greatly augmented after the surfactant modification [51]. Moreover, the absorption of peroxidase on fly ash improves its effectiveness in degrading BPA when compared to its free form [52]. Fly ash is highly effective and stable for the oxidative polymerization and removal of BPA and other toxicants.

2. Effects of BPA Exposure on Different Body Systems

2.1. The Changes Occuring in Different Systems of the Body

2.1.1. Reproductive System

The roles of BPA in endocrine disruption, oxidative stress, epigenetic modification, the release of cytokines, and oxidative stress are linked to its associated adverse effects. BPA is well known for its estrogenic activity. BPA was initially explored for its estrogenic properties and was found to influence the synthesis of estrogen and testosterone [53,54]. In subsequent studies, BPA was found to interfere with sex hormone activities and associated with developmental toxicity and functional disturbances of the reproductive system. BPA is responsible for the pathogenesis of female infertility [55]. In a study, serum BPA levels were detected (limit of assay detection: 0.5 ng/mL) in 41.8% of infertile women and 23.3% of fertile women [56]. Interestingly, higher BPA exposure and levels in infertile women in a metropolitan area show evidence of a greater presence of economic activities using these chemicals and more usage in food and consumer products [56]. It cannot be refuted that BPA may be detected in infertile women. In females, the BPA-induced reproductive abnormalities include increased endometrial wall thickness, the occurrence of polycystic ovary syndrome, an increased risk of recurrent miscarriage, neonatal mortality, defective placental function, irregular cycles, and reduced primordial follicles [57,58,59,60,61,62,63,64]. Experimental and epidemiological studies have confirmed that BPA exposure during pregnancy affects the development and growth of offspring. Exposure to BPA in utero has been shown to affect the development of the uterus and mammary glands [65,66]. A direct association was also found between urinary BPA levels and implantation failure [67]. In males, BPA can interfere with the regulation of spermatogenesis via the hypothalamic–pituitary–gonadal axis. BPA has been shown to impair male reproductive function with a reduction in sperm quality, defective ejaculation, reduced libido, and erectile dysfunction [68,69]. In experimental animals, administration of BPA significantly decreased the expression of the GnRH gene in cells of the preoptic area and circulating levels of gonadotropins and/or testosterone [70]. Occupational exposure to BPA among adult males in China has been reported to be associated with changes in serum hormone levels and male sexual dysfunction [69].

2.1.2. Cardiovascular System

Prenatal BPA exposure was also linked to an increased risk of developing cardiovascular disorders and non-alcoholic liver disease in later life [71,72,73,74,75]. Furthermore, BPA-induced neuroendocrine regulation may result in mental and behavioral consequences in the offspring. Higher maternal BPA levels increase the risk of developing behavior problems in preschool children [76]. Prenatal BPA exposure was also strongly associated with anxiety and depression in children [77]. Clinical evidence shows an association between serum and/or urinary BPA levels and cardiovascular diseases [78,79]. Increased serum BPA levels in dilated cardiomyopathic patients were also reported [80]. Experimental studies confirmed that BPA exposure could adversely affect cardiac structure and function [81,82]. Furthermore, BPA exposure increases systolic blood pressure, alters heartbeat in isolated heart preparations, and blocks cardiac sodium channel receptors [83,84,85]. BPA can also alter calcium homeostasis in the heart by stimulating estrogen receptors on the plasma membrane [86]. BPA exposure was also associated with the development of atherosclerosis and peripheral arterial disease [87,88,89].

2.1.3. Endocrine System

Recent animal studies have observed that BPA can cause developmental programmings of metabolic diseases, such as diabetes mellitus and obesity in later stages of life [74,90,91]. BPA exposure affects glucose metabolism by disrupting pancreatic cell function and producing insulin secretion [92]. It also affects adipocytes’ metabolic functions, leading to insulin resistance development. In an in vivo study, BPA exposure promoted insulin resistance by reducing adiponectin levels and increasing adipocytokines levels [93]. Urinary BPA levels were positively linked with metabolic syndrome [88]. Few epidemiological studies have found a link between BPA exposure and diabetes mellitus in patients who were not predisposed to the disease due to factors, such as age, serum cholesterol levels, or body mass index [88,94,95]. In obese pregnant women, BPA exposure was associated with an increased risk of altered glucose metabolism [96]. Furthermore, it was found that BPA shows these effects in specific trimesters, particularly in the second trimester [97]. Higher urinary BPA levels were associated with childhood obesity as well as abdominal obesity [98]. In addition, BPA perinatal exposure induces the development of diabetes mellitus in the offspring. BPA-induced developmental programming is thought to be due to epigenetic modifications [99].

2.1.4. Urinary System

Since BPA is a xenoestrogen and the kidneys possess several receptors for estrogen, BPA stimulates the receptors, leading to the proliferation of epithelial cells and also increases the volume of proximal and distal cells leading to hydronephrosis [100]. BPA treatment in animals showed bladder enlargement, hypertrophy, and urinary voiding dysfunction [101]. The late manifestations of voiding dysfunction were also observed in mice treated with testosterone and BPA [101]. The authors observed that in adulthood, BPA exposure is associated with lower urinary tract dysfunction [101]. Interestingly, narrowing of the lumen of the prostatic urethra of mice treated with BPA testosterone was observed [101]. This may be similar to prostate enlargement and bladder alterations in humans. Enlargement of the prostate and urinary bladder may decrease the average flow rate. Higher BPA levels were strongly associated with reduced glomerular filtration rate and impaired renal function [102]. Chronic BPA exposure caused inflammatory infiltration, fibrosis, and tubular injury in the kidney. BPA-induced defective autophagy flux was the key mechanism behind these effects [103].

2.1.5. Gastrointestinal System

In vitro studies have shown that BPA promotes mitochondrial dysfunction, oxidative stress, and inflammation [104,105]. BPA is well known to affect liver enzymes’ activities and promote hepatic lipid accumulation [106]. High urinary BPA levels were found to be associated with non-alcoholic fatty liver disease in adults [107]. BPA has been demonstrated to promote oxidative phosphorylation abnormalities in the liver mitochondria by inhibiting the first complex of the electron transport chain [108]. In several studies, BPA has been shown to pose deleterious effects on liver function and structure in both people and animals. BPA can promote hepatic steatosis in humans [109], enhance insulin resistance in HepG2 cells [110], alter its shape, and raise liver function enzymes [111]. The upregulation of sterol regulatory element binding protein 1 has been implicated in BPA-induced hepatic lipid accumulation [112].

2.1.6. Immune System

As polymorphonuclear neutrophils (PMN) are essential in stimulating the congenital immune response, various studies looked into the effects of BPA on PMN. Findings of one study showed that BPA exposure (of more than 16 μM) caused a decline in human polymorphonuclear neutrophils (PMN) viability and demonstrated morphological alterations in these cells in both sexes [113]. A subsequent study revealed that BPA alters the immunophenotype of PMN at a dose corresponding to the serum level in healthy subjects and also at higher doses, which may eventually cause immunity problems linked to the malfunctioning of these cells [114]. BPA has also been demonstrated to exert a direct genotoxic effect in human lymphocytes by inducing the double-strand breaks of the DNA [26]. Another in vitro study revealed a significant increase in reactive oxygen species (ROS) production in erythrocytes when BPA concentration exposed was increased from 1 to 100 μM [115].
BPA exposure is known to exert complex modulatory effects on the immune system, with stimulatory or suppressive roles [116]. BPA exposure was positively linked with increased serum IgE levels [117]. In addition, higher urinary BPA levels were associated with childhood asthma [118]. Perinatal BPA exposure has been shown to increase the development of asthma and allergic disorders in children [119,120]. Studies have also shown that BPA can increase the risk of developing cancers, including prostate, breast, ovarian, lung, cervical cancer, etc. [5,121,122]. The estrogenic activities of BPA have been implicated in the mechanism behind BPA-induced cancers. In another study, BPA exposure was positively associated with the risk of developing an autism spectrum disorder (ASD) [123]. In addition, BPA was observed to increase oxidative stress-induced mitochondrial dysfunction, leading to behavioral changes in children with ASD [124].

2.1.7. Respiratory System

It has been found that postnatal exposure to BPA is a risk factor for the development of childhood asthma [125]. BPA has been reported to be associated with bronchial eosinophilic inflammation/allergic sensitization [126]. A research report published in 2019 showed that a doubling of BPA in a mother’s urine sample corresponded with (approximately) a 5 mL decrease in the child’s lung capacity [127]. In adult murine asthma models, researchers showed an aggravating effect of BPA on eosinophil infiltration and airway inflammation as evidenced by increasing levels of Th2 cytokines and chemokines [128]. The same study found that BPA affected allergic inflammation in allergic asthmatics [128]. Hence, BPA exposure may have detrimental effects on the respiratory system.

2.1.8. Nervous System

Recent research studies found that a derivative of BPA, i.e., Bisphenol F, is responsible for neuroinflammation and apoptosis of central nervous system cells, leading to abnormal neurological development in the early life stage of zebrafish [129]. A disturbance in the neurotransmitter function may be responsible for the disturbance in the nervous system. One of the neurotransmitters, GABA, is responsible for maintaining the balance between the excitatory and inhibitory systems necessary for the development of a normal brain [129]. Research studies on animal models have shown that prenatal exposure to BPA affects the mevalonate (MVA) pathway in rat brain fetuses [130]. The MVA pathway is important for the development and function of the brain [130]. Interestingly, hypothalamic exposure to BPA showed an increase in micro RNA (miRNA) miR-708-5p, which is responsible for controlling neuropeptides directly linked to obesity [131].

2.2. Underlying Mechanisms of BPA Exposure-Induced Toxicity

In 1936, Dowds and Lawson were the first to describe BPA’s estrogenic properties in vivo [132]. Later in 1997, BPA was found to act through estrogen receptors, Erα, and ERβ [133,134]. BPA is considered a “weak estrogen” as it exerts a weaker affinity with the estrogen receptors when compared to estradiol. Several investigations have been conducted into other possible mechanisms. Alternatively, BPA binds to the membrane estrogen receptor (mER) and activates non-ERS-dependent signaling pathways, causing biological dysfunction even at picomolar to nanomolar concentrations [135]. These concentrations are lower than those necessary to stimulate nuclear ERs [136]. The G protein-coupled estrogen receptor is a mER that plays a major role in BPA-induced toxicity [137].
These studies have shown that BPA-induced adverse health effects are mediated through its potential binding capacity with various nuclear receptors, including estrogen-related receptor (ERRγ), androgen receptor (AR), thyroid receptors (TRα and TRβ), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) [133,138,139]. The binding capacity of BPA with ERRγ is 80-fold higher than ERα [140]. This explains the high BPA levels in the placenta and its placental transfer and subsequent developmental effects [141]. BPA binds with AR to form an AR/BPA complex. This complex inhibits the endogenous androgen-mediated gene transcription, which is the key mechanism behind the BPA-induced anti-androgenetic effects [142,143]. BPA can bind to TR, and by acting as an antagonist, inhibit the TR-mediated transcription [144]. Similar to cortisol and dexamethasone, BPA can bind to GR and promote glucocorticoid-mediated biological functions [145]. BPA has been shown to alter the GR-linked feedback of the hypothalamic–pituitary–adrenal axis through GR expression regulation. BPA was also found to alter the expression of MR [146].
The genotoxic mechanisms of BPA are well established in the literature [147,148,149]. BPA has been shown to induce oxidative damage in human lung fibroblasts and promote DNA damage in human epithelial type 2 cells [149]. In human hepatocytes, BPA exposure at a very low concentration induced DNA damage as well as increased proliferation by enhancing cell-cycle protein expression and DNA synthesis [148]. BPA is involved in the dysfunction of certain enzymes. BPA promotes oxidative damage by reducing antioxidant enzymes [150]. BPA has been shown to influence the function of xanthine oxidase [151], lipoprotein lipase (Lpl), fatty acid acetyl-coenzyme A carboxylase β synthase [152], and fatty acid amide hydrolase [153]. BPA can cause three forms of epigenetic modifications: DNA methylation, histone modification, and miRNA alterations [154]. Growing evidence suggests that BPA-induced autophagy modulation is associated with the pathogenesis of some diseases. However, the molecular mechanisms involving BPA-induced autophagy modulation are yet to be fully understood. This may help in future treatments and drug discoveries [155,156].

3. Various Natural Products That Are Effective against BPA-Induced Toxicity

Evidence from molecular studies indicates that BPA affects various signaling pathways that are closely associated with the pathogenesis of chronic diseases. Therefore, it is important to develop new strategies that modulate/inhibit the BPA-induced toxic effects on the pathophysiologic processes of a disease. In this line of research, various studies have been performed to explore the effects of natural products against the BPA-induced toxic effects using different experimental models, including rodents, Drosophila, and zebrafish [Table 1]. In this section, we describe the effects of plant extracts or natural products against BPA-induced toxicity in two subsections: the ameliorative potential of plant extracts and natural compounds.

3.1. Plant Extract/Mixture of Natural Compounds

3.1.1. Pistacia integerrima

Pistacia integerrima is a small size tree in the family of cashew Anacardiaceae, grown in the northern area of Pakistan [157]. It has various biological functions, including antioxidant, analgesic, anti-inflammatory, and anti-microbial activities [158]. Traditionally, some of its parts have been used to treat different diseases, such as liver disorders, asthma, snake bites, and cough [159]. Despite the large number of reports on the biological activities of P. integerrima, only one study has been conducted to explore its biological activity on BPA toxicity. It was demonstrated that P. integerrima ameliorates BPA exposure-induced cardiotoxicity in rats by neutralizing oxidative stress and suppressing apoptosis through the Ubc13/p53 pathway in rats [157]. The anti-apoptotic effects of P. integerrima are shown in Figure 1.

3.1.2. Fenugreek (Trigonella foenum-graecum)

Fenugreek (Trigonella foenum-graecum) belongs to the Fabaceae family. It is a short-lived annual plant. It is one of the most well-known medicinal plants known for its healing benefits [161]. To date, several studies have focused on the health benefits of fenugreek. Previous studies have reported the anti-inflammatory [162], antioxidant [163], antidiabetic [164], anticancer [165], anti-obesity [166], hepatoprotective [167], women’s health [168], anti-hyperlipidemic [169], and sexual health-modulating activities [170] of the plant. Fenugreek seed extract treatment in mice prevented BPA exposure-induced testicular damage by decreasing malondialdehyde levels and increasing the levels of antioxidant enzymes [171].

3.1.3. Kefir

Kefir is a probiotic drink known for its health benefits. Kefir is produced through the fermentation of milk with kefir grains. Kefir grains contain various bacterial and fungal species. Kefir is known to reduce inflammation and serum cholesterol levels. It has anti-carcinogenic effects and can enhance gut health and digestion. It can also reduce hypertension and regulate reactive oxygen species. Lactobacillus species are the main bacterial flora in kefir [172]. The benefits of kefir are attributed to the complex microbiota and metabolites produced during the fermentation process [173]. In infant rats, probiotic kefir treatment attenuated the progression of BPA exposure-induced hypertension and vascular changes, including vascular ROS/NO imbalance, endothelial dysfunction and damage, and pro-apoptotic effects [174].

3.1.4. Grape Seed (Vitis vinifera L.)

Grape seed proanthocyanidins (GSP) include a complex combination of polyphenolic compounds [175]. GSP is known for its protective effects against lipid peroxidation and DNA damage, particularly in the brain and liver. In addition, it has antibacterial, antidiabetic, anti-inflammatory, and anticancer effects [176]. GSP exerts protective effects against brain damage through its antioxidant properties and chelating ability [177]. GSP has a protective role against depression and age-related mental disorders by promoting hippocampal neurogenesis [178]. A study has shown that BPA exposure caused neuroinflammation, neuronal tissue damage, increased oxidative stress, and altered the levels of neuro-specific enzymes and neurotransmitters. Treatment with GSP significantly prevented BPA-induced neurotoxicity by ameliorating all oxidative and neurotoxic parameters in Wistar rats [179].
Grape seed extracts (GSEs), which are high in flavonoids, particularly proanthocyanidin, have been demonstrated to possess potent antioxidant properties [180]. Oral treatment of GSE reduces ROS production and plasma protein carbonyl groups while increasing the activity of the endogenous antioxidant system [180]. GSE has antimutagenic and anticarcinogenic properties because it inhibits enzyme systems that produce free radicals. It protects against oxidant-induced extracellular matrix component synthesis and deposition, leading to hepatic fibrosis. GSE’s antioxidant properties have been established in clinical investigations [181]. GSE has been shown to possess anti-inflammatory and antioxidant properties, which may explain its therapeutic efficacy in a collagen-induced arthritis animal model [181]. In an isolated rat model, BPA exposure induced vascular toxicity by decreasing the vasoconstriction and vasorelaxation responses and elevating the aorta MDA levels, as well as via an in vitro analysis—BPA induced endothelial dysfunction by increasing the adhesion molecules levels [182]. In rats, RSV and GSE significantly prevented vascular toxicity [182] and metabolic syndrome [183]. The beneficial effects of GSE and RSV against BPA-induced metabolic syndrome were associated with antioxidant properties, insulin signaling regulation, and ABCG8 expression [183]. The schematic representation of insulin signaling promoting the potential of resveratrol and GSE is shown in Figure 2.

3.1.5. Ficus deltoidea (Mas Cotek)

Ficus deltoidea (FD) is an evergreen plant native to the Malayan Archipelago [184]. A wide range of chemical compounds, including terpenoids, aliphatic groups, moretenol, lupeol, luteolin, rutin, quercetin, naringenin, vitexin, and isovitexin, have been isolated and characterized from FD [185,186,187,188]. FD has been shown to have antinociceptive, antimelanogenic, antioxidant, antiphotoaging, antibacterial, and antiulcerogenic properties, and is used in diabetes and inflammation conditions [189]. A study on BPA-induced female reproductive toxicity conducted on experimental animals, showed improvement in the BPA-induced uterine abnormalities, and enhanced the expression of ERα and ERβ and the immunity gene C3 [190]. In another study, FD exerted a preventive role against BPA-induced toxicity on the ovaries in rats [191].

3.1.6. Sweet Potato (Ipomoea batatas L. Lam.)

Sweet potato (Ipomoea batatas L. Lam.), which originated from Central America, is one of the world’s most consumed crops [192]; it contains various bioactive compounds and nutrients, the sweet potato leaves, which are rich sources of antioxidants and can reduce malnutrition [192]. In addition to the antioxidant properties of sweet potato leaves, they are known for their minerals, vitamins, essential fatty acids, and dietary fibers [193,194]. A study has demonstrated that BPA administration was found to alter the structure and function of reproduction organs, eventually leading to infertility in rats. Eventually, an aqueous extract of Ipomoea batatas was found to prevent the structural alterations and biochemical changes of the testis [193].

3.1.7. Quercus dilatata Lindl. ex Royle

Quercus dilatata Lindl. ex Royle (QD) is one of the Quercus species, which is also known as Holly Oak and belongs to the family Fagaceae [195]. QD is considered a substantial source of bioactive metabolites. It is a traditional medicine for treating various diseases due to its biological activities, including antibacterial, hepatoprotective, anti-inflammatory, antioxidant, anticoagulant, and antidepressant properties [196,197,198]. Kazimi et al. have shown that the extracts of QD display protective effects against hepatotoxicity induced by BPA in rats [199]. This is the only report demonstrating QD’s ameliorative effect on BPA toxicity. They attributed this to the antioxidant and anti-inflammatory activities of QD.

3.1.8. Tualang Honey

Tualang honey is found in Malaysia and is produced by wild honey bees feeding on the nectar of Tualang trees [200]. Compared with other Malaysian types of honey, Tualang honey had the highest content of flavonoids and phenolic compounds [201,202]. Its antioxidant and anti-inflammatory properties have been investigated in various diseases [203]. However, few studies have explored its ameliorative effect on BPA-induced toxicity. A study reported that the phytochemical properties of Tualang honey ameliorate the uterine disruption induced by BPA in rats [204]. In the same study, Tualang honey treatment restored the expression and distribution of ERα, ERβ, and complement 3 (C3) in the uterus [204]. In another study, authors found that treatment with Tualang honey in BPA-exposed rats improved the normal estrous cycle and protected the uterus by reducing its morphological abnormalities [205].

3.1.9. Sesame Lignans

Sesame lignans are phytochemicals derived from sesame oil and have many biological properties [206]. They can be categorized into two types, inherent lignans, i.e., (sesamolin, sesamin), and lignans mainly formed during the process of oil production, i.e., (sesaminol, sesamol, sesamolinol, pinoresinol, matairesinol, lariciresinol, and episesamin [207]. These antioxidant lignans exhibit several biological activities, including anti-cancerous, antihypertensive, hypocholesterolemic, and antibacterial [208]. Despite the many studies that have been conducted on its biological activities, only a few studies have been performed to investigate their ameliorative effects against BPA-induced conditions. Eweda et al. have shown that hepatotoxicity and cardiotoxicity induced by BPA administration in Wistar rats were significantly attenuated by co-administration of sesame lignans. These lignans were able to restore the integrity of the heart and liver via the improvement of endogenous antioxidants [209]. In addition, oral gavage of sesame oil, a source of sesame lignans, ameliorates hepatotoxicity and DNA damage induced by BPA in mice [187]. A similar study revealed the protective activity of sesame oil against BPA exposure-induced cardiac effects in rats [210].

3.1.10. Propolis

Propolis is a natural resin-like material produced by honeybees, by mixing beeswax with their saliva and substances collected from exudates and buds [211]. Bees use propolis to construct and maintain their hives [212]. The beneficial effects of propolis on human health have been reported since ancient history. It has various biological and pharmacological activities such as anti-inflammatory, antioxidant, antibacterial, anticancer, and antifungal [213]. Due to these properties and several health benefits, propolis and its extracts have been applied in treating different diseases [214]. The protective effects of propolis supplementation against BPA toxicity have been investigated. A study showed that co-administration of propolis significantly ameliorated liver toxicity induced by BPA in freshwater fish [215]. In addition, feed intake and growth that were retarded by BPA have been significantly improved by propolis supplementation. Another study also found that co-supplementation of propolis minimizes BPA-induced structural changes in rat lungs [216]. These reports indicated that propolis can be used as a protective agent against BPA toxicity.

3.1.11. Nigella sativa Oil

Nigella sativa oil (NO) is pressed from the seeds of Nigella sativa, a widely used medicinal plant with a wide spectrum of health benefits [217,218]. Since antiquity, Nigella sativa seeds and their oil have been used to treat various diseases [218]. The therapeutic benefits of Nigella sativa seeds are attributed to the essential oil that contains thymoquinone, thymohydroquinone, carvacrol, nigellidine, and thymol [217,219]. Hyperlipidemia and obesity induced by BPA in mice were significantly alleviated by the ingestion of NO [220]. NO has also improved the reproductive and hematological functions in BPA-treated female mice [221]. In addition, in rats, co-supplementation of NO and thymoquinone have alleviated the metabolic disorders induced by BPA [222]. Thymoquinone, the major bioactive ingredient in NO has improved liver functions after BPA administration in rats [223]. Thymoquinone supplementation ameliorated BPA-induced oxidative stress and improved the antioxidant enzymes in the liver functions [223]. These reports indicate that Nigella sativa (and its oil) is an effective and natural compound for the treatment of various diseases.

3.1.12. Green Tea

Green tea is one of the most popular drinks consumed worldwide [224]. It is processed from the plant Camellia sinensis, the same plant from which black tea and Oolong tea are processed [224]. However, green tea is a non-fermented tea due to the different processing during manufacturing, which started by steaming fresh Camellia sinensis leaves to prevent fermentation, maintain a green color, and preserve compounds with healthy properties [225]. Many researchers have studied green tea (and its extracts) due to its potential for preventing and treating various diseases such as cancer, diabetes, obesity, and cardiovascular diseases [226]. These health benefits were attributed to the high content of antioxidants, and anti-inflammatory components that influence different metabolic pathways [226,227,228]. Green tea has many health benefits due to its high content of polyphenolic compounds, including phenolic acid, flavonoids, flavonols, and flavandiols [229]. Its preventive effect against BPA toxicity has also been reported. Mohsenzadeh et al. have shown that vascular toxicity induced by BPA was prevented by the co-supplementation of green tea extract, epigallocatechin gallate (EGCG), or vitamin E in rats [230]. Another experimental study in rats has shown that green tea extract or EGCG co-supplementation prevented metabolic disorders induced by BPA through improving insulin signaling pathways (Figure 2) and lipid metabolism, which are attributed to their anti-inflammatory, and antioxidant properties [231]. An in vitro and in silico study by Suthar et al. revealed that green tea extract significantly mitigated the oxidative stress induced by BPA on erythrocytes [232].

3.1.13. Soybean

Soybean, also known as soya bean, is a legume of the pea family Fabaceae. Consumption of soybeans has been associated with many beneficial effects on diseases, including diabetes, cancer, cardiovascular diseases, and obesity [233]. In addition to the high nutritional content, soybeans contain isoflavones that exhibit antioxidant, anti-inflammatory, and antimicrobial properties. In NMRI mice, co-administration of soybean extract with BPA significantly reduced fasting blood glucose and malondialdehyde levels in mice. Soybean also showed protective activity against some of the negative effects of BPA by increasing total antioxidative capacity, HOMA- and serum insulin levels [234]. In addition, in rats, the concurrent consumption of a soy-based diet counteracts the anxiogenic behavior induced by BPA [235]. The same study reported that the beneficial effects of a soy diet against BPA exposure-associated anxiogenic effects were mediated through the downregulation of estrogen receptor beta (Esr2) and melanocortin receptor (Mc3r, Mc4r) expressions in the amygdala (Figure 2).
Figure 2. (a) The schematic representation of the insulin signaling promoting potential of resveratrol, grape seed extract [183], and epigallocatechin gallate (EGCG) [231]. (b) Developmental BPA exposure is associated with anxiogenic effects in juvenile rats via downregulating the expression of estrogen receptor beta (Esr2) and melanocortin receptors (Mc3r, Mc4r) in amygdala. The soy diet supplementation mitigated anxiogenic effects by upregulating these genes [235]. IRS: insulin receptor substrate; PI3K: phosphatidylinositol 3-kinase; Akt: protein kinase B.
Figure 2. (a) The schematic representation of the insulin signaling promoting potential of resveratrol, grape seed extract [183], and epigallocatechin gallate (EGCG) [231]. (b) Developmental BPA exposure is associated with anxiogenic effects in juvenile rats via downregulating the expression of estrogen receptor beta (Esr2) and melanocortin receptors (Mc3r, Mc4r) in amygdala. The soy diet supplementation mitigated anxiogenic effects by upregulating these genes [235]. IRS: insulin receptor substrate; PI3K: phosphatidylinositol 3-kinase; Akt: protein kinase B.
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3.1.14. Pumpkin Seed Oil

Pumpkin seed oil (PSO) is rich in antioxidants and other nutritionally important nutrients such as vital fatty acids, phytosterols, amino acids, selenium, carotenes, etc. [236]. Tyrosol, ferulic acid, vanillic acid, vanillin, and luteolin are among the phenolic chemicals found in PSO. Furthermore, it has been proven to possess significant quantities of tocopherol, which translates to its antioxidant activity in minimizing lipid peroxidation [237]. Fawzy and colleagues investigated the beneficial effects of PSO on BPA exposure-induced toxicity in hepatic and testicular tissues of mice. PSO supplementation reduced DNA damage and improved histopathological changes in the liver and testes tissues exposed to BPA [238]. Additionally, administering PSO to mice before BPA treatment was the most effective method for reducing BPA’s negative effects, followed by administering PSO after BPA treatment [238].

3.1.15. Ginkgo biloba

Ginkgo biloba (Gb) (Ginkgoaceae; Maidenhair tree) has recently received a lot of interest for its neuroprotective properties [239,240]. The two principal components responsible for its distinctive pharmacological impact were flavonoids and terpenoids [241]. Gb has been shown to have estrogenic [242], antioxidant [243], and adiponectin pro-secretory effects [244] capabilities, ensuring its flexibility as a learning and memory supplement. In an animal model of rats, researchers investigated the neuroprotective effects of Gb on BPA exposure-induced neurotoxicity and discovered that Gb pretreatment enhanced cognitive function, which might be due to increased hippocampus levels of estrogen-dependent biogenic amines [245]. Simultaneously, Gb was able to effectively reduce BPA-induced oxidative stress by increasing SOD activity and adiponectin levels while lowering nitric oxide and malondialdehyde levels. Finally, Gb reduced the histopathological damage caused by BPA and blocked the activation of NF-B and caspase-3 [245].

3.1.16. Ginseng

Ginseng belongs to the Panax genus of the Araliaceae family. In folk medicine, it is used to heal various health conditions. There are various Panax species, among them the Panax ginseng (Korean ginseng), Panax notoginseng (Chinese ginseng), and Panax quinquefolius (American ginseng) are widely used species. These species differ in their ginsenoside contents. Ginsenoside Rf is one of the important compounds unique to Korean ginseng. The Korean Red Ginseng (KRG) is the end product of processed Korean ginseng and is well recognized by the Korean Food and Drug Administration [246]. KRG is effective against cancer, atherosclerosis, and neurodegenerative diseases through anti-oxidant and anti-inflammatory properties [247,248,249,250]. In an in vitro study, KRG showed anti-inflammatory effects on BPA-treated A549 lung cells by reducing the production of reactive oxygen species and altering the NF-κB activation and COX-2 expression [251]. In another in vitro study, ginseng prevented BPA-induced apoptosis by upregulating the anti-apoptosis systems [252]. The effect of KRG supplementation on BPA-induced changes in the liver and uterus of ovariectomized (OVX) animal model has also been studied, which concluded that KRG is protective against BPA-induced inflammatory responses and chemotaxis in ovariectomized (OVX) mice [253]. In another study of the OVX mice animal model, KRG inhibited BPA-induced altered lipid metabolism by regulating the lipid metabolic process-related genes [254]. In rats, ginseng alleviated the BPA-induced reproductive toxicity during pregnancy by reversing abnormal testosterone and progesterone levels to normal [255].

3.1.17. Murraya koenigii

Murraya koenigii (MK) (curry-leaf tree) belongs to the Rutaceae family. In Indian traditional medicine (Ayurveda), it is used to treat various diseases. The plant leaves were used as appetizers, analgesics, anthelmintics, and digestives. They effectively treat various conditions, including piles, itching, edema, inflammation, fresh cuts, dysentery, and bruises [256]. In experimental studies, its antimicrobial, nephroprotective, anti-oxidative, hepatoprotective, antifungal, and anti-inflammatory properties have been reported [257,258,259]. Its hydroethanolic leaf extract possesses carbazole alkaloids, which have antioxidant and radicle scavenging activities [260]. In BALB/c mice, MK extract treatment significantly alleviated the BPA-induced testicular damage as well as apoptosis. In this study, MK extract treatment improved the sperm parameters, germ cell number, and antioxidant enzyme activity, and also increased Bcl-2 and decreased caspase-9 and caspase-3 gene expression in BPA-exposed mice [261].

3.1.18. Asparagus officinalis

Asparagus officinalis (AO) has been traditionally used in many parts of Europe and Asia as traditional medicine and is consumed in salads, vegetable dishes, and soups [262]. AO has been reported to exhibit antifungal, antimutagenic, anti-inflammatory, and diuretic properties [263]. One of the complications of diabetes mellitus, i.e., diabetic nephropathy, has been effectively treated with AO [264]. Active compounds, such as flavonoids and polyphenols, were reported to be responsible for the beneficial antioxidant effect of AO [265]. In a study on the protective effects of AO against BPA-induced liver and kidney tissue damage in rats, it was shown that AO co-supplementation significantly prevented BPA-induced toxicity in these tissues, potentially by preventing GSH depletion, suppressing lipid peroxidation, and promoting antioxidative capacities [100].

3.1.19. Aloe vera (Aloe barbadensis Miller)

Aloe vera belongs to the Xanthorrhoeaceae family. It is a perennial green herb consisting of stiff gray-green lance-shaped leaves with a gel in a central mucilaginous pulp [266]. Traditionally, it is used to treat dermal problems. Additionally, it possesses anti-inflammatory, anticancer, antioxidant, antidiabetic, and antihyperlipidemic properties [267]. It has been shown to promote spermatogenesis [268]. Aloe vera gel extract co-supplementation in rats significantly ameliorated BPA-testicular toxicity attributed to its antioxidant properties [269].

3.1.20. Tribulus terrestris L.

Tribulus terrestris L. (TT) is an annual creeper generally available in India, South Africa, Australia, and Europe. It belongs to the Zygophyllaceae family. Its beneficial effects against various diseases have been mentioned in the traditional medicine of China, Indian Ayurveda, and Bulgaria [270]. It is a well-known, commercially available natural herbal product in the form of powder, capsules, and tea. It is rich in vitamins, flavonoids, alkaloids, tannins, steroids, spooning, unsaturated fatty acids, etc. [271]. Both in vitro and in vivo studies have demonstrated its anti-inflammatory, anti-hyperglycemic, antioxidant, and antibacterial properties. In a recent clinical study, TT treatment positively affected male sexual dysfunction [272]. In rats, TT supplementation significantly prevented BPA exposure-induced histopathological changes in the testes and reduced testosterone hormone levels [273].

3.2. Natural Compounds

3.2.1. Resveratrol

Resveratrol (RSV) is a biologically active polyphenol compound produced in plants that are exposed to ionizing or infectious radiation [274]. It was first isolated from white hellebore roots, and since then has been identified in almost 70 plant species. Red grapes possess high amounts of RSV, probably as a result of Vitis vinifera (grapevine) response to fungal infection. It is also present in red wine. Commercially, it is synthesized by yeasts called Saccharomyces cerevisiae [275,276,277]. RSV butyrate esters (RBE) are derived from RSV and butyric acid, and they present higher bioavailability but similar bioactivity to RSV. Perinatal BPA exposure increased body weight, lipid accumulation, and blood lipid levels, and also affected the intestinal microbiota in the female offspring rats [278]. Perinatal RBE supplementation ameliorated the BPA-induced obesity in female offspring rats. Further RBE reduced the Lactobacillus abundance, and Firmicutes/Bacteroidetes (F/B) ratio, and increased the S24-7 abundance. It also reduced fecal acetate levels [278]. In another study, RSV and mesenchymal stem cell supplementation, either alone or in combination in rats, significantly ameliorated the BPA-induced uterine endometrial damage in rodents. These effects were mediated through various molecular mechanisms of regulation, such as promoting gonadal hormone synthesis, anti-fibrotic changes, reducing oxidative stress markers, and apoptosis-related genes [279]. RSV treatment has been shown to be effective against BPA-induced cellular toxicity in rat salivary glands [280]. In a recent study, RSV was a potential candidate for preventing perinatal BPA-induced atherosclerosis lesion formation in the adult offspring Apo E mice [155]. In rats, RSV treatment was effective in preventing liver histopathological changes caused by BPA exposure [281].
In ovarian cancer cells, RSV prevented cell proliferation by suppressing the cross-talk between estrogen receptor α and insulin growth factor-1 receptor signaling pathways [282]. In another in vitro study, RSV treatment reduced calcium levels and TRPM2 channel currents in BPA-exposed cortical collecting duct cells in the kidney [283]. It also ameliorated the BPA-promoted membrane depolarization of mitochondria and apoptosis [283]. Furthermore, in rats, RSV was also shown to be a potential candidate for preventing BPA and high-fat-diet-induced developmental programming of hypertension in adult offspring [160]. These beneficial effects against BPA and high-fat-diet-induced developmental programming of hypertension were found to be mediated through AhR signaling pathways (Figure 1). In a recent study involving rats, RSV butyrate ester treatment attenuated the perinatal BPA-induced liver damage by suppressing oxidative stress and modulating the gut-microbiota, specifically Adlercreutzia and S24-7 [284]. In mice, RSV treatment was also shown to inhibit BPA-induced male reproductive toxicity [285]. Another study involving rats showed a protective effect of RSV against BPA exposure-induced damage in oral mucosa and the tongue [286].

3.2.2. Luteolin

Luteolin (3′,4′,5,7-tetrahydroxyflavone) is a naturally occurring flavonoid. Luteolin is normally found in glycosylated forms in green pepper, basic perilla leaf, seed, celery, honeysuckle bloom, and chamomile blossom [287,288,289]. Research suggests that luteolin has potent anti-inflammatory, antidiabetic, antitumor, antiapoptotic, hepatoprotective, and chemoprotective properties [290,291,292]. Having a C (6-3-6) structure, luteolin belongs to the flavone group of flavonoids. The hydroxyl moieties and double bonds are basic structures incorporated into luteolin that are known to be linked to its biochemical and biological activities [293].
In a study by Adesanoye and colleagues, BPA exposure induced antioxidant-oxidative stress imbalance and behavioral deficits in Drosophila melanogaster flies [294]. Luteolin treatment increased the survival rate and enhanced antioxidant markers in flies. It was also revealed that luteolin could ameliorate the BPA exposure-induced fatty degeneration, behavioral changes, oxidative stress, cell viability reduction, and eclosion rate of flies [294]. Oral administration of luteolin reduced BPA exposure-induced kidney abnormalities, blood urea nitrogen, creatinine, and serum uric acid levels in rats [293]. In addition, luteolin reduced inflammatory mediators caused by BPA, such as interleukin 1 beta, tumor necrosis factor-alpha, and interleukin 6. Luteolin treatment also enhanced heme oxygenase 1 (HO-1) as well as nuclear factor-like 2 (Nrf2) expressions, indicating its nephroprotective role through the Nrf2/antioxidant response element (ARE)/HO-1 pathway [293] (Figure 3).

3.2.3. Lycopene

Lycopene is a natural lipophilic unsaturated carotenoid present in red-colored fruits and vegetables, particularly tomatoes. It exerts strong antioxidant and free radical scavenging properties [295]. Its anti-oxidative capacity in ameliorating the toxic effects of different compounds has been tested previously [296,297,298]. In experimental animal studies, lycopene treatment was effective in preventing BPA exposure-induced lung injury [299], hepatic toxicity [300], and reproductive toxicity [301] through its anti-apoptotic, antioxidant, and anti-inflammatory effects. In Wistar rats, lycopene treatment reversed the BPA exposure-induced metabolic changes, such as increased total antioxidant capacity, altered lipid profile, increased glucose intolerance and insulin resistance, and decreased thyroid hormone levels [302]. Lycopene also ameliorates BPA exposure-induced memory impairment and hippocampal neuronal damage in rats [303]. The molecular mechanism of lycopene against BPA exposure-induced neurotoxicity is shown in Figure 3.
Figure 3. (a) The molecular mechanism of antioxidant effects of luteolin against BPA-induced renal toxicity through Nrf2/ARE/HO-1 pathway modulation [293]. (b) The molecular mechanism of lycopene [303], Astragalus spinosus saponins (ASS), and Astragaloside IV (AS IV) [304] against BPA exposure-induced neurotoxicity. Nrf2: nuclear factor-like 2; ARE: antioxidant response element; HO-1: heme oxygenase 1; BDNF: brain-derived neurotrophic factor; TrKb: tyrosine receptor kinase B; ERK: extracellular signal-regulated kinases; MAPK: mitogen-activated protein kinase; CREB: cAMP response element-binding protein.
Figure 3. (a) The molecular mechanism of antioxidant effects of luteolin against BPA-induced renal toxicity through Nrf2/ARE/HO-1 pathway modulation [293]. (b) The molecular mechanism of lycopene [303], Astragalus spinosus saponins (ASS), and Astragaloside IV (AS IV) [304] against BPA exposure-induced neurotoxicity. Nrf2: nuclear factor-like 2; ARE: antioxidant response element; HO-1: heme oxygenase 1; BDNF: brain-derived neurotrophic factor; TrKb: tyrosine receptor kinase B; ERK: extracellular signal-regulated kinases; MAPK: mitogen-activated protein kinase; CREB: cAMP response element-binding protein.
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3.2.4. Astragalus spinosus saponins and Astragaloside IV

Astragaloside IV (AS IV) is the core bioactive component of Astragalus spinosus. It is recognized by the presence of 3-, 6-, and/or 25-coupled glucose moieties [305]. AS IV is known to have various biological activities, such as anti-inflammatory, antiapoptotic, and antilipolytic properties [306]. AS IV supplementation lowered the nitric oxide (NO) production in brain tissues and improved the blood–brain barrier’s (BBB) permeability following ischemia [307]. Saponins are fundamental biologically active components of Astragalus spinosus [308]. A. spinosus has potential neuroprotective effects linked to its antioxidant, anti-depressive, and anti-apoptotic roles [309]. In rats, administration of ASIV or A. spinosus saponins prevented BPA exposure-induced neurotoxicity by reducing oxidative stress and restoring the expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptors [304]. The role of A. spinosus saponins and ASIV on brain-derived neurotrophic factor expression regulation is shown in Figure 3. Both treatments also improved histological changes caused by BPA exposure in various regions of the brain [304]. In another study in rats, administration of AS IV and A. spinosus saponins reversed the BPA-induced anxiogenic and depressive-like behaviors [310]. Furthermore, these compounds improved memory, restored serotonin, dopamine, and monoamine oxidase levels, and normalized the expression of Tph2 mRNA [310].

3.2.5. Naringin

Naringin (4′,5,7-Trihydroxyflavanone-7-Rhamnoglucoside) is a well-known flavanone glycoside found in various plant species, predominantly citrus fruits. Other sources of naringin include cacao, cherries, and tomatoes [311]. Naringin is known for its pharmacological benefits against inflammation, tumors, oxidative stress, and apoptosis. It is effective in preventing cardiovascular diseases, neurodegenerative disorders, genetic damage, and bone loss [312,313]. In a recent study, BPA exposure-induced cardiac toxicity by increasing the levels of aspartate aminotransferase, lactate dehydrogenase, creatine kinase–MB, triglyceride, lipid peroxidation, as well as decreasing the levels of glutathione, superoxide dismutase, catalase, and glutathione peroxidase. Interestingly, in Wistar rats treatment with higher doses of Naringin significantly ameliorated the BPA-induced cardiac toxicity parameters [314]. Mahdavinia et al. demonstrated that co-administration of Naringin ameliorated the BPA-induced cognitive dysfunction and oxidative damage in Wistar rats [315].

3.2.6. Taurine

Taurine (2-aminoethanesulfonic acid) is a natural amino acid found in various mammalian tissues, including their reproductive systems [316]. Taurine has a primary role as an antioxidant in the body [317]. It exhibits antioxidant, anticancer, antitumor, and antifibrotic activities [318,319]. Important biological functions of taurine include membrane stability, sperm motility, glucose balance, and the development of the CNS [320]. A study has shown that BPA exposure in NMRI mice impaired spermatozoa viability, and motility. Pretreatment with taurine suppressed mitochondrial oxidative stress and improved sperm motility and viability [321]. In another study, the neuroprotective effects of taurine against BPA-induced neurotoxicity were investigated. Taurine co-administration ameliorated the BPA exposure-induced behavioral changes of zebrafish by reducing oxidative stress [322].

3.2.7. Quercetin

Quercetin (3, 3′, 4′, 5, 7-pentahydroxyflavone) is a flavonoid found in plants with health benefits [323]. Quercetin is usually found in fruits, vegetables, and cereal [324]. Quercetin is widely known for its properties against allergy, inflammation, ischemia, cancer, and viral infections [325]. Mahdavinia et al. highlighted the benefits of quercetin in a BPA-induced hepatotoxicity rat model by preventing mitochondrial damage and reducing oxidative stress [108]. Likewise, the findings of Shirani et al. showed that quercetin could reduce the toxic effects of BPA in isolated mitochondria from rat kidney tissues [326]. Quercetin treatment in rats also ameliorated the toxic effects of BPA on the testis and epididymis, the impairment of spermatogenesis, and the imbalance in hormonal levels and lipid profile [327]. Quercetin has also been shown to improve neurobehavioral response in zebrafish [328], reduce oxidative stress in human erythrocytes [329], and protect against liver and kidney damage in mice [330].

3.2.8. Genistein

Genistein is a natural isoflavone and phytoestrogen of the soybean with a wide range of pharmacological properties [331]. Genistein has several biological effects, such as antioxidant, antibacterial, and anti-inflammatory activities. Thus, it has been used to treat various diseases, including osteoporosis, diabetes, lipid metabolism, and cardiovascular disease [332]. Moreover, the protective effects of genistein have been examined against BPA-induced toxicity in different organs. Maternal genistein supplementation in rats attenuated the adverse effects of gestational BPA exposure on early and late prostate development through the alteration of epithelial cell proliferation and the expression of androgen receptors [333]. Yakimchuk et al. suggested that phytoestrogen supplementation for lymphoma patients prevented lymphoid malignancies [334]. Surprisingly, prepubertal exposures to BPA and genistein modified the expression of a large number of proteins in rat sera at postnatal days 21 and 35 [335].

3.2.9. Curcumin

Turmeric (Curcuma longa), often known as ‘curcuma domestica’ belongs to the Zingiberaceae family. It is a herbaceous perennial plant [336]. Despite the fact that it contains over 300 active components, the principal biologically active component establishing the basis for the therapeutic capabilities of this plant is a substance taken from its root called curcumin [337], which is a polyphenolic molecule [338]. It has a wide range of pharmacological effects, including antioxidant, antiproliferative, anticancer, immunomodulatory, antimicrobial, and anti-inflammatory properties [339]. Curcumin has also been demonstrated to possess renoprotective [340], neuroprotective [339], and cardioprotective [340] properties. Uzunhisarcikli and Aslanturk investigated the potential therapeutic effects of curcumin and taurine by targeting the BPA-induced liver injury in rats [341]. Both curcumin and taurine reduced the negative effects of BPA in the liver by reducing lipid peroxidation products and oxidative stress [341]. A previous study that investigated the protective effects of turmeric against BPA exposure-induced genotoxicity in Wistar NIN rats revealed that turmeric treatment decreased serum malondialdehyde and urinary 8-hydroxy-2′-deoxyguanosine levels. In addition, turmeric co-administration decreased the formation of micronuclei and DNA migration in hepatic and renal tissues [342]. Curcumin has been shown to reduce BPA-induced oxidative stress and histopathological alterations in Wistar rats’ testis and cardiac tissues [343,344]. The summary of the beneficial effects of various natural compounds against BPA-induced adverse effects of experimental animal models is shown in Table 1.
A schematic diagram showing the various NPs evaluated for their potential ameliorating roles against specific BPA-induced toxicity is presented in Figure 4.

4. Conclusions

Exposure to BPA in everyday life is practically unavoidable. BPA is an estrogenic endocrine disrupting chemical, and the adverse effects on different body organs are a cause of concern. Therefore, there is a need to curb exposure to BPA in both adults and pregnant women. Even though potential molecular mechanisms underlying BPA-induced toxicity have been investigated, there is currently no specific targeted treatment for BPA-induced toxicity in humans. Hence, there is a need to develop a therapeutic drug that antagonizes BPA-induced toxicity. In the past, NPs have significantly contributed to drug discovery to treat diseases, particularly cancer and infectious diseases. An example is a fungus-derived fingolimod drug, which the FDA approved for the treatment of multiple sclerosis [345,346]. One of the major advantages of NPs in drug discovery is that they confer multiple “targets” by targeting more than one signaling pathway [347]. In addition, most NPs showed beneficial effects through their antioxidant, anti-inflammatory, and anti-apoptotic properties. The plant extracts, including P. integerrima, green tea, soy-rich diet, Gb, KRG, and ginseng, seem to be the most promising in alleviating BPA-induced toxicity. However, the active compounds in these extracts need to be explored. On the other hand, natural compounds, such as RSV, luteolin, lycopene, AS IV, genistein, and curcumin are found to be most promising in mitigating BPA toxicity. In the future, more research should be conducted to explore the complex network of molecular mechanisms to precisely understand the roles of NPs. The main challenges of NP-based drug development are attributed to its poor bioavailability and determining the optimal dose. Hence, further pharmacokinetic studies in clinical settings are warranted.

Author Contributions

Conceptualization, S.R.S., I.A.-H., H.S., M.M., S.D.; methodology, S.R.S., S.D.; software, S.R.S., S.D.; data curation, S.R.S., I.A.-H., H.S., M.M., S.D., N.J., I.F.A.; writing, S.R.S., I.A.-H., H.S., M.M., S.D., N.J., I.F.A.; editing, S.R.S., I.A.-H., H.S., M.M., S.D., N.J., I.F.A. All authors have read and agreed to the published version of the manuscript.


The present study is supported by an internal grant (IG/MED/ANAT/18/01) received from Sultan Qaboos University.


Figure 1, Figure 2, Figure 3 and Figure 4 were Created with (accessed on 15 August 2022).

Conflicts of Interest

The authors declare no conflict of interest.


  1. Carcía-Córcoles, M.T.; Cipa, M.; Rodríguez-Gómez, R.; Rivas, A.; Olea-Serrano, F.; Vílchez, J.L.; Zafra-Gómez, A. Determination of bisphenols with estrogenic activity in plastic packaged baby food samples using solid-liquid extraction and clean-up with dispersive sorbents followed by gas chromatography tandem mass spectrometry analysis. Talanta 2018, 178, 441–448. [Google Scholar] [CrossRef] [PubMed]
  2. Eladak, S.; Grisin, T.; Moison, D.; Guerquin, M.J.; N’Tumba-Byn, T.; Pozzi-Gaudin, S.; Benachi, A.; Livera, G.; Rouiller-Fabre, V.; Habert, R. A new chapter in the bisphenol A story: Bisphenol S and bisphenol F are not safe alternatives to this compound. Fertil. Steril. 2015, 103, 11–21. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Huo, X.; Chen, D.; He, Y.; Zhu, W.; Zhou, W.; Zhang, J. Bisphenol-A and Female Infertility: A Possible Role of Gene-Environment Interactions. Int. J. Environ. Res. Public Health 2015, 12, 11101–11116. [Google Scholar] [CrossRef] [PubMed]
  4. Vandenberg, L.N.; Hunt, P.A.; Myers, J.P.; Vom Saal, F.S. Human exposures to bisphenol A: Mismatches between data and assumptions. Rev. Environ. Health 2013, 28, 37–58. [Google Scholar] [CrossRef]
  5. Zhang, Z.; Alomirah, H.; Cho, H.S.; Li, Y.F.; Liao, C.; Minh, T.B.; Mohd, M.A.; Nakata, H.; Ren, N.; Kannan, K. Urinary bisphenol A concentrations and their implications for human exposure in several Asian countries. Environ. Sci. Technol. 2011, 45, 7044–7050. [Google Scholar] [CrossRef]
  6. Cousins, I.T.; Staples, C.A.; Kleĉka, G.M.; Mackay, D. A Multimedia Assessment of the Environmental Fate of Bisphenol A. Hum. Ecol. Risk Assess. Int. J. 2002, 8, 1107–1135. [Google Scholar] [CrossRef]
  7. Le, H.H.; Carlson, E.M.; Chua, J.P.; Belcher, S.M. Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol. Lett. 2008, 176, 149–156. [Google Scholar] [CrossRef][Green Version]
  8. Nam, S.H.; Seo, Y.M.; Kim, M.G. Bisphenol A migration from polycarbonate baby bottle with repeated use. Chemosphere 2010, 79, 949–952. [Google Scholar] [CrossRef]
  9. Cao, X.L.; Corriveau, J.; Popovic, S. Bisphenol a in canned food products from canadian markets. J. Food Prot. 2010, 73, 1085–1089. [Google Scholar] [CrossRef]
  10. Sajiki, J.; Miyamoto, F.; Fukata, H.; Mori, C.; Yonekubo, J.; Hayakawa, K. Bisphenol A (BPA) and its source in foods in Japanese markets. Food Addit. Contam. 2007, 24, 103–112. [Google Scholar] [CrossRef]
  11. Braunrath, R.; Podlipna, D.; Padlesak, S.; Cichna-Markl, M. Determination of bisphenol A in canned foods by immunoaffinity chromatography, HPLC, and fluorescence detection. J. Agric. Food Chem. 2005, 53, 8911–8917. [Google Scholar] [CrossRef]
  12. Biedermann, S.; Tschudin, P.; Grob, K. Transfer of bisphenol A from thermal printer paper to the skin. Anal. Bioanal. Chem. 2010, 398, 571–576. [Google Scholar] [CrossRef]
  13. Calafat, A.M.; Weuve, J.; Ye, X.; Jia, L.T.; Hu, H.; Ringer, S.; Huttner, K.; Hauser, R. Exposure to bisphenol A and other phenols in neonatal intensive care unit premature infants. Environ. Health Perspect. 2009, 117, 639–644. [Google Scholar] [CrossRef][Green Version]
  14. Kanno, Y.; Okada, H.; Kobayashi, T.; Takenaka, T.; Suzuki, H. Effects of endocrine disrupting substance on estrogen receptor gene transcription in dialysis patients. Ther. Apher. Dial. Off. Peer-Rev. J. Int. Soc. Apher. Jpn. Soc. Apher. Jpn. Soc. Dial. Ther. 2007, 11, 262–265. [Google Scholar] [CrossRef]
  15. Zimmerman-Downs, J.M.; Shuman, D.; Stull, S.C.; Ratzlaff, R.E. Bisphenol A blood and saliva levels prior to and after dental sealant placement in adults. J. Dent. Hyg. JDH 2010, 84, 145–150. [Google Scholar]
  16. Husøy, T.; Beausoleil, C.; Benford, D.; Brantsaeter, A.L.; Calamandrei, G.; Doerge, D.; Fowler, P.; Greaves, P.; Gundert-Remy, U.; Hart, A.; et al. Scientific Opinion on the Risks to Public Health Related to the Presence of Bisphenol A (BPA) in Foodstuffs: Part I-Exposure Assessment. EFSA J. 2015, 13, 3978. [Google Scholar]
  17. Almeida, S.; Raposo, A.; Almeida-González, M.; Carrascosa, C. Bisphenol A: Food Exposure and Impact on Human Health. Compr. Rev. Food Sci. Food Saf. 2018, 17, 1503–1517. [Google Scholar] [CrossRef][Green Version]
  18. Inoue, H.; Yuki, G.; Yokota, H.; Kato, S. Bisphenol A glucuronidation and absorption in rat intestine. Drug Metab. Dispos. Biol. Fate Chem. 2003, 31, 140–144. [Google Scholar] [CrossRef][Green Version]
  19. Yokota, H.; Iwano, H.; Endo, M.; Kobayashi, T.; Inoue, H.; Ikushiro, S.; Yuasa, A. Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver. Biochem. J. 1999, 340 Pt 2, 405–409. [Google Scholar] [CrossRef]
  20. Genuis, S.J.; Beesoon, S.; Birkholz, D.; Lobo, R.A. Human excretion of bisphenol A: Blood, urine, and sweat (BUS) study. J. Environ. Public Health 2012, 2012, 185731. [Google Scholar] [CrossRef][Green Version]
  21. Ginsberg, G.; Rice, D.C. Does rapid metabolism ensure negligible risk from bisphenol A? Environ. Health Perspect. 2009, 117, 1639–1643. [Google Scholar] [CrossRef]
  22. Martínez, M.; González, N.; Martí, A.; Marquès, M.; Rovira, J.; Kumar, V.; Nadal, M. Human biomonitoring of bisphenol A along pregnancy: An exposure reconstruction of the EXHES-Spain cohort. Environ. Res. 2021, 196, 110941. [Google Scholar] [CrossRef]
  23. Völkel, W.; Colnot, T.; Csanády, G.A.; Filser, J.G.; Dekant, W. Metabolism and kinetics of bisphenol a in humans at low doses following oral administration. Chem. Res. Toxicol. 2002, 15, 1281–1287. [Google Scholar] [CrossRef]
  24. Vandenberg, L.N.; Chahoud, I.; Heindel, J.J.; Padmanabhan, V.; Paumgartten, F.J.; Schoenfelder, G. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ. Health Perspect. 2010, 118, 1055–1070. [Google Scholar] [CrossRef][Green Version]
  25. Soriano, S.; Ripoll, C.; Alonso-Magdalena, P.; Fuentes, E.; Quesada, I.; Nadal, A.; Martinez-Pinna, J. Effects of Bisphenol A on ion channels: Experimental evidence and molecular mechanisms. Steroids 2016, 111, 12–20. [Google Scholar] [CrossRef][Green Version]
  26. Hafezi, S.A.; Abdel-Rahman, W.M. The Endocrine Disruptor Bisphenol A (BPA) Exerts a Wide Range of Effects in Carcinogenesis and Response to Therapy. Curr. Mol. Pharmacol. 2019, 12, 230–238. [Google Scholar] [CrossRef]
  27. Csanády, G.A.; Oberste-Frielinghaus, H.R.; Semder, B.; Baur, C.; Schneider, K.T.; Filser, J.G. Distribution and unspecific protein binding of the xenoestrogens bisphenol A and daidzein. Arch. Toxicol. 2002, 76, 299–305. [Google Scholar] [CrossRef] [PubMed]
  28. Geens, T.; Neels, H.; Covaci, A. Distribution of bisphenol-A, triclosan and n-nonylphenol in human adipose tissue, liver and brain. Chemosphere 2012, 87, 796–802. [Google Scholar] [CrossRef] [PubMed]
  29. Staples, C.A.; Dorn, P.B.; Klecka, G.M.; O’Block, S.T.; Harris, L.R. A review of the environmental fate, effects, and exposures of bisphenol A. Chemosphere 1998, 36, 2149–2173. [Google Scholar] [CrossRef]
  30. Shehab, Z.N.; Jamil, N.R.; Aris, A.Z. Occurrence, environmental implications and risk assessment of Bisphenol A in association with colloidal particles in an urban tropical river in Malaysia. Sci. Rep. 2020, 10, 20360. [Google Scholar] [CrossRef]
  31. Selvaraj, K.K.; Shanmugam, G.; Sampath, S.; Larsson, D.G.; Ramaswamy, B.R. GC-MS determination of bisphenol A and alkylphenol ethoxylates in river water from India and their ecotoxicological risk assessment. Ecotoxicol. Environ. Saf. 2014, 99, 13–20. [Google Scholar] [CrossRef]
  32. Esteban, S.; Gorga, M.; Petrovic, M.; González-Alonso, S.; Barceló, D.; Valcárcel, Y. Analysis and occurrence of endocrine-disrupting compounds and estrogenic activity in the surface waters of Central Spain. Sci. Total Environ. 2014, 466–467, 939–951. [Google Scholar] [CrossRef]
  33. Heemken, O.P.; Reincke, H.; Stachel, B.; Theobald, N. The occurrence of xenoestrogens in the Elbe river and the North Sea. Chemosphere 2001, 45, 245–259. [Google Scholar] [CrossRef]
  34. Wang, Q.; Chen, M.; Shan, G.; Chen, P.; Cui, S.; Yi, S.; Zhu, L. Bioaccumulation and biomagnification of emerging bisphenol analogues in aquatic organisms from Taihu Lake, China. Sci. Total Environ. 2017, 598, 814–820. [Google Scholar] [CrossRef]
  35. Chiriac, F.L.; Paun, I.; Pirvu, F.; Pascu, L.F.; Galaon, T. Occurrence and Fate of Bisphenol A and its Congeners in Two Wastewater Treatment Plants and Receiving Surface Waters in Romania. Environ. Toxicol. Chem. 2021, 40, 435–446. [Google Scholar] [CrossRef]
  36. Kim, D.; Kwak, J.I.; An, Y.J. Effects of bisphenol A in soil on growth, photosynthesis activity, and genistein levels in crop plants (Vigna radiata). Chemosphere 2018, 209, 875–882. [Google Scholar] [CrossRef]
  37. Gibson, R.; Durán-Álvarez, J.C.; Estrada, K.L.; Chávez, A.; Jiménez Cisneros, B. Accumulation and leaching potential of some pharmaceuticals and potential endocrine disruptors in soils irrigated with wastewater in the Tula Valley, Mexico. Chemosphere 2010, 81, 1437–1445. [Google Scholar] [CrossRef]
  38. Staples, C.; Friederich, U.; Hall, T.; Klečka, G.; Mihaich, E.; Ortego, L.; Caspers, N.; Hentges, S. Estimating potential risks to terrestrial invertebrates and plants exposed to bisphenol A in soil amended with activated sludge biosolids. Environ. Toxicol. Chem. 2010, 29, 467–475. [Google Scholar] [CrossRef]
  39. Arp, H.P.H.; Morin, N.A.O.; Hale, S.E.; Okkenhaug, G.; Breivik, K.; Sparrevik, M. The mass flow and proposed management of bisphenol A in selected Norwegian waste streams. Waste Manag. 2017, 60, 775–785. [Google Scholar] [CrossRef]
  40. Bi, X.; Simoneit, B.; Wang, Z.; Wang, X.; Sheng, G.; Fu, J. The Major Components of Particles Emitted During Recycling of Waste Printed Circuit Boards in a Typical E-Waste Workshop of South China. Atmos. Environ. 2010, 44, 4440–4445. [Google Scholar] [CrossRef]
  41. Gasser, C.A.; Yu, L.; Svojitka, J.; Wintgens, T.; Ammann, E.M.; Shahgaldian, P.; Corvini, P.F.; Hommes, G. Advanced enzymatic elimination of phenolic contaminants in wastewater: A nano approach at field scale. Appl. Microbiol. Biotechnol. 2014, 98, 3305–3316. [Google Scholar] [CrossRef][Green Version]
  42. Li, X.; Chen, S.; Li, L.; Quan, X.; Zhao, H. Electrochemically enhanced adsorption of nonylphenol on carbon nanotubes: Kinetics and isotherms study. J. Colloid Interface Sci. 2014, 415, 159–164. [Google Scholar] [CrossRef]
  43. Cajthaml, T.; Kresinová, Z.; Svobodová, K.; Möder, M. Biodegradation of endocrine-disrupting compounds and suppression of estrogenic activity by ligninolytic fungi. Chemosphere 2009, 75, 745–750. [Google Scholar] [CrossRef]
  44. Asgher, M.; Bhatti, H.N.; Ashraf, M.; Legge, R.L. Recent developments in biodegradation of industrial pollutants by white rot fungi and their enzyme system. Biodegradation 2008, 19, 771–783. [Google Scholar] [CrossRef] [PubMed]
  45. Hirano, T.; Honda, Y.; Watanabe, T.; Kuwahara, M. Degradation of bisphenol A by the lignin-degrading enzyme, manganese peroxidase, produced by the white-rot basidiomycete, Pleurotus ostreatus. Biosci. Biotechnol. Biochem. 2000, 64, 1958–1962. [Google Scholar] [CrossRef] [PubMed][Green Version]
  46. Chouhan, S.; Yadav, S.K.; Prakash, J.; Swati; Singh, S.P. Effect of Bisphenol A on human health and its degradation by microorganisms: A review. Ann. Microbiol. 2014, 64, 13–21. [Google Scholar] [CrossRef]
  47. Lontie, R. Copper Proteins and Copper Enzymes; CRC Press: Boca Raton, FL, USA, 1984; Volume 1. [Google Scholar]
  48. Tsutsumi, Y.; Haneda, T.; Nishida, T. Removal of estrogenic activities of bisphenol A and nonylphenol by oxidative enzymes from lignin-degrading basidiomycetes. Chemosphere 2001, 42, 271–276. [Google Scholar] [CrossRef][Green Version]
  49. Temuujin, J.; Surenjav, E.; Ruescher, C.H.; Vahlbruch, J. Processing and uses of fly ash addressing radioactivity (critical review). Chemosphere 2019, 216, 866–882. [Google Scholar] [CrossRef]
  50. Xie, J.; Meng, W.; Wu, D.; Zhang, Z.; Kong, H. Removal of organic pollutants by surfactant modified zeolite: Comparison between ionizable phenolic compounds and non-ionizable organic compounds. J. Hazard. Mater. 2012, 231–232, 57–63. [Google Scholar] [CrossRef]
  51. Dong, Y.; Wu, D.; Chen, X.; Lin, Y. Adsorption of bisphenol A from water by surfactant-modified zeolite. J. Colloid Interface Sci. 2010, 348, 585–590. [Google Scholar] [CrossRef]
  52. Karim, Z.; Husain, Q. Application of fly ash adsorbed peroxidase for the removal of bisphenol A in batch process and continuous reactor: Assessment of genotoxicity of its product. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2010, 48, 3385–3390. [Google Scholar] [CrossRef]
  53. Galloway, T.; Cipelli, R.; Guralnik, J.; Ferrucci, L.; Bandinelli, S.; Corsi, A.M.; Money, C.; McCormack, P.; Melzer, D. Daily bisphenol A excretion and associations with sex hormone concentrations: Results from the InCHIANTI adult population study. Environ. Health Perspect. 2010, 118, 1603–1608. [Google Scholar] [CrossRef][Green Version]
  54. Arase, S.; Ishii, K.; Igarashi, K.; Aisaki, K.; Yoshio, Y.; Matsushima, A.; Shimohigashi, Y.; Arima, K.; Kanno, J.; Sugimura, Y. Endocrine disrupter bisphenol A increases in situ estrogen production in the mouse urogenital sinus. Biol. Reprod. 2011, 84, 734–742. [Google Scholar] [CrossRef]
  55. Pivonello, C.; Muscogiuri, G.; Nardone, A.; Garifalos, F.; Provvisiero, D.P.; Verde, N.; de Angelis, C.; Conforti, A.; Piscopo, M.; Auriemma, R.S.; et al. Bisphenol A: An emerging threat to female fertility. Reprod. Biol. Endocrinol. RBE 2020, 18, 22. [Google Scholar] [CrossRef]
  56. La Rocca, C.; Tait, S.; Guerranti, C.; Busani, L.; Ciardo, F.; Bergamasco, B.; Stecca, L.; Perra, G.; Mancini, F.R.; Marci, R.; et al. Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas. Int. J. Environ. Res. Public Health 2014, 11, 10146–10164. [Google Scholar] [CrossRef][Green Version]
  57. Tachibana, T.; Wakimoto, Y.; Nakamuta, N.; Phichitraslip, T.; Wakitani, S.; Kusakabe, K.; Hondo, E.; Kiso, Y. Effects of bisphenol A (BPA) on placentation and survival of the neonates in mice. J. Reprod. Dev. 2007, 53, 509–514. [Google Scholar] [CrossRef][Green Version]
  58. Honma, S.; Suzuki, A.; Buchanan, D.L.; Katsu, Y.; Watanabe, H.; Iguchi, T. Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. Reprod. Toxicol. 2002, 16, 117–122. [Google Scholar] [CrossRef]
  59. Lawson, C.; Gieske, M.; Murdoch, B.; Ye, P.; Li, Y.; Hassold, T.; Hunt, P.A. Gene expression in the fetal mouse ovary is altered by exposure to low doses of bisphenol A. Biol. Reprod. 2011, 84, 79–86. [Google Scholar] [CrossRef]
  60. Rodríguez, H.A.; Santambrosio, N.; Santamaría, C.G.; Muñoz-de-Toro, M.; Luque, E.H. Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reprod. Toxicol. 2010, 30, 550–557. [Google Scholar] [CrossRef]
  61. Sugiura-Ogasawara, M.; Ozaki, Y.; Sonta, S.; Makino, T.; Suzumori, K. Exposure to bisphenol A is associated with recurrent miscarriage. Hum. Reprod. 2005, 20, 2325–2329. [Google Scholar] [CrossRef][Green Version]
  62. Mínguez-Alarcón, L.; Gaskins, A.J.; Chiu, Y.H.; Williams, P.L.; Ehrlich, S.; Chavarro, J.E.; Petrozza, J.C.; Ford, J.B.; Calafat, A.M.; Hauser, R. Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic. Hum. Reprod. 2015, 30, 2120–2128. [Google Scholar] [CrossRef] [PubMed][Green Version]
  63. Vahedi, M.; Saeedi, A.; Poorbaghi, S.L.; Sepehrimanesh, M.; Fattahi, M. Metabolic and endocrine effects of bisphenol A exposure in market seller women with polycystic ovary syndrome. Environ. Sci. Pollut. Res. Int. 2016, 23, 23546–23550. [Google Scholar] [CrossRef] [PubMed]
  64. Shen, Y.; Zheng, Y.; Jiang, J.; Liu, Y.; Luo, X.; Shen, Z.; Chen, X.; Wang, Y.; Dai, Y.; Zhao, J.; et al. Higher urinary bisphenol A concentration is associated with unexplained recurrent miscarriage risk: Evidence from a case-control study in eastern China. PLoS ONE 2015, 10, e0127886. [Google Scholar] [CrossRef] [PubMed][Green Version]
  65. Schönfelder, G.; Friedrich, K.; Paul, M.; Chahoud, I. Developmental effects of prenatal exposure to bisphenol a on the uterus of rat offspring. Neoplasia 2004, 6, 584–594. [Google Scholar] [CrossRef][Green Version]
  66. Markey, C.M.; Luque, E.H.; Munoz De Toro, M.; Sonnenschein, C.; Soto, A.M. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol. Reprod. 2001, 65, 1215–1223. [Google Scholar] [CrossRef][Green Version]
  67. Ehrlich, S.; Williams, P.L.; Missmer, S.A.; Flaws, J.A.; Berry, K.F.; Calafat, A.M.; Ye, X.; Petrozza, J.C.; Wright, D.; Hauser, R. Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization. Environ. Health Perspect. 2012, 120, 978–983. [Google Scholar] [CrossRef][Green Version]
  68. Ji, H.; Miao, M.; Liang, H.; Shi, H.; Ruan, D.; Li, Y.; Wang, J.; Yuan, W. Exposure of environmental Bisphenol A in relation to routine sperm parameters and sperm movement characteristics among fertile men. Sci. Rep. 2018, 8, 17548. [Google Scholar] [CrossRef]
  69. Li, D.; Zhou, Z.; Qing, D.; He, Y.; Wu, T.; Miao, M.; Wang, J.; Weng, X.; Ferber, J.R.; Herrinton, L.J.; et al. Occupational exposure to bisphenol-A (BPA) and the risk of self-reported male sexual dysfunction. Hum. Reprod. 2010, 25, 519–527. [Google Scholar] [CrossRef][Green Version]
  70. Jin, P.; Wang, X.; Chang, F.; Bai, Y.; Li, Y.; Zhou, R.; Chen, L. Low dose bisphenol A impairs spermatogenesis by suppressing reproductive hormone production and promoting germ cell apoptosis in adult rats. J. Biomed. Res. 2013, 27, 135–144. [Google Scholar] [CrossRef]
  71. Sirasanagandla, S.R.; Al-Huseini, I.; Sofin, R.G.S.; Das, S. Perinatal exposure to Bisphenol A and developmental programming of the cardiovascular changes in the offspring. Curr. Med. Chem. 2022, 29, 4235–4250. [Google Scholar] [CrossRef]
  72. Wei, J.; Lin, Y.; Li, Y.; Ying, C.; Chen, J.; Song, L.; Zhou, Z.; Lv, Z.; Xia, W.; Chen, X.; et al. Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet. Endocrinology 2011, 152, 3049–3061. [Google Scholar] [CrossRef][Green Version]
  73. Ma, Y.; Xia, W.; Wang, D.Q.; Wan, Y.J.; Xu, B.; Chen, X.; Li, Y.Y.; Xu, S.Q. Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia 2013, 56, 2059–2067. [Google Scholar] [CrossRef]
  74. Alonso-Magdalena, P.; Vieira, E.; Soriano, S.; Menes, L.; Burks, D.; Quesada, I.; Nadal, A. Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environ. Health Perspect. 2010, 118, 1243–1250. [Google Scholar] [CrossRef][Green Version]
  75. Miyawaki, J.; Sakayama, K.; Kato, H.; Yamamoto, H.; Masuno, H. Perinatal and postnatal exposure to bisphenol a increases adipose tissue mass and serum cholesterol level in mice. J. Atheroscler. Thromb. 2007, 14, 245–252. [Google Scholar] [CrossRef][Green Version]
  76. Chen, X.; Bao, H.H.; Wu, W.K.; Yan, S.Q.; Sheng, J.; Xu, Y.Y.; Gu, C.L.; Huang, K.; Cao, H.; Su, P.Y.; et al. Exposure to bisphenol A during maternal pregnancy and the emotional and behavioral impact on their preschool children. Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi 2018, 39, 188–193. [Google Scholar] [CrossRef]
  77. Perera, F.; Nolte, E.L.R.; Wang, Y.; Margolis, A.E.; Calafat, A.M.; Wang, S.; Garcia, W.; Hoepner, L.A.; Peterson, B.S.; Rauh, V.; et al. Bisphenol A exposure and symptoms of anxiety and depression among inner city children at 10-12 years of age. Environ. Res. 2016, 151, 195–202. [Google Scholar] [CrossRef][Green Version]
  78. Lang, I.A.; Galloway, T.S.; Scarlett, A.; Henley, W.E.; Depledge, M.; Wallace, R.B.; Melzer, D. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 2008, 300, 1303–1310. [Google Scholar] [CrossRef]
  79. Melzer, D.; Gates, P.; Osborne, N.J.; Henley, W.E.; Cipelli, R.; Young, A.; Money, C.; McCormack, P.; Schofield, P.; Mosedale, D.; et al. Urinary bisphenol a concentration and angiography-defined coronary artery stenosis. PLoS ONE 2012, 7, e43378. [Google Scholar] [CrossRef]
  80. Xiong, Q.; Liu, X.; Shen, Y.; Yu, P.; Chen, S.; Hu, J.; Yu, J.; Li, J.; Wang, H.S.; Cheng, X.; et al. Elevated serum Bisphenol A level in patients with dilated cardiomyopathy. Int. J. Environ. Res. Public Health 2015, 12, 5329–5337. [Google Scholar] [CrossRef][Green Version]
  81. Patel, B.B.; Raad, M.; Sebag, I.A.; Chalifour, L.E. Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice. Toxicol. Sci. Off. J. Soc. Toxicol. 2013, 133, 174–185. [Google Scholar] [CrossRef][Green Version]
  82. Posnack, N.G.; Jaimes, R., 3rd; Asfour, H.; Swift, L.M.; Wengrowski, A.M.; Sarvazyan, N.; Kay, M.W. Bisphenol A exposure and cardiac electrical conduction in excised rat hearts. Environ. Health Perspect. 2014, 122, 384–390. [Google Scholar] [CrossRef][Green Version]
  83. Cagampang, F.R.; Torrens, C.; Anthony, F.W.; Hanson, M.A. Developmental exposure to bisphenol A leads to cardiometabolic dysfunction in adult mouse offspring. J. Dev. Orig. Health Dis. 2012, 3, 287–292. [Google Scholar] [CrossRef]
  84. Yan, S.; Chen, Y.; Dong, M.; Song, W.; Belcher, S.M.; Wang, H.S. Bisphenol A and 17β-estradiol promote arrhythmia in the female heart via alteration of calcium handling. PLoS ONE 2011, 6, e25455. [Google Scholar] [CrossRef][Green Version]
  85. O’Reilly, A.O.; Eberhardt, E.; Weidner, C.; Alzheimer, C.; Wallace, B.A.; Lampert, A. Bisphenol A binds to the local anesthetic receptor site to block the human cardiac sodium channel. PLoS ONE 2012, 7, e41667. [Google Scholar] [CrossRef] [PubMed]
  86. Belcher, S.M.; Chen, Y.; Yan, S.; Wang, H.S. Rapid estrogen receptor-mediated mechanisms determine the sexually dimorphic sensitivity of ventricular myocytes to 17β-estradiol and the environmental endocrine disruptor bisphenol A. Endocrinology 2012, 153, 712–720. [Google Scholar] [CrossRef] [PubMed]
  87. Lind, P.M.; Lind, L. Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis in the elderly. Atherosclerosis 2011, 218, 207–213. [Google Scholar] [CrossRef] [PubMed]
  88. Shankar, A.; Teppala, S.; Sabanayagam, C. Bisphenol A and peripheral arterial disease: Results from the NHANES. Environ. Health Perspect. 2012, 120, 1297–1300. [Google Scholar] [CrossRef] [PubMed]
  89. Sui, Y.; Park, S.H.; Helsley, R.N.; Sunkara, M.; Gonzalez, F.J.; Morris, A.J.; Zhou, C. Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice. J. Am. Heart Assoc. 2014, 3, e000492. [Google Scholar] [CrossRef][Green Version]
  90. Choi, Y.J.; Lee, Y.A.; Hong, Y.C.; Cho, J.; Lee, K.S.; Shin, C.H.; Kim, B.N.; Kim, J.I.; Park, S.J.; Bisgaard, H.; et al. Effect of prenatal bisphenol A exposure on early childhood body mass index through epigenetic influence on the insulin-like growth factor 2 receptor (IGF2R) gene. Environ. Int. 2020, 143, 105929. [Google Scholar] [CrossRef]
  91. Junge, K.M.; Leppert, B.; Jahreis, S.; Wissenbach, D.K.; Feltens, R.; Grützmann, K.; Thürmann, L.; Bauer, T.; Ishaque, N.; Schick, M.; et al. MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development. Clin. Epigenetics 2018, 10, 58. [Google Scholar] [CrossRef]
  92. Ropero, A.B.; Alonso-Magdalena, P.; García-García, E.; Ripoll, C.; Fuentes, E.; Nadal, A. Bisphenol-A disruption of the endocrine pancreas and blood glucose homeostasis. Int. J. Androl. 2008, 31, 194–200. [Google Scholar] [CrossRef]
  93. Moon, M.K.; Jeong, I.K.; Oh, T.J.; Ahn, H.Y.; Kim, H.H.; Park, Y.J.; Jang, H.C.; Park, K.S. Long-term oral exposure to bisphenol A induces glucose intolerance and insulin resistance. J. Endocrinol. 2015, 226, 35–42. [Google Scholar] [CrossRef][Green Version]
  94. Duan, Y.; Yao, Y.; Wang, B.; Han, L.; Wang, L.; Sun, H.; Chen, L. Association of urinary concentrations of bisphenols with type 2 diabetes mellitus: A case-control study. Environ. Pollut. 2018, 243, 1719–1726. [Google Scholar] [CrossRef]
  95. Li, A.J.; Xue, J.; Lin, S.; Al-Malki, A.L.; Al-Ghamdi, M.A.; Kumosani, T.A.; Kannan, K. Urinary concentrations of environmental phenols and their association with type 2 diabetes in a population in Jeddah, Saudi Arabia. Environ. Res. 2018, 166, 544–552. [Google Scholar] [CrossRef]
  96. Bellavia, A.; Cantonwine, D.E.; Meeker, J.D.; Hauser, R.; Seely, E.W.; McElrath, T.F.; James-Todd, T. Pregnancy urinary bisphenol-A concentrations and glucose levels across BMI categories. Environ. Int. 2018, 113, 35–41. [Google Scholar] [CrossRef]
  97. Chiu, Y.H.; Mínguez-Alarcón, L.; Ford, J.B.; Keller, M.; Seely, E.W.; Messerlian, C.; Petrozza, J.; Williams, P.L.; Ye, X.; Calafat, A.M.; et al. Trimester-Specific Urinary Bisphenol A Concentrations and Blood Glucose Levels Among Pregnant Women From a Fertility Clinic. J. Clin. Endocrinol. Metab. 2017, 102, 1350–1357. [Google Scholar] [CrossRef][Green Version]
  98. Eng, D.S.; Lee, J.M.; Gebremariam, A.; Meeker, J.D.; Peterson, K.; Padmanabhan, V. Bisphenol A and chronic disease risk factors in US children. Pediatrics 2013, 132, e637–e645. [Google Scholar] [CrossRef][Green Version]
  99. Akash, M.S.H.; Sabir, S.; Rehman, K. Bisphenol A-induced metabolic disorders: From exposure to mechanism of action. Environ. Toxicol. Pharmacol. 2020, 77, 103373. [Google Scholar] [CrossRef]
  100. Poormoosavi, S.M.; Najafzadehvarzi, H.; Behmanesh, M.A.; Amirgholami, R. Protective effects of Asparagus officinalis extract against Bisphenol A- induced toxicity in Wistar rats. Toxicol. Rep. 2018, 5, 427–433. [Google Scholar] [CrossRef]
  101. Nicholson, T.M.; Nguyen, J.L.; Leverson, G.E.; Taylor, J.A.; Vom Saal, F.S.; Wood, R.W.; Ricke, W.A. Endocrine disruptor bisphenol A is implicated in urinary voiding dysfunction in male mice. Am. J. Physiol. Ren. Physiol. 2018, 315, F1208–F1216. [Google Scholar] [CrossRef]
  102. Kataria, A.; Trasande, L.; Trachtman, H. The effects of environmental chemicals on renal function. Nat. Rev Nephrol. 2015, 11, 610–625. [Google Scholar] [CrossRef] [PubMed]
  103. Priego, A.R.; Parra, E.G.; Mas, S.; Morgado-Pascual, J.L.; Ruiz-Ortega, M.; Rayego-Mateos, S. Bisphenol A Modulates Autophagy and Exacerbates Chronic Kidney Damage in Mice. Int. J. Mol. Sci. 2021, 22, 7189. [Google Scholar] [CrossRef] [PubMed]
  104. Bosch-Panadero, E.; Mas, S.; Civantos, E.; Abaigar, P.; Camarero, V.; Ruiz-Priego, A.; Ortiz, A.; Egido, J.; González-Parra, E. Bisphenol A is an exogenous toxin that promotes mitochondrial injury and death in tubular cells. Environ. Toxicol. 2018, 33, 325–332. [Google Scholar] [CrossRef] [PubMed]
  105. Gassman, N.R. Induction of oxidative stress by bisphenol A and its pleiotropic effects. Environ. Mol. Mutagenesis 2017, 58, 60–71. [Google Scholar] [CrossRef] [PubMed][Green Version]
  106. Lee, M.R.; Park, H.; Bae, S.; Lim, Y.H.; Kim, J.H.; Cho, S.H.; Hong, Y.C. Urinary bisphenol A concentrations are associated with abnormal liver function in the elderly: A repeated panel study. J. Epidemiol. Community Health 2014, 68, 312–317. [Google Scholar] [CrossRef] [PubMed]
  107. Kim, D.; Yoo, E.R.; Li, A.A.; Cholankeril, G.; Tighe, S.P.; Kim, W.; Harrison, S.A.; Ahmed, A. Elevated urinary bisphenol A levels are associated with non-alcoholic fatty liver disease among adults in the United States. Liver Int. Off. J. Int. Assoc. Study Liver 2019, 39, 1335–1342. [Google Scholar] [CrossRef] [PubMed]
  108. Mahdavinia, M.; Alizadeh, S.; Raesi Vanani, A.; Dehghani, M.A.; Shirani, M.; Alipour, M.; Shahmohammadi, H.A.; Rafiei Asl, S. Effects of quercetin on bisphenol A-induced mitochondrial toxicity in rat liver. Iran. J. Basic Med. Sci. 2019, 22, 499–505. [Google Scholar] [CrossRef]
  109. Martella, A.; Silvestri, C.; Maradonna, F.; Gioacchini, G.; Allarà, M.; Radaelli, G.; Overby, D.R.; Di Marzo, V.; Carnevali, O. Bisphenol A Induces Fatty Liver by an Endocannabinoid-Mediated Positive Feedback Loop. Endocrinology 2016, 157, 1751–1763. [Google Scholar] [CrossRef][Green Version]
  110. Geng, S.; Wang, S.; Zhu, W.; Xie, C.; Li, X.; Wu, J.; Zhu, J.; Jiang, Y.; Yang, X.; Li, Y.; et al. Curcumin attenuates BPA-induced insulin resistance in HepG2 cells through suppression of JNK/p38 pathways. Toxicol. Lett. 2017, 272, 75–83. [Google Scholar] [CrossRef]
  111. Nakagawa, Y.; Tayama, S. Metabolism and cytotoxicity of bisphenol A and other bisphenols in isolated rat hepatocytes. Arch. Toxicol. 2000, 74, 99–105. [Google Scholar] [CrossRef]
  112. Lin, Y.; Ding, D.; Huang, Q.; Liu, Q.; Lu, H.; Lu, Y.; Chi, Y.; Sun, X.; Ye, G.; Zhu, H.; et al. Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease. Biochim. Biophys. Acta. Mol. Cell Biol. Lipids 2017, 1862, 869–882. [Google Scholar] [CrossRef]
  113. Ratajczak-Wrona, W.; Nowak, K.; Garley, M.; Grubczak, K.; Dabrowska, D.; Iwaniuk, A.; Wilk, S.; Moniuszko, M.; Czerniecki, J.; Wolczynski, S.; et al. Expression of serine proteases in neutrophils from women and men: Regulation by endocrine disruptor bisphenol A. Environ. Toxicol. Pharmacol. 2019, 71, 103212. [Google Scholar] [CrossRef]
  114. Ratajczak-Wrona, W.; Rusak, M.; Nowak, K.; Dabrowska, M.; Radziwon, P.; Jablonska, E. Effect of bisphenol A on human neutrophils immunophenotype. Sci. Rep. 2020, 10, 3083. [Google Scholar] [CrossRef][Green Version]
  115. Baralla, E.; Demontis, M.P.; Varoni, M.V.; Pasciu, V. Bisphenol A and Bisphenol S Oxidative Effects in Sheep Red Blood Cells: An In Vitro Study. BioMed Res. Int. 2021, 2021, 6621264. [Google Scholar] [CrossRef]
  116. Michałowicz, J. Bisphenol A—Sources, toxicity and biotransformation. Environ. Toxicol. Pharmacol. 2014, 37, 738–758. [Google Scholar] [CrossRef]
  117. Wang, I.J.; Chen, C.Y.; Bornehag, C.G. Bisphenol A exposure may increase the risk of development of atopic disorders in children. Int. J. Hyg. Environ. Health 2016, 219, 311–316. [Google Scholar] [CrossRef]
  118. Donohue, K.M.; Miller, R.L.; Perzanowski, M.S.; Just, A.C.; Hoepner, L.A.; Arunajadai, S.; Canfield, S.; Resnick, D.; Calafat, A.M.; Perera, F.P.; et al. Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children. J. Allergy Clin. Immunol. 2013, 131, 736–742. [Google Scholar] [CrossRef][Green Version]
  119. Spanier, A.J.; Kahn, R.S.; Kunselman, A.R.; Hornung, R.; Xu, Y.; Calafat, A.M.; Lanphear, B.P. Prenatal exposure to bisphenol A and child wheeze from birth to 3 years of age. Environ. Health Perspect. 2012, 120, 916–920. [Google Scholar] [CrossRef][Green Version]
  120. Gascon, M.; Casas, M.; Morales, E.; Valvi, D.; Ballesteros-Gómez, A.; Luque, N.; Rubio, S.; Monfort, N.; Ventura, R.; Martínez, D.; et al. Prenatal exposure to bisphenol A and phthalates and childhood respiratory tract infections and allergy. J. Allergy Clin. Immunol. 2015, 135, 370–378. [Google Scholar] [CrossRef]
  121. Leung, Y.K.; Govindarajah, V.; Cheong, A.; Veevers, J.; Song, D.; Gear, R.; Zhu, X.; Ying, J.; Kendler, A.; Medvedovic, M.; et al. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk. Endocr.-Relat. Cancer 2017, 24, 365–378. [Google Scholar] [CrossRef][Green Version]
  122. Tse, L.A.; Lee, P.M.Y.; Ho, W.M.; Lam, A.T.; Lee, M.K.; Ng, S.S.M.; He, Y.; Leung, K.S.; Hartle, J.C.; Hu, H.; et al. Bisphenol A and other environmental risk factors for prostate cancer in Hong Kong. Environ. Int. 2017, 107, 1–7. [Google Scholar] [CrossRef] [PubMed]
  123. Rahbar, M.H.; Swingle, H.M.; Christian, M.A.; Hessabi, M.; Lee, M.; Pitcher, M.R.; Campbell, S.; Mitchell, A.; Krone, R.; Loveland, K.A.; et al. Environmental Exposure to Dioxins, Dibenzofurans, Bisphenol A, and Phthalates in Children with and without Autism Spectrum Disorder Living near the Gulf of Mexico. Int. J. Environ. Res. Public Health 2017, 14, 1425. [Google Scholar] [CrossRef] [PubMed][Green Version]
  124. Metwally, F.M.; Rashad, H.; Zeidan, H.M.; Kilany, A.; Abdol Raouf, E.R. Study of the Effect of Bisphenol A on Oxidative Stress in Children with Autism Spectrum Disorders. Indian J. Clin. Biochem. IJCB 2018, 33, 196–201. [Google Scholar] [CrossRef] [PubMed]
  125. Wu, M.; Wang, S.; Weng, Q.; Chen, H.; Shen, J.; Li, Z.; Wu, Y.; Zhao, Y.; Li, M.; Wu, Y.; et al. Prenatal and postnatal exposure to Bisphenol A and Asthma: A systemic review and meta-analysis. J. Thorac. Dis. 2021, 13, 1684–1696. [Google Scholar] [CrossRef] [PubMed]
  126. Midoro-Horiuti, T.; Tiwari, R.; Watson, C.S.; Goldblum, R.M. Maternal bisphenol a exposure promotes the development of experimental asthma in mouse pups. Environ. Health Perspect. 2010, 118, 273–277. [Google Scholar] [CrossRef][Green Version]
  127. Foundation, E.L. Exposure to BPA in the Womb Linked to Wheezing and Poorer Lung Function in Children. Available online:,Exposure%20to%20BPA%20in%20the%20womb%20linked%20to,poorer%20lung%20function%20in%20children&text=Summary%3A,function%2C%20according%20to%20new%20research.%20Accessed%20on%202.4.2022 (accessed on 2 April 2022).
  128. He, M.; Ichinose, T.; Yoshida, S.; Takano, H.; Nishikawa, M.; Shibamoto, T.; Sun, G. Exposure to bisphenol A enhanced lung eosinophilia in adult male mice. Allergy Asthma Clin. Immunol. Off. J. Can. Soc. Allergy Clin. Immunol. 2016, 12, 16. [Google Scholar] [CrossRef][Green Version]
  129. Gu, J.; Guo, M.; Yin, X.; Huang, C.; Qian, L.; Zhou, L.; Wang, Z.; Wang, L.; Shi, L.; Ji, G. A systematic comparison of neurotoxicity of bisphenol A and its derivatives in zebrafish. Sci. Total Environ. 2022, 805, 150210. [Google Scholar] [CrossRef]
  130. Tonini, C.; Segatto, M.; Gagliardi, S.; Bertoli, S.; Leone, A.; Barberio, L.; Mandalà, M.; Pallottini, V. Maternal Dietary Exposure to Low-Dose Bisphenol A Affects Metabolic and Signaling Pathways in the Brain of Rat Fetuses. Nutrients 2020, 12, 1448. [Google Scholar] [CrossRef]
  131. McIlwraith, E.K.; Lieu, C.V.; Belsham, D.D. Bisphenol A induces miR-708-5p through an ER stress-mediated mechanism altering neuronatin and neuropeptide Y expression in hypothalamic neuronal models. Mol. Cell. Endocrinol. 2022, 539, 111480. [Google Scholar] [CrossRef]
  132. Dodds, E.C.; Lawson, W. Synthetic strogenic Agents without the Phenanthrene Nucleus. Nature 1936, 137, 996. [Google Scholar] [CrossRef]
  133. Kuiper, G.G.; Carlsson, B.; Grandien, K.; Enmark, E.; Häggblad, J.; Nilsson, S.; Gustafsson, J.A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997, 138, 863–870. [Google Scholar] [CrossRef] [PubMed]
  134. Mileva, G.; Baker, S.L.; Konkle, A.T.; Bielajew, C. Bisphenol-A: Epigenetic reprogramming and effects on reproduction and behavior. Int. J. Environ. Res. Public Health 2014, 11, 7537–7561. [Google Scholar] [CrossRef] [PubMed]
  135. Thomas, P.; Dong, J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: A potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 2006, 102, 175–179. [Google Scholar] [CrossRef] [PubMed]
  136. Watson, C.S.; Bulayeva, N.N.; Wozniak, A.L.; Alyea, R.A. Xenoestrogens are potent activators of nongenomic estrogenic responses. Steroids 2007, 72, 124–134. [Google Scholar] [CrossRef] [PubMed][Green Version]
  137. Qie, Y.; Qin, W.; Zhao, K.; Liu, C.; Zhao, L.; Guo, L.H. Environmental Estrogens and Their Biological Effects through GPER Mediated Signal Pathways. Environ. Pollut. 2021, 278, 116826. [Google Scholar] [CrossRef]
  138. Carmeci, C.; Thompson, D.A.; Ring, H.Z.; Francke, U.; Weigel, R.J. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 1997, 45, 607–617. [Google Scholar] [CrossRef]
  139. Wang, H.; Ding, Z.; Shi, Q.M.; Ge, X.; Wang, H.X.; Li, M.X.; Chen, G.; Wang, Q.; Ju, Q.; Zhang, J.P.; et al. Anti-androgenic mechanisms of Bisphenol A involve androgen receptor signaling pathway. Toxicology 2017, 387, 10–16. [Google Scholar] [CrossRef]
  140. Matsushima, A.; Liu, X.; Okada, H.; Shimohigashi, M.; Shimohigashi, Y. Bisphenol AF is a full agonist for the estrogen receptor ERalpha but a highly specific antagonist for ERbeta. Environ. Health Perspect. 2010, 118, 1267–1272. [Google Scholar] [CrossRef][Green Version]
  141. Takeda, Y.; Liu, X.; Sumiyoshi, M.; Matsushima, A.; Shimohigashi, M.; Shimohigashi, Y. Placenta expressing the greatest quantity of bisphenol A receptor ERR{gamma} among the human reproductive tissues: Predominant expression of type-1 ERRgamma isoform. J. Biochem. 2009, 146, 113–122. [Google Scholar] [CrossRef]
  142. Sun, H.; Xu, L.C.; Chen, J.F.; Song, L.; Wang, X.R. Effect of bisphenol A, tetrachlorobisphenol A and pentachlorophenol on the transcriptional activities of androgen receptor-mediated reporter gene. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2006, 44, 1916–1921. [Google Scholar] [CrossRef]
  143. Teng, C.; Goodwin, B.; Shockley, K.; Xia, M.; Huang, R.; Norris, J.; Merrick, B.A.; Jetten, A.M.; Austin, C.P.; Tice, R.R. Bisphenol A affects androgen receptor function via multiple mechanisms. Chem.-Biol. Interact. 2013, 203, 556–564. [Google Scholar] [CrossRef][Green Version]
  144. Moriyama, K.; Tagami, T.; Akamizu, T.; Usui, T.; Saijo, M.; Kanamoto, N.; Hataya, Y.; Shimatsu, A.; Kuzuya, H.; Nakao, K. Thyroid hormone action is disrupted by bisphenol A as an antagonist. J. Clin. Endocrinol. Metab. 2002, 87, 5185–5190. [Google Scholar] [CrossRef]
  145. Prasanth, G.K.; Divya, L.M.; Sadasivan, C. Bisphenol-A can bind to human glucocorticoid receptor as an agonist: An in silico study. J. Appl. Toxicol. JAT 2010, 30, 769–774. [Google Scholar] [CrossRef]
  146. Chen, F.; Zhou, L.; Bai, Y.; Zhou, R.; Chen, L. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A. Brain Res. 2014, 1571, 12–24. [Google Scholar] [CrossRef]
  147. Pfeifer, D.; Chung, Y.M.; Hu, M.C. Effects of Low-Dose Bisphenol A on DNA Damage and Proliferation of Breast Cells: The Role of c-Myc. Environ. Health Perspect. 2015, 123, 1271–1279. [Google Scholar] [CrossRef]
  148. Kim, S.; Mun, G.I.; Choi, E.; Kim, M.; Jeong, J.S.; Kang, K.W.; Jee, S.; Lim, K.M.; Lee, Y.S. Submicromolar bisphenol A induces proliferation and DNA damage in human hepatocyte cell lines in vitro and in juvenile rats in vivo. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2018, 111, 125–132. [Google Scholar] [CrossRef]
  149. Ramos, C.; Ladeira, C.; Zeferino, S.; Dias, A.; Faria, I.; Cristovam, E.; Gomes, M.; Ribeiro, E. Cytotoxic and genotoxic effects of environmental relevant concentrations of bisphenol A and interactions with doxorubicin. Mutat. Res. Genet. Toxicol. Environ. Mutagenesis 2019, 838, 28–36. [Google Scholar] [CrossRef]
  150. Olukole, S.G.; Lanipekun, D.O.; Ola-Davies, E.O.; Oke, B.O. Melatonin attenuates bisphenol A-induced toxicity of the adrenal gland of Wistar rats. Environ. Sci. Pollut. Res. Int. 2019, 26, 5971–5982. [Google Scholar] [CrossRef]
  151. Ma, L.; Hu, J.; Li, J.; Yang, Y.; Zhang, L.; Zou, L.; Gao, R.; Peng, C.; Wang, Y.; Luo, T.; et al. Bisphenol A promotes hyperuricemia via activating xanthine oxidase. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2018, 32, 1007–1016. [Google Scholar] [CrossRef][Green Version]
  152. Lee, H.S.; Park, Y. Identification of metabolic pathways related to the bisphenol A-induced adipogenesis in differentiated murine adipocytes by using RNA-sequencing. Environ. Res. 2019, 171, 161–169. [Google Scholar] [CrossRef]
  153. Zbucka-Kretowska, M.; Zbucki, R.; Parfieniuk, E.; Maslyk, M.; Lazarek, U.; Miltyk, W.; Czerniecki, J.; Wolczynski, S.; Kretowski, A.; Ciborowski, M. Evaluation of Bisphenol A influence on endocannabinoid system in pregnant women. Chemosphere 2018, 203, 387–392. [Google Scholar] [CrossRef]
  154. Onuzulu, C.D.; Rotimi, O.A.; Rotimi, S.O. Epigenetic modifications associated with in utero exposure to endocrine disrupting chemicals BPA, DDT and Pb. Rev. Environ. Health 2019, 34, 309–325. [Google Scholar] [CrossRef]
  155. Sirasanagandla, S.R.; Al-Huseini, I.; Al Mushaiqri, M.; Al-Abri, N.; Al-Ghafri, F. Maternal resveratrol supplementation ameliorates bisphenol A-induced atherosclerotic lesions formation in adult offspring ApoE(-/-) mice. 3 Biotech 2022, 12, 36. [Google Scholar] [CrossRef]
  156. Sirasanagandla, S.R.; Sofin, R.G.S.; Al-Huseini, I.; Das, S. Role of Bisphenol A in Autophagy Modulation: Understanding the Molecular Concepts and Therapeutic Options. Mini Rev. Med. Chem. 2022, 22, 2513–2523. [Google Scholar] [CrossRef]
  157. Ishtiaq, A.; Bakhtiar, A.; Silas, E.; Saeed, J.; Ajmal, S.; Mushtaq, I.; Ali, T.; Wahedi, H.M.; Khan, W.; Khan, U.; et al. Pistacia integerrima alleviated Bisphenol A induced toxicity through Ubc13/p53 signalling. Mol. Biol. Rep. 2020, 47, 6545–6559. [Google Scholar] [CrossRef] [PubMed]
  158. Rana, S.; Shahzad, M.; Shabbir, A. Pistacia integerrima ameliorates airway inflammation by attenuation of TNF-α, IL-4, and IL-5 expression levels, and pulmonary edema by elevation of AQP1 and AQP5 expression levels in mouse model of ovalbumin-induced allergic asthma. Phytomedicine Int. J. Phytother. Phytopharm. 2016, 23, 838–845. [Google Scholar] [CrossRef] [PubMed]
  159. Bibi, Y.; Zia, M.; Qayyum, A. Review-An overview of Pistacia integerrima a medicinal plant species: Ethnobotany, biological activities and phytochemistry. Pak. J. Pharm. Sci. 2015, 28, 1009–1013. [Google Scholar] [PubMed]
  160. Hsu, C.N.; Lin, Y.J.; Tain, Y.L. Maternal Exposure to Bisphenol A Combined with High-Fat Diet-Induced Programmed Hypertension in Adult Male Rat Offspring: Effects of Resveratrol. Int. J. Mol. Sci. 2019, 20, 4382. [Google Scholar] [CrossRef][Green Version]
  161. Petropoulos, G.A. Fenugreek: The Genus Trigonella; CRC Press: Boca Raton, FL, USA, 2002; Volume 1. [Google Scholar]
  162. Gautam, S.; Ishrat, N.; Yadav, P.; Singh, R.; Narender, T.; Srivastava, A.K. 4-Hydroxyisoleucine attenuates the inflammation-mediated insulin resistance by the activation of AMPK and suppression of SOCS-3 coimmunoprecipitation with both the IR-β subunit as well as IRS-1. Mol. Cell Biochem. 2016, 414, 95–104. [Google Scholar] [CrossRef]
  163. Dixit, P.; Ghaskadbi, S.; Mohan, H.; Devasagayam, T.P. Antioxidant properties of germinated fenugreek seeds. Phytother. Res. PTR 2005, 19, 977–983. [Google Scholar] [CrossRef]
  164. Raju, J.; Gupta, D.; Rao, A.R.; Yadava, P.K.; Baquer, N.Z. Trigonellafoenum graecum (fenugreek) seed powder improves glucose homeostasis in alloxan diabetic rat tissues by reversing the altered glycolytic, gluconeogenic and lipogenic enzymes. Mol. Cell Biochem. 2001, 224, 45–51. [Google Scholar] [CrossRef]
  165. Shabbeer, S.; Sobolewski, M.; Anchoori, R.K.; Kachhap, S.; Hidalgo, M.; Jimeno, A.; Davidson, N.; Carducci, M.A.; Khan, S.R. Fenugreek: A naturally occurring edible spice as an anticancer agent. Cancer Biol. Ther. 2009, 8, 272–278. [Google Scholar] [CrossRef][Green Version]
  166. Gao, F.; Du, W.; Zafar, M.I.; Shafqat, R.A.; Jian, L.; Cai, Q.; Lu, F. 4-Hydroxyisoleucine ameliorates an insulin resistant-like state in 3T3-L1 adipocytes by regulating TACE/TIMP3 expression. Drug Des. Dev. Ther. 2015, 9, 5727–5736. [Google Scholar] [CrossRef][Green Version]
  167. Ulbricht, C.; Basch, E.; Burke, D.; Cheung, L.; Ernst, E.; Giese, N.; Foppa, I.; Hammerness, P.; Hashmi, S.; Kuo, G.; et al. Fenugreek (Trigonella foenum-graecum L. Leguminosae): An evidence-based systematic review by the natural standard research collaboration. J. Herb. Pharmacother. 2007, 7, 143–177. [Google Scholar] [CrossRef]
  168. Doshi, M.; Mirza, A.; Umarji, B.; Karambelkar, R. Effect of Trigonella foenum-graecum (fenugreek/methi) on hemoglobin levels in females of child bearing age. Biomed. Res. Int. 2012, 23, 47–50. [Google Scholar]
  169. Chaturvedi, U.; Shrivastava, A.; Bhadauria, S.; Saxena, J.K.; Bhatia, G. A mechanism-based pharmacological evaluation of efficacy of Trigonella foenum graecum (fenugreek) seeds in regulation of dyslipidemia and oxidative stress in hyperlipidemic rats. J. Cardiovasc. Pharmacol. 2013, 61, 505–512. [Google Scholar] [CrossRef]
  170. Aswar, U.; Bodhankar, S.L.; Mohan, V.; Thakurdesai, P.A. Effect of furostanol glycosides from Trigonella foenum-graecum on the reproductive system of male albino rats. Phytother. Res. PTR 2010, 24, 1482–1488. [Google Scholar] [CrossRef]
  171. Kaur, S.; Sadwal, S. Studies on the phytomodulatory potential of fenugreek (Trigonella foenum-graecum) on bisphenol-A induced testicular damage in mice. Andrologia 2020, 52, e13492. [Google Scholar] [CrossRef]
  172. Dobson, A.; O’Sullivan, O.; Cotter, P.D.; Ross, P.; Hill, C. High-throughput sequence-based analysis of the bacterial composition of kefir and an associated kefir grain. FEMS Microbiol. Lett. 2011, 320, 56–62. [Google Scholar] [CrossRef]
  173. Bengoa, A.A.; Iraporda, C.; Garrote, G.L.; Abraham, A.G. Kefir micro-organisms: Their role in grain assembly and health properties of fermented milk. J. Appl. Microbiol. 2019, 126, 686–700. [Google Scholar] [CrossRef][Green Version]
  174. Friques, A.G.F.; Santos, F.D.N.; Angeli, D.B.; Silva, F.A.C.; Dias, A.T.; Aires, R.; Leal, M.A.S.; Nogueira, B.V.; Amorim, F.G.; Campagnaro, B.P.; et al. Bisphenol A contamination in infant rats: Molecular, structural, and physiological cardiovascular changes and the protective role of kefir. J. Nutr. Biochem. 2020, 75, 108254. [Google Scholar] [CrossRef] [PubMed]
  175. Unusan, N. Proanthocyanidins in grape seeds: An updated review of their health benefits and potential uses in the food industry. J. Funct. Foods 2020, 67, 103861. [Google Scholar] [CrossRef]
  176. Kamran, H.; Raza, I.; Saleem, Y.; Aslam, M. Health perspectives of grape seed extract (GSE). Asian J. Allied Health Sci. 2020, 5, 88–98. [Google Scholar]
  177. Chu, K.O.; Chan, S.O.; Pang, C.P.; Wang, C.C. Pro-oxidative and antioxidative controls and signaling modification of polyphenolic phytochemicals: Contribution to health promotion and disease prevention? J. Agric. Food Chem. 2014, 62, 4026–4038. [Google Scholar] [CrossRef]
  178. Sutcliffe, T.C.; Winter, A.N.; Punessen, N.C.; Linseman, D.A. Procyanidin B2 Protects Neurons from Oxidative, Nitrosative, and Excitotoxic Stress. Antioxidants 2017, 6, 77. [Google Scholar] [CrossRef]
  179. Abdou, H.M.; Abd Elkader, H.A.E.; El-Gendy, A.H.; Eweda, S.M. Neurotoxicity and neuroinflammatory effects of bisphenol A in male rats: The neuroprotective role of grape seed proanthocyanidins. Environ. Sci. Pollut. Res. Int. 2022, 29, 9257–9268. [Google Scholar] [CrossRef]
  180. Fesharaki, M.; Nasimi, A.; Mokhtari, S.; Mokhtari, R.; Moradian, R.; Amirpoor, N. Reactive oxygen metabolites and anti-oxidative defenses in aspirin-induced gastric damage in rats: Gastroprotection by Vitamin E. Pathophysiol. Off. J. Int. Soc. Pathophysiol. 2006, 13, 237–243. [Google Scholar] [CrossRef]
  181. Abbas, A.M.; Sakr, H.F. Effect of selenium and grape seed extract on indomethacin-induced gastric ulcers in rats. J. Physiol. Biochem. 2013, 69, 527–537. [Google Scholar] [CrossRef]
  182. Rameshrad, M.; Imenshahidi, M.; Razavi, B.M.; Iranshahi, M.; Hosseinzadeh, H. Bisphenol A vascular toxicity: Protective effect of Vitis vinifera (grape) seed extract and resveratrol. Phytother. Res. PTR 2018, 32, 2396–2407. [Google Scholar] [CrossRef]
  183. Rameshrad, M.; Razavi, B.M.; Imenshahidi, M.; Hosseinzadeh, H. Vitis vinifera (grape) seed extract and resveratrol alleviate bisphenol-A-induced metabolic syndrome: Biochemical and molecular evidences. Phytother. Res. PTR 2019, 33, 832–844. [Google Scholar] [CrossRef]
  184. Corner, E.J.H. The complex of Fixcus Deltoidea; A recent invasion of the sunda shelf. Philosophical Transactions of the Royal Society of London. Biol. Sci. 1969, 256, 281–317. [Google Scholar]
  185. Lip, J.M.; Hisham, D.N.; Zaidi, J.A.; Musa, Y.; Ahmad, A.W.; Normah, A.; Sharizan, A. Isolation and identification of moretenol from Ficus deltoidea leaves. J. Trop. Agric. Food Sci. 2009, 37, 195–201. [Google Scholar]
  186. Omar, M.H.; Mullen, W.; Crozier, A. Identification of proanthocyanidin dimers and trimers, flavone C-Glycosides, and antioxidants in Ficus deltoidea, a malaysian herbal tea. J. Agric. Food Chem. 2011, 59, 1363–1369. [Google Scholar] [CrossRef]
  187. Ong, S.L.; Ling, A.P.K.; Poospooragi, R.; Moosa, S. Production of flavonoid compounds in cell cultures of Ficus deltoidea as influenced by medium composition. Int. J. Med. Aromat. Plants 2011, 1, 62–74. [Google Scholar]
  188. Suryati; Nurdin, H.; Hamidi, D.; Lajis, M. STRUCTURE ELUCIDATION OF ANTIBACTERIAL COMPOUND FROM Ficus deltoidea Jack LEAVES. Indones. J. Chem. 2011, 11, 67–70. [Google Scholar] [CrossRef]
  189. Bunawan, H.; Amin, N.M.; Bunawan, S.N.; Baharum, S.N.; Mohd Noor, N. Ficus deltoidea Jack: A Review on Its Phytochemical and Pharmacological Importance. Evid.-Based Complementary Altern. Med. 2014, 2014, 902734. [Google Scholar] [CrossRef][Green Version]
  190. Zaid, S.S.M.; Othman, S.; Kassim, N.M. Protective role of Mas Cotek (Ficus deltoidea) against the toxic effects of bisphenol A on morphology and sex steroid receptor expression in the rat uterus. Biomed. Pharmacother. 2021, 140, 111757. [Google Scholar] [CrossRef]
  191. Zaid, S.S.M.; Othman, S.; Kassim, N.M. Protective role of Ficus deltoidea against BPA-induced impairments of the follicular development, estrous cycle, gonadotropin and sex steroid hormones level of prepubertal rats. J. Ovarian Res. 2018, 11, 99. [Google Scholar] [CrossRef][Green Version]
  192. Sun, H.; Mu, T.; Xi, L.; Zhang, M.; Chen, J. Sweet potato (Ipomoea batatas L.) leaves as nutritional and functional foods. Food Chem. 2014, 156, 380–389. [Google Scholar] [CrossRef]
  193. Revathy, R.; Langeswaran, K.; Ponnulakshmi, R.; Balasubramanian, M.P.; Selvaraj, J. Ipomoea batatas Tuber Efficiency on Bisphenol A-induced Male Reproductive Toxicity in Sprague Dawley Rats. J. Biol. Act. Prod. Nat. 2017, 7, 118–130. [Google Scholar] [CrossRef]
  194. Johnson, M.; Pace, R.D. Sweet potato leaves: Properties and synergistic interactions that promote health and prevent disease. Nutr. Rev. 2010, 68, 604–615. [Google Scholar] [CrossRef] [PubMed]
  195. Ahmed, M.; Fatima, H.; Qasim, M.; Gul, B.; Ihsan Ul, H. Polarity directed optimization of phytochemical and in vitro biological potential of an indigenous folklore: Quercus dilatata Lindl. ex Royle. BMC Complementary Altern. Med. 2017, 17, 386. [Google Scholar] [CrossRef] [PubMed][Green Version]
  196. Taib, M.; Rezzak, Y.; Bouyazza, L.; Lyoussi, B. Medicinal Uses, Phytochemistry, and Pharmacological Activities of Quercus Species. Evid.-Based Complementary Altern. Med. 2020, 2020, 1920683. [Google Scholar] [CrossRef] [PubMed]
  197. Jamil, M.; ul Haq, I.; Mirza, B.; Qayyum, M. Isolation of antibacterial compounds from Quercus dilatata L. through bioassay guided fractionation. Ann. Clin. Microbiol. Antimicrob. 2012, 11, 11. [Google Scholar] [CrossRef][Green Version]
  198. Ismail, H.; Rasheed, A.; Haq, I.U.; Jafri, L.; Ullah, N.; Dilshad, E.; Sajid, M.; Mirza, B. Five Indigenous Plants of Pakistan with Antinociceptive, Anti-Inflammatory, Antidepressant, and Anticoagulant Properties in Sprague Dawley Rats. Evid.-Based Complementary Altern. Med. 2017, 2017, 7849501. [Google Scholar] [CrossRef][Green Version]
  199. Kazmi, S.T.B.; Majid, M.; Maryam, S.; Rahat, A.; Ahmed, M.; Khan, M.R.; Haq, I.U. Quercus dilatata Lindl. ex Royle ameliorates BPA induced hepatotoxicity in Sprague Dawley rats. Biomed. Pharmacother. 2018, 102, 728–738. [Google Scholar] [CrossRef]
  200. Mohamed, M.; Sirajudeen, K.; Swamy, M.; Yaacob, N.S.; Sulaiman, S.A. Studies on the antioxidant properties of Tualang honey of Malaysia. Afr. J. Tradit. Complementary Altern. Med. AJTCAM 2009, 7, 59–63. [Google Scholar] [CrossRef][Green Version]
  201. Khalil, M.I.; Alam, N.; Moniruzzaman, M.; Sulaiman, S.A.; Gan, S.H. Phenolic acid composition and antioxidant properties of Malaysian honeys. J. Food Sci. 2011, 76, C921–C928. [Google Scholar] [CrossRef]
  202. Qaid, E.Y.A.; Zakaria, R.; Mohd Yusof, N.A.; Sulaiman, S.F.; Shafin, N.; Othman, Z.; Ahmad, A.H.; Abd Aziz, C.B.; Muthuraju, S. Tualang Honey Ameliorates Hypoxia-induced Memory Deficits by Reducing Neuronal Damage in the Hippocampus of Adult Male Sprague Dawley Rats. Turk. J. Pharm. Sci. 2020, 17, 555–564. [Google Scholar] [CrossRef]
  203. Kishore, R.K.; Halim, A.S.; Syazana, M.S.; Sirajudeen, K.N. Tualang honey has higher phenolic content and greater radical scavenging activity compared with other honey sources. Nutr. Res. 2011, 31, 322–325. [Google Scholar] [CrossRef]
  204. Mohamad Zaid, S.S.; Kassim, N.M.; Othman, S. Tualang Honey Protects against BPA-Induced Morphological Abnormalities and Disruption of ERα, ERβ, and C3 mRNA and Protein Expressions in the Uterus of Rats. Evid.-Based Complementary Altern. Med. 2015, 2015, 202874. [Google Scholar] [CrossRef][Green Version]
  205. Zaid, S.S.; Othman, S.; Kassim, N.M. Potential protective effect of Tualang honey on BPA-induced ovarian toxicity in prepubertal rat. BMC Complementary Altern. Med. 2014, 14, 509. [Google Scholar] [CrossRef][Green Version]
  206. Mahendra Kumar, C.; Singh, S.A. Bioactive lignans from sesame (Sesamum indicum L.): Evaluation of their antioxidant and antibacterial effects for food applications. J. Food Sci. Technol. 2015, 52, 2934–2941. [Google Scholar] [CrossRef][Green Version]
  207. Wan, Y.; Li, H.; Fu, G.; Chen, X.; Chen, F.; Xie, M. The relationship of antioxidant components and antioxidant activity of sesame seed oil. J. Sci. Food Agric. 2015, 95, 2571–2578. [Google Scholar] [CrossRef]
  208. Dar, A.A.; Arumugam, N. Lignans of sesame: Purification methods, biological activities and biosynthesis—A review. Bioorganic Chem. 2013, 50, 1–10. [Google Scholar] [CrossRef]
  209. Eweda, S.M.; Newairy, A.S.A.; Abdou, H.M.; Gaber, A.S. Bisphenol A-induced oxidative damage in the hepatic and cardiac tissues of rats: The modulatory role of sesame lignans. Exp. Ther. Med. 2020, 19, 33–44. [Google Scholar] [CrossRef][Green Version]
  210. Abo El Wafa, S. The protective role of sesame oil against bisphenol A-induced cardiotoxicity: A histological and immunohistochemical study. Kasr Al Ainy Med. J. 2020, 25, 87–98. [Google Scholar]
  211. Wagh, V.D. Propolis: A wonder bees product and its pharmacological potentials. Adv. Pharmacol. Sci. 2013, 2013, 308249. [Google Scholar] [CrossRef][Green Version]
  212. Burdock, G.A. Review of the biological properties and toxicity of bee propolis (propolis). Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 1998, 36, 347–363. [Google Scholar] [CrossRef]
  213. Farooqui, T.; Farooqui, A.A. Beneficial effects of propolis on human health and neurological diseases. Front. Biosci. 2012, 4, 779–793. [Google Scholar] [CrossRef]
  214. Pasupuleti, V.R.; Sammugam, L.; Ramesh, N.; Gan, S.H. Honey, Propolis, and Royal Jelly: A Comprehensive Review of Their Biological Actions and Health Benefits. Oxid. Med. Cell Longev. 2017, 2017, 1259510. [Google Scholar] [CrossRef] [PubMed]
  215. Hamed, H.S.; Abdel-Tawwab, M. Ameliorative effect of propolis supplementation on alleviating bisphenol-A toxicity: Growth performance, biochemical variables, and oxidative stress biomarkers of Nile tilapia, Oreochromis niloticus (L.) fingerlings. Comp. Biochem. Physiology. Toxicol. Pharmacol. CBP 2017, 202, 63–69. [Google Scholar] [CrossRef] [PubMed]
  216. Soliman, M.A.E.; Noya, D.A.E. Effect of Bisphenol A on the lung of adult male albino rats and the possible protective role of propolis: Light and electron microscopic study. Egypt. J. Histol. 2021. [Google Scholar] [CrossRef]
  217. Hannan, M.A.; Rahman, M.A.; Sohag, A.A.M.; Uddin, M.J.; Dash, R.; Sikder, M.H.; Rahman, M.S.; Timalsina, B.; Munni, Y.A.; Sarker, P.P.; et al. Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety. Nutrients 2021, 13, 1784. [Google Scholar] [CrossRef] [PubMed]
  218. Ahmad, A.; Husain, A.; Mujeeb, M.; Khan, S.A.; Najmi, A.K.; Siddique, N.A.; Damanhouri, Z.A.; Anwar, F. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac. J. Trop. Biomed. 2013, 3, 337–352. [Google Scholar] [CrossRef][Green Version]
  219. Kooti, W.; Hasanzadeh-Noohi, Z.; Sharafi-Ahvazi, N.; Asadi-Samani, M.; Ashtary-Larky, D. Phytochemistry, pharmacology, and therapeutic uses of black seed (Nigella sativa). Chin. J. Nat. Med. 2016, 14, 732–745. [Google Scholar] [CrossRef]
  220. Sujan, K.; Haque, E.; Rakib, M.; Haque, M.; Mustari, A.; Miah, M.; Islam, M. Effects of Bisphenol-A (BPA) and black seed oil on body weight, lipid profile and serum glucose in male and female mice. Bangladesh J. Vet. Med. 2019, 17, 77–82. [Google Scholar] [CrossRef][Green Version]
  221. Sujan, K.M.; Hoque, E.; Haque, M.I.; Mustari, A.; Miah, M.A.; Islam, M.K. Ameliorating Effects of Black Seed Oil on Bisphenol-A Induced Abnormality of Blood, Hormone Profile and Gonadal Histology of Female Mice. J. Adv. Biotechnol. Exp. Ther. 2020, 3, 43–48. [Google Scholar] [CrossRef]
  222. Fadishei, M.; Ghasemzadeh Rahbardar, M.; Imenshahidi, M.; Mohajeri, A.; Razavi, B.M.; Hosseinzadeh, H. Effects of Nigella sativa oil and thymoquinone against bisphenol A-induced metabolic disorder in rats. Phytother. Res. PTR 2021, 35, 2005–2024. [Google Scholar] [CrossRef]
  223. Abdel-Wahab, W.M. Thymoquinone attenuates toxicity and oxidative stress induced by bisphenol A in liver of male rats. Pak. J. Biol. Sci. 2014, 17, 1152–1160. [Google Scholar] [CrossRef][Green Version]
  224. Cabrera, C.; Artacho, R.; Giménez, R. Beneficial effects of green tea—A review. J. Am. Coll. Nutr. 2006, 25, 79–99. [Google Scholar] [CrossRef]
  225. Chacko, S.M.; Thambi, P.T.; Kuttan, R.; Nishigaki, I. Beneficial effects of green tea: A literature review. Chin. Med. 2010, 5, 13. [Google Scholar] [CrossRef][Green Version]
  226. Ohishi, T.; Goto, S.; Monira, P.; Isemura, M.; Nakamura, Y. Anti-inflammatory Action of Green Tea. Anti-Inflamm. Anti-Allergy Agents Med. Chem. 2016, 15, 74–90. [Google Scholar] [CrossRef]
  227. Chatterjee, P.; Chandra, S.; Dey, P.; Bhattacharya, S. Evaluation of anti-inflammatory effects of green tea and black tea: A comparative in vitro study. J. Adv. Pharm. Technol. Res. 2012, 3, 136–138. [Google Scholar] [CrossRef]
  228. Maiti, S.; Nazmeen, A.; Medda, N.; Patra, R.; Ghosh, T.K. Flavonoids green tea against oxidant stress and inflammation with related human diseases. Clin. Nutr. Exp. 2019, 24, 1–14. [Google Scholar] [CrossRef][Green Version]
  229. Tallei, T.E.; Fatimawali; Niode, N.J.; Idroes, R.; Zidan, B.; Mitra, S.; Celik, I.; Nainu, F.; Ağagündüz, D.; Emran, T.B.; et al. A Comprehensive Review of the Potential Use of Green Tea Polyphenols in the Management of COVID-19. Evid.-Based Complementary Altern. Med. 2021, 2021, 7170736. [Google Scholar] [CrossRef]
  230. Mohsenzadeh, M.S.; Razavi, B.M.; Imenshahidi, M.; Mohajeri, S.A.; Rameshrad, M.; Hosseinzadeh, H. Evaluation of green tea extract and epigallocatechin gallate effects on bisphenol A-induced vascular toxicity in isolated rat aorta and cytotoxicity in human umbilical vein endothelial cells. Phytother. Res. PTR 2021, 35, 996–1009. [Google Scholar] [CrossRef]
  231. Mohsenzadeh, M.S.; Razavi, B.M.; Imenshahidi, M.; Tabatabaee Yazdi, S.A.; Mohajeri, S.A.; Hosseinzadeh, H. Potential role of green tea extract and epigallocatechin gallate in preventing bisphenol A-induced metabolic disorders in rats: Biochemical and molecular evidence. Phytomedicine Int. J. Phytother. Phytopharm. 2021, 92, 153754. [Google Scholar] [CrossRef]
  232. Suthar, H.; Verma, R.J.; Patel, S.; Jasrai, Y.T. Green tea potentially ameliorates bisphenol a-induced oxidative stress: An in vitro and in silico study. Biochem. Res. Int. 2014, 2014, 259763. [Google Scholar] [CrossRef][Green Version]
  233. Chatterjee, C.; Gleddie, S.; Xiao, C.W. Soybean Bioactive Peptides and Their Functional Properties. Nutrients 2018, 10, 1211. [Google Scholar] [CrossRef][Green Version]
  234. Veissi, M.; Jafarirad, S.; Ahangarpour, A.; Mohaghegh, S.M.; Malehi, A.S. Co-exposure to endocrine disruptors: Effect of bisphenol A and soy extract on glucose homeostasis and related metabolic disorders in male mice. Endocr. Regul. 2018, 52, 76–84. [Google Scholar] [CrossRef][Green Version]
  235. Patisaul, H.B.; Sullivan, A.W.; Radford, M.E.; Walker, D.M.; Adewale, H.B.; Winnik, B.; Coughlin, J.L.; Buckley, B.; Gore, A.C. Anxiogenic effects of developmental bisphenol A exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy. PLoS ONE 2012, 7, e43890. [Google Scholar] [CrossRef]
  236. Procida, G.; Stancher, B.; Cateni, F.; Zacchigna, M. Chemical composition and functional characterisation of commercial pumpkin seed oil. J. Sci. Food Agric. 2013, 93, 1035–1041. [Google Scholar] [CrossRef]
  237. Shahidi, F.; de Camargo, A.C. Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits. Int. J. Mol. Sci. 2016, 17, 1745. [Google Scholar] [CrossRef]
  238. Fawzy, E.I.; El Makawy, A.I.; El-Bamby, M.M.; Elhamalawy, H.O. Improved effect of pumpkin seed oil against the bisphenol-A adverse effects in male mice. Toxicol. Rep. 2018, 5, 857–863. [Google Scholar] [CrossRef]
  239. Jahanshahi, M.; Nickmahzar, E.G.; Babakordi, F. Effect of Gingko biloba extract on scopolamine-induced apoptosis in the hippocampus of rats. Anat. Sci. Int. 2013, 88, 217–222. [Google Scholar] [CrossRef][Green Version]
  240. Wu, Y.; Sun, J.; George, J.; Ye, H.; Cui, Z.; Li, Z.; Liu, Q.; Zhang, Y.; Ge, D.; Liu, Y. Study of neuroprotective function of Ginkgo biloba extract (EGb761) derived-flavonoid monomers using a three-dimensional stem cell-derived neural model. Biotechnol. Prog. 2016, 32, 735–744. [Google Scholar] [CrossRef]
  241. Kleijnen, J.; Knipschild, P. Ginkgo biloba for cerebral insufficiency. Br. J. Clin. Pharmacol. 1992, 34, 352–358. [Google Scholar] [CrossRef] [PubMed][Green Version]
  242. Dias, M.C.; Furtado, K.S.; Rodrigues, M.A.; Barbisan, L.F. Effects of Ginkgo biloba on chemically-induced mammary tumors in rats receiving tamoxifen. BMC Complementary Altern. Med. 2013, 13, 93. [Google Scholar] [CrossRef] [PubMed][Green Version]
  243. Yallapragada, P.R.; Velaga, M.K. Effect of Ginkgo biloba Extract on Lead-Induced Oxidative Stress in Different Regions of Rat Brain. J. Environ. Pathol. Toxicol. Oncol. Off. Organ Int. Soc. Environ. Toxicol. Cancer 2015, 34, 161–173. [Google Scholar] [CrossRef] [PubMed]
  244. Lim, S.; Yoon, J.W.; Kang, S.M.; Choi, S.H.; Cho, B.J.; Kim, M.; Park, H.S.; Cho, H.J.; Shin, H.; Kim, Y.B.; et al. EGb761, a Ginkgo biloba extract, is effective against atherosclerosis in vitro, and in a rat model of type 2 diabetes. PLoS ONE 2011, 6, e20301. [Google Scholar] [CrossRef] [PubMed]
  245. El Tabaa, M.M.; Sokkar, S.S.; Ramadan, E.S.; Abd El Salam, I.Z.; Zaid, A. Neuroprotective role of Ginkgo biloba against cognitive deficits associated with Bisphenol A exposure: An animal model study. Neurochem. Int. 2017, 108, 199–212. [Google Scholar] [CrossRef] [PubMed]
  246. So, S.H.; Lee, J.W.; Kim, Y.S.; Hyun, S.H.; Han, C.K. Red ginseng monograph. J. Ginseng Res. 2018, 42, 549–561. [Google Scholar] [CrossRef] [PubMed]
  247. Lee, Y.M.; Yoon, H.; Park, H.M.; Song, B.C.; Yeum, K.J. Implications of red Panax ginseng in oxidative stress associated chronic diseases. J. Ginseng Res. 2017, 41, 113–119. [Google Scholar] [CrossRef][Green Version]
  248. Kim, K.H.; Lee, D.; Lee, H.L.; Kim, C.E.; Jung, K.; Kang, K.S. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: Past findings and future directions. J. Ginseng Res. 2018, 42, 239–247. [Google Scholar] [CrossRef]
  249. Ahuja, A.; Kim, J.H.; Kim, J.H.; Yi, Y.S.; Cho, J.Y. Functional role of ginseng-derived compounds in cancer. J. Ginseng Res. 2018, 42, 248–254. [Google Scholar] [CrossRef]
  250. Saba, E.; Lee, Y.Y.; Kim, M.; Kim, S.H.; Hong, S.B.; Rhee, M.H. A comparative study on immune-stimulatory and antioxidant activities of various types of ginseng extracts in murine and rodent models. J. Ginseng Res. 2018, 42, 577–584. [Google Scholar] [CrossRef]
  251. Song, H.; Lee, Y.Y.; Park, J.; Lee, Y. Korean Red Ginseng suppresses bisphenol A-induced expression of cyclooxygenase-2 and cellular migration of A549 human lung cancer cell through inhibition of reactive oxygen species. J. Ginseng Res. 2021, 45, 119–125. [Google Scholar] [CrossRef]
  252. Ok, S.; Kang, J.S.; Kim, K.M. Cultivated wild ginseng extracts upregulate the anti-apoptosis systems in cells and mice induced by bisphenol A. Mol. Cell. Toxicol. 2017, 13, 73–82. [Google Scholar] [CrossRef]
  253. Lee, J.; Park, J.; Lee, Y.Y.; Lee, Y. Comparative transcriptome analysis of the protective effects of Korean Red Ginseng against the influence of bisphenol A in the liver and uterus of ovariectomized mice. J. Ginseng Res. 2020, 44, 519–526. [Google Scholar] [CrossRef]
  254. Park, J.; Choi, K.; Lee, J.; Jung, J.M.; Lee, Y. The Effect of Korean Red Ginseng on Bisphenol A-Induced Fatty Acid Composition and Lipid Metabolism-Related Gene Expression Changes. Am. J. Chin. Med. 2020, 48, 1841–1858. [Google Scholar] [CrossRef]
  255. Saadeldin, I.M.; Hussein, M.A.; Suleiman, A.H.; Abohassan, M.G.; Ahmed, M.M.; Moustafa, A.A.; Moumen, A.F.; Abdel-Aziz Swelum, A. Ameliorative effect of ginseng extract on phthalate and bisphenol A reprotoxicity during pregnancy in rats. Environ. Sci. Pollut. Res. Int. 2018, 25, 21205–21215. [Google Scholar] [CrossRef]
  256. Balakrishnan, R.; Vijayraja, D.; Jo, S.H.; Ganesan, P.; Su-Kim, I.; Choi, D.K. Medicinal Profile, Phytochemistry, and Pharmacological Activities of Murraya koenigii and its Primary Bioactive Compounds. Antioxidants 2020, 9, 101. [Google Scholar] [CrossRef][Green Version]
  257. Ma, Q.G.; Xu, K.; Sang, Z.P.; Wei, R.R.; Liu, W.M.; Su, Y.L.; Yang, J.B.; Wang, A.G.; Ji, T.F.; Li, L.J. Alkenes with antioxidative activities from Murraya koenigii (L.) Spreng. Bioorganic Med. Chem. Lett. 2016, 26, 799–803. [Google Scholar] [CrossRef]
  258. Tripathi, Y.; Anjum, N.; Rana, A. Chemical Composition and In vitro Antifungal and Antioxidant Activities of Essential Oil from Murraya koenigii (L.) Spreng. Leaves. Asian J. Biomed. Pharm. Sci. 2018, 8, 6–13. [Google Scholar] [CrossRef][Green Version]
  259. Rautela, R.; Das, G.; Khan, F.; Prasad, S.; Kumar, A.; Prasad, J.; Ghosh, S.; Dhanze, H.; Katiyar, R.; Srivastava, S.K. Antibacterial, anti-inflammatory and antioxidant effects of Aegle marmelos and Murraya koenigii in dairy cows with endometritis. Livest. Sci. 2018, 214, 142–148. [Google Scholar] [CrossRef]
  260. Ningappa, M.B.; Dinesha, R.; Srinivas, L. Antioxidant and free radical scavenging activities of polyphenol-enriched curry leaf (Murraya koenigii L.) extracts. Food Chem. 2008, 106, 720–728. [Google Scholar] [CrossRef]
  261. Kaur, S.; Singh, G.; Sadwal, S.; Aniqa, A. Alleviating impact of hydroethanolic Murraya koenigii leaves extract on bisphenol A instigated testicular lethality and apoptosis in mice. Andrologia 2020, 52, e13504. [Google Scholar] [CrossRef]
  262. Huang, X.F.; Lin, Y.Y.; Kong, L.Y. Steroids from the roots of Asparagus officinalis and their cytotoxic activity. J. Integr. Plant Biol. 2008, 50, 717–722. [Google Scholar] [CrossRef]
  263. Schilcher, H.R.H. Nachweis der aquaretischen Wirkung von Birkenblätter- und Goldrutenkrautauszügen im Tierversuch. Urol. B 1988, 28, 274–280. [Google Scholar]
  264. Somania, R.; Singhai, A.K.; Shivgunde, P.; Jain, D. Asparagus racemosus Willd (Liliaceae) ameliorates early diabetic nephropathy in STZ induced diabetic rats. Indian J. Exp. Biol. 2012, 50, 469–475. [Google Scholar] [PubMed]
  265. Dohare, S.; Shuaib, M.; Naquvi, K. In vitro antioxidant activity of Asparagus racemose roots. Int. J. Bio. Res. 2011, 4, 228–235. [Google Scholar]
  266. Rajasekaran, S.; Sivagnanam, K.; Subramanian, S. Antioxidant effect of Aloe vera gel extract in streptozotocin-induced diabetes in rats. Pharmacol. Rep. PR 2005, 57, 90–96. [Google Scholar] [PubMed]
  267. Sánchez, M.; González-Burgos, E.; Iglesias, I.; Gómez-Serranillos, M.P. Pharmacological Update Properties of Aloe Vera and its Major Active Constituents. Molecules 2020, 25, 1324. [Google Scholar] [CrossRef] [PubMed][Green Version]
  268. Shahraki, A.; Mojahed, A.S.; Afshar-Goli, J. The effects of hydroalcoholic extract of Aloe vera gel on spermatogenesis of adult male rats. Int. J. Biosci. 2014, 5, 158–165. [Google Scholar]
  269. Behmanesh, M.A.; Najafzadehvarzi, H.; Poormoosavi, S.M. Protective Effect of Aloe vera Extract against Bisphenol A Induced Testicular Toxicity in Wistar Rats. Cell J. 2018, 20, 278–283. [Google Scholar] [CrossRef] [PubMed]
  270. Chhatre, S.; Nesari, T.; Somani, G.; Kanchan, D.; Sathaye, S. Phytopharmacological overview of Tribulus terrestris. Pharmacogn. Rev. 2014, 8, 45–51. [Google Scholar] [CrossRef] [PubMed][Green Version]
  271. Saied, N.M.; Darwish, S.K. A possible ameliorating effects of Tribulus terrestris on testicular dysfunction induced by xenoestrogens exposure in adult rats. Curr. Sci. Int. 2015, 4, 73–89. [Google Scholar]
  272. Kamenov, Z.; Fileva, S.; Kalinov, K.; Jannini, E.A. Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction-A prospective, randomized, double-blind, placebo-controlled clinical trial. Maturitas 2017, 99, 20–26. [Google Scholar] [CrossRef]
  273. Munir, B.; Qadir, A.; Tahir, M. Negative effects of bisphenol A on testicular functions in albino rats and their abolitions with Tribulus terristeris L. Braz. J. Pharm. Sci. 2017, 53, e00104. [Google Scholar] [CrossRef][Green Version]
  274. Renaud, S.; de Lorgeril, M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992, 339, 1523–1526. [Google Scholar] [CrossRef]
  275. Nawaz, W.; Zhou, Z.; Deng, S.; Ma, X.; Ma, X.; Li, C.; Shu, X. Therapeutic Versatility of Resveratrol Derivatives. Nutrients 2017, 9, 1188. [Google Scholar] [CrossRef][Green Version]
  276. Li, M.; Kildegaard, K.R.; Chen, Y.; Rodriguez, A.; Borodina, I.; Nielsen, J. De novo production of resveratrol from glucose or ethanol by engineered Saccharomyces cerevisiae. Metab. Eng. 2015, 32, 1–11. [Google Scholar] [CrossRef]
  277. Wang, Y.; Halls, C.; Zhang, J.; Matsuno, M.; Zhang, Y.; Yu, O. Stepwise increase of resveratrol biosynthesis in yeast Saccharomyces cerevisiae by metabolic engineering. Metab. Eng. 2011, 13, 455–463. [Google Scholar] [CrossRef]
  278. Shih, M.K.; Tain, Y.L.; Chen, Y.W.; Hsu, W.H.; Yeh, Y.T.; Chang, S.K.C.; Liao, J.X.; Hou, C.Y. Resveratrol Butyrate Esters Inhibit Obesity Caused by Perinatal Exposure to Bisphenol A in Female Offspring Rats. Molecules 2021, 26, 4010. [Google Scholar] [CrossRef]
  279. Fouad, H.; Faruk, E.M.; Alasmari, W.A.; Nadwa, E.H.; Ebrahim, U.F.A. Structural and chemical role of mesenchymal stem cells and resveratrol in regulation of apoptotic -induced genes in Bisphenol-A induced uterine damage in adult female albino rats. Tissue Cell 2021, 70, 101502. [Google Scholar] [CrossRef]
  280. Çetin, Y.S.; Altındağ, F.; Berköz, M. Protective role of resveratrol and apigenin against toxic effects of bisphenol a in rat salivary gland. Drug Chem. Toxicol. 2021, 1–9. [Google Scholar] [CrossRef]
  281. Bordbar, H.; Soleymani, F.; Nadimi, E.; Yahyavi, S.S.; Fazelian-Dehkordi, K. A Quantitative Study on the Protective Effects of Resveratrol against Bisphenol A-induced Hepatotoxicity in Rats: A Stereological Study. Iran. J. Med. Sci. 2021, 46, 218–227. [Google Scholar] [CrossRef]
  282. Kang, N.H.; Hwang, K.A.; Lee, H.R.; Choi, D.W.; Choi, K.C. Resveratrol regulates the cell viability promoted by 17β-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen receptor α and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2013, 59, 373–379. [Google Scholar] [CrossRef]
  283. Çiğ, B.; Yildizhan, K. Resveratrol diminishes bisphenol A-induced oxidative stress through TRPM2 channel in the mouse kidney cortical collecting duct cells. J. Recept. Signal Transduct. Res. 2020, 40, 570–583. [Google Scholar] [CrossRef]
  284. Liao, J.X.; Chen, Y.W.; Shih, M.K.; Tain, Y.L.; Yeh, Y.T.; Chiu, M.H.; Chang, S.K.C.; Hou, C.Y. Resveratrol Butyrate Esters Inhibit BPA-Induced Liver Damage in Male Offspring Rats by Modulating Antioxidant Capacity and Gut Microbiota. Int. J. Mol. Sci. 2021, 22, 5273. [Google Scholar] [CrossRef]
  285. Golmohammadi, M.G.; Khoshdel, F.; Salimnejad, R. Protective effect of resveratrol against bisphenol A-induced reproductive toxicity in male mice. Toxin Rev. 2021, 1–9. [Google Scholar] [CrossRef]
  286. Rahmani Moghadam, E.; Nadimi, E.; Bordbar, A.; Ayareh, N.; Bordbar, E.; Bordbar, H. A Quantitative Study on the Protective Effect of Resveratrol against Bisphenol-A-Induced Oral Mucosa and Tongue Toxicity in Male Rats: A Stereological Study. Iran. Red Crescent Med. J. 2022, 24, e992. [Google Scholar] [CrossRef]
  287. Miceli, N.; Cavò, E.; Ragusa, S.; Cacciola, F.; Dugo, P.; Mondello, L.; Marino, A.; Cincotta, F.; Condurso, C.; Taviano, M.F. Phytochemical Characterization and Biological Activities of a Hydroalcoholic Extract Obtained from the Aerial Parts of Matthiola incana (L.) R.Br. subsp. incana (Brassicaceae) Growing Wild in Sicily (Italy). Chem. Biodivers. 2019, 16, e1800677. [Google Scholar] [CrossRef] [PubMed]
  288. Soheili, M.; Salami, M. Lavandula angustifolia biological characteristics: An in vitro study. J. Cell. Physiol. 2019, 234, 16424–16430. [Google Scholar] [CrossRef] [PubMed]
  289. López-Lázaro, M. Distribution and biological activities of the flavonoid luteolin. Mini Rev. Med. Chem. 2009, 9, 31–59. [Google Scholar] [CrossRef]
  290. Adesanoye, O.A.; Farombi, E.O. Hepatoprotective effects of Vernonia amygdalina (astereaceae) in rats treated with carbon tetrachloride. Exp. Toxicol. Pathol. Off. J. Ges. Fur Toxikol. Pathol. 2010, 62, 197–206. [Google Scholar] [CrossRef] [PubMed]
  291. Sun, D.W.; Zhang, H.D.; Mao, L.; Mao, C.F.; Chen, W.; Cui, M.; Ma, R.; Cao, H.X.; Jing, C.W.; Wang, Z.; et al. Luteolin Inhibits Breast Cancer Development and Progression In Vitro and In Vivo by Suppressing Notch Signaling and Regulating MiRNAs. Cell. Physiol. Biochem. 2015, 37, 1693–1711. [Google Scholar] [CrossRef][Green Version]
  292. Zhang, B.C.; Zhang, C.W.; Wang, C.; Pan, D.F.; Xu, T.D.; Li, D.Y. Luteolin Attenuates Foam Cell Formation and Apoptosis in Ox-LDL-Stimulated Macrophages by Enhancing Autophagy. Cell. Physiol. Biochem. 2016, 39, 2065–2076. [Google Scholar] [CrossRef][Green Version]
  293. Alekhya Sita, G.J.; Gowthami, M.; Srikanth, G.; Krishna, M.M.; Rama Sireesha, K.; Sajjarao, M.; Nagarjuna, K.; Nagarjuna, M.; Chinnaboina, G.K.; Mishra, A.; et al. Protective role of luteolin against bisphenol A-induced renal toxicity through suppressing oxidative stress, inflammation, and upregulating Nrf2/ARE/HO-1 pathway. IUBMB Life 2019, 71, 1041–1047. [Google Scholar] [CrossRef]
  294. Adesanoye, O.A.; Abolaji, A.O.; Faloye, T.R.; Olaoye, H.O.; Adedara, A.O. Luteolin-Supplemented diets ameliorates Bisphenol A-Induced toxicity in Drosophila melanogaster. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2020, 142, 111478. [Google Scholar] [CrossRef]
  295. Kong, K.W.; Khoo, H.E.; Prasad, K.N.; Ismail, A.; Tan, C.P.; Rajab, N.F. Revealing the power of the natural red pigment lycopene. Molecules 2010, 15, 959–987. [Google Scholar] [CrossRef][Green Version]
  296. Kumar, P.; Kalonia, H.; Kumar, A. Lycopene modulates nitric oxide pathways against 3-nitropropionic acid-induced neurotoxicity. Life Sci. 2009, 85, 711–718. [Google Scholar] [CrossRef]
  297. Datta, S.; Jamwal, S.; Deshmukh, R.; Kumar, P. Beneficial effects of lycopene against haloperidol induced orofacial dyskinesia in rats: Possible neurotransmitters and neuroinflammation modulation. Eur. J. Pharmacol. 2016, 771, 229–235. [Google Scholar] [CrossRef]
  298. Palabiyik, S.S.; Erkekoglu, P.; Zeybek, N.D.; Kizilgun, M.; Baydar, D.E.; Sahin, G.; Giray, B.K. Protective effect of lycopene against ochratoxin A induced renal oxidative stress and apoptosis in rats. Exp. Toxicol. Pathol. Off. J. Ges. Fur Toxikol. Pathol. 2013, 65, 853–861. [Google Scholar] [CrossRef]
  299. Faheem, N.M.; El Askary, A.; Gharib, A.F. Lycopene attenuates bisphenol A-induced lung injury in adult albino rats: A histological and biochemical study. Environ. Sci. Pollut. Res. Int. 2021, 28, 49139–49152. [Google Scholar] [CrossRef]
  300. Abdel-Rahman, H.G.; Abdelrazek, H.M.A.; Zeidan, D.W.; Mohamed, R.M.; Abdelazim, A.M. Lycopene: Hepatoprotective and Antioxidant Effects toward Bisphenol A-Induced Toxicity in Female Wistar Rats. Oxid. Med. Cell Longev. 2018, 2018, 5167524. [Google Scholar] [CrossRef][Green Version]
  301. Ma, S.; Li, R.; Gong, X.; Shi, W.; Zhong, X. Lycopene reduces in utero bisphenol A exposure-induced mortality, benefits hormones, and development of reproductive organs in offspring mice. Environ. Sci. Pollut. Res. Int. 2018, 25, 24041–24051. [Google Scholar] [CrossRef]
  302. Elgawish, R.A.; El-Beltagy, M.A.; El-Sayed, R.M.; Gaber, A.A.; Abdelrazek, H.M.A. Protective role of lycopene against metabolic disorders induced by chronic bisphenol A exposure in rats. Environ. Sci. Pollut. Res. Int. 2020, 27, 9192–9201. [Google Scholar] [CrossRef]
  303. El Morsy, E.M.; Ahmed, M. Protective effects of lycopene on hippocampal neurotoxicity and memory impairment induced by bisphenol A in rats. Hum. Exp. Toxicol. 2020, 39, 1066–1078. [Google Scholar] [CrossRef]
  304. Essawy, A.E.; Abd Elkader, H.A.E.; Khamiss, O.A.; Eweda, S.M.; Abdou, H.M. Therapeutic effects of astragaloside IV and Astragalus spinosus saponins against bisphenol A-induced neurotoxicity and DNA damage in rats. PeerJ 2021, 9, e11930. [Google Scholar] [CrossRef] [PubMed]
  305. Ionkova, I.; Shkondrov, A.; Krasteva, I.; Ionkov, T. Recent progress in phytochemistry, pharmacology and biotechnology of Astragalus saponins. Phytochem. Rev. 2014, 13, 343–374. [Google Scholar] [CrossRef]
  306. Lu, M.; Tang, F.; Zhang, J.; Luan, A.; Mei, M.; Xu, C.; Zhang, S.; Wang, H.; Maslov, L.N. Astragaloside IV attenuates injury caused by myocardial ischemia/reperfusion in rats via regulation of toll-like receptor 4/nuclear factor-κB signaling pathway. Phytother. Res. PTR 2015, 29, 599–606. [Google Scholar] [CrossRef] [PubMed]
  307. Huang, X.P.; Tan, H.; Chen, B.Y.; Deng, C.Q. Combination of total Astragalus extract and total Panax notoginseng saponins strengthened the protective effects on brain damage through improving energy metabolism and inhibiting apoptosis after cerebral ischemia-reperfusion in mice. Chin. J. Integr. Med. 2017, 23, 445–452. [Google Scholar] [CrossRef]
  308. Yang, L.P.; Shen, J.G.; Xu, W.C.; Li, J.; Jiang, J.Q. Secondary metabolites of the genus Astragalus: Structure and biological-activity update. Chem. Biodivers. 2013, 10, 1004–1054. [Google Scholar] [CrossRef]
  309. Kamal, M.; Arif, D.M.; Jawaid, T. Adaptogenic medicinal plants utilized for strengthening the power of resistance during chemotherapy—A review. Orient. Pharm. Exp. Med. 2017, 17, 1–18. [Google Scholar] [CrossRef]
  310. Abd Elkader, H.A.E.; Abdou, H.M.; Khamiss, O.A.; Essawy, A.E. Anti-anxiety and antidepressant-like effects of astragaloside IV and saponins extracted from Astragalus spinosus against the bisphenol A-induced motor and cognitive impairments in a postnatal rat model of schizophrenia. Environ. Sci. Pollut. Res. Int. 2021, 28, 35171–35187. [Google Scholar] [CrossRef]
  311. Podder, B.; Song, H.Y.; Kim, Y.S. Naringenin exerts cytoprotective effect against paraquat-induced toxicity in human bronchial epithelial BEAS-2B cells through NRF2 activation. J. Microbiol. Biotechnol. 2014, 24, 605–613. [Google Scholar] [CrossRef][Green Version]
  312. Joshi, R.; Kulkarni, Y.A.; Wairkar, S. Pharmacokinetic, pharmacodynamic and formulations aspects of Naringenin: An update. Life Sci. 2018, 215, 43–56. [Google Scholar] [CrossRef]
  313. Rivoira, M.A.; Rodriguez, V.; Talamoni, G.; Tolosa de Talamoni, N. New Perspectives in the Pharmacological Potential of Naringin in Medicine. Curr. Med. Chem. 2021, 28, 1987–2007. [Google Scholar] [CrossRef]
  314. Khodayar, M.J.; Kalantari, H.; Mahdavinia, M.; Khorsandi, L.; Alboghobeish, S.; Samimi, A.; Alizadeh, S.; Zeidooni, L. Protective effect of naringin against BPA-induced cardiotoxicity through prevention of oxidative stress in male Wistar rats. Drug Chem. Toxicol. 2020, 43, 85–95. [Google Scholar] [CrossRef]
  315. Mahdavinia, M.; Ahangarpour, A.; Zeidooni, L.; Samimi, A.; Alizadeh, S.; Dehghani, M.A.; Alboghobeish, S. Protective Effect of Naringin on Bisphenol A-Induced Cognitive Dysfunction and Oxidative Damage in Rats. Int. J. Mol. Cell. Med. 2019, 8, 141–153. [Google Scholar] [CrossRef]
  316. De Luca, A.; Pierno, S.; Camerino, D.C. Taurine: The appeal of a safe amino acid for skeletal muscle disorders. J. Transl. Med. 2015, 13, 243. [Google Scholar] [CrossRef][Green Version]
  317. Sarkar, P.; Basak, P.; Ghosh, S.; Kundu, M.; Sil, P.C. Prophylactic role of taurine and its derivatives against diabetes mellitus and its related complications. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2017, 110, 109–121. [Google Scholar] [CrossRef]
  318. Abdel-Moneim, A.M.; Al-Kahtani, M.A.; El-Kersh, M.A.; Al-Omair, M.A. Free Radical-Scavenging, Anti-Inflammatory/Anti-Fibrotic and Hepatoprotective Actions of Taurine and Silymarin against CCl4 Induced Rat Liver Damage. PLoS ONE 2015, 10, e0144509. [Google Scholar] [CrossRef][Green Version]
  319. Rashid, K.; Das, J.; Sil, P.C. Taurine ameliorate alloxan induced oxidative stress and intrinsic apoptotic pathway in the hepatic tissue of diabetic rats. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2013, 51, 317–329. [Google Scholar] [CrossRef]
  320. Yang, J.; Zong, X.; Wu, G.; Lin, S.; Feng, Y.; Hu, J. Taurine increases testicular function in aged rats by inhibiting oxidative stress and apoptosis. Amino Acids 2015, 47, 1549–1558. [Google Scholar] [CrossRef]
  321. Rezaee-Tazangi, F.; Zeidooni, L.; Rafiee, Z.; Fakhredini, F.; Kalantari, H.; Alidadi, H.; Khorsandi, L. Taurine effects on Bisphenol A-induced oxidative stress in the mouse testicular mitochondria and sperm motility. JBRA Assist. Reprod. 2020, 24, 428–435. [Google Scholar] [CrossRef]
  322. Pradhan, L.K.; Sahoo, P.K.; Aparna, S.; Sargam, M.; Biswal, A.K.; Polai, O.; Chauhan, N.R.; Das, S.K. Suppression of bisphenol A-induced oxidative stress by taurine promotes neuroprotection and restores altered neurobehavioral response in zebrafish (Danio rerio). Environ. Toxicol. 2021, 36, 2342–2353. [Google Scholar] [CrossRef]
  323. Fraga, C.G.; Galleano, M.; Verstraeten, S.V.; Oteiza, P.I. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol. Asp. Med. 2010, 31, 435–445. [Google Scholar] [CrossRef]
  324. Zou, W.; Liu, W.; Yang, B.; Wu, L.; Yang, J.; Zou, T.; Liu, F.; Xia, L.; Zhang, D. Quercetin protects against perfluorooctanoic acid-induced liver injury by attenuating oxidative stress and inflammatory response in mice. Int. Immunopharmacol. 2015, 28, 129–135. [Google Scholar] [CrossRef] [PubMed]
  325. Erden Inal, M.; Kahraman, A. The protective effect of flavonol quercetin against ultraviolet a induced oxidative stress in rats. Toxicology 2000, 154, 21–29. [Google Scholar] [CrossRef]
  326. Shirani, M.; Alizadeh, S.; Mahdavinia, M.; Dehghani, M.A. The ameliorative effect of quercetin on bisphenol A-induced toxicity in mitochondria isolated from rats. Environ. Sci. Pollut. Res. Int. 2019, 26, 7688–7696. [Google Scholar] [CrossRef] [PubMed]
  327. Jahan, S.; Ain, Q.U.; Ullah, H. Therapeutic effects of quercetin against bisphenol A induced testicular damage in male Sprague Dawley rats. Syst. Biol. Reprod. Med. 2016, 62, 114–124. [Google Scholar] [CrossRef][Green Version]
  328. Sahoo, P.K.; Pradhan, L.K.; Aparna, S.; Agarwal, K.; Banerjee, A.; Das, S.K. Quercetin abrogates bisphenol A induced altered neurobehavioral response and oxidative stress in zebrafish by modulating brain antioxidant defence system. Environ. Toxicol. Pharmacol. 2020, 80, 103483. [Google Scholar] [CrossRef] [PubMed]
  329. Sangai, N.P.; Patel, C.N.; Pandya, H.A. Ameliorative effects of quercetin against bisphenol A-caused oxidative stress in human erythrocytes: An in vitro and in silico study. Toxicol. Res. 2018, 7, 1091–1099. [Google Scholar] [CrossRef] [PubMed][Green Version]
  330. Sangai, N.P.; Verma, R.J.; Trivedi, M.H. Testing the efficacy of quercetin in mitigating bisphenol A toxicity in liver and kidney of mice. Toxicol. Ind. Health 2014, 30, 581–597. [Google Scholar] [CrossRef] [PubMed]
  331. Coughlin, J.L.; Thomas, P.E.; Buckley, B. Inhibition of genistein glucuronidation by bisphenol A in human and rat liver microsomes. Drug Metab. Dispos. Biol. Fate Chem. 2012, 40, 481–485. [Google Scholar] [CrossRef]
  332. Sharifi-Rad, J.; Quispe, C.; Imran, M.; Rauf, A.; Nadeem, M.; Gondal, T.A.; Ahmad, B.; Atif, M.; Mubarak, M.S.; Sytar, O.; et al. Genistein: An Integrative Overview of Its Mode of Action, Pharmacological Properties, and Health Benefits. Oxidative Med. Cell. Longev. 2021, 2021, 3268136. [Google Scholar] [CrossRef]
  333. Bernardo, B.D.; Brandt, J.Z.; Grassi, T.F.; Silveira, L.T.; Scarano, W.R.; Barbisan, L.F. Genistein reduces the noxious effects of in utero bisphenol A exposure on the rat prostate gland at weaning and in adulthood. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2015, 84, 64–73. [Google Scholar] [CrossRef]
  334. Yakimchuk, K.; Bangalore Revanna, C.; Huang, D.; Inzunza, J.; Okret, S. Suppression of lymphoma growth by the xenoestrogens bisphenol A and genistein. Endocr. Connect. 2018, 7, 1472–1479. [Google Scholar] [CrossRef][Green Version]
  335. Betancourt, A.; Mobley, J.A.; Wang, J.; Jenkins, S.; Chen, D.; Kojima, K.; Russo, J.; Lamartiniere, C.A. Alterations in the rat serum proteome induced by prepubertal exposure to bisphenol a and genistein. J. Proteome Res. 2014, 13, 1502–1514. [Google Scholar] [CrossRef]
  336. Priyadarsini, K.I. The chemistry of curcumin: From extraction to therapeutic agent. Molecules 2014, 19, 20091–20112. [Google Scholar] [CrossRef][Green Version]
  337. Gupta, S.C.; Sung, B.; Kim, J.H.; Prasad, S.; Li, S.; Aggarwal, B.B. Multitargeting by turmeric, the golden spice: From kitchen to clinic. Mol. Nutr. Food Res. 2013, 57, 1510–1528. [Google Scholar] [CrossRef]
  338. Yu, C.; Mei, X.T.; Zheng, Y.P.; Xu, D.H. Zn(II)-curcumin protects against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism. Environ. Toxicol. Pharmacol. 2014, 37, 729–737. [Google Scholar] [CrossRef]
  339. Sankar, P.; Gopal Telang, A.; Kalaivanan, R.; Karunakaran, V.; Manikam, K.; Sarkar, S.N. Effects of nanoparticle-encapsulated curcumin on arsenic-induced liver toxicity in rats. Environ. Toxicol. 2015, 30, 628–637. [Google Scholar] [CrossRef] [PubMed]
  340. Benzer, F.; Kandemir, F.M.; Kucukler, S.; Comaklı, S.; Caglayan, C. Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: By modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch. Physiol. Biochem. 2018, 124, 448–457. [Google Scholar] [CrossRef] [PubMed]
  341. Uzunhisarcikli, M.; Aslanturk, A. Hepatoprotective effects of curcumin and taurine against bisphenol A-induced liver injury in rats. Environ. Sci. Pollut. Res. Int. 2019, 26, 37242–37253. [Google Scholar] [CrossRef]
  342. Panpatil, V.V.; Kumari, D.; Chatterjee, A.; Kumar, S.; Bhaskar, V.; Polasa, K.; Ghosh, S. Protective Effect of Turmeric against Bisphenol-A Induced Genotoxicity in Rats. J. Nutr. Sci. Vitaminol. 2020, 66, S336–S342. [Google Scholar] [CrossRef] [PubMed]
  343. Apaydin, F.G.; Aslanturk, A.; Uzunhisarcikli, M.; Bas, H.; Kalender, S.; Kalender, Y. Histopathological and biochemical studies on the effect of curcumin and taurine against bisphenol A toxicity in male rats. Environ. Sci. Pollut. Res. Int. 2019, 26, 12302–12310. [Google Scholar] [CrossRef] [PubMed]
  344. Kalender, S.; Apaydin, F.G.; Kalender, Y. Testicular toxicity of orally administrated bisphenol A in rats and protective role of taurine and curcumin. Pak. J. Pharm. Sci. 2019, 32, 1043–1047. [Google Scholar]
  345. Newman, D.J. Are Microbial Endophytes the ’Actual’ Producers of Bioactive Antitumor Agents? Trends Cancer 2018, 4, 662–670. [Google Scholar] [CrossRef]
  346. Tintore, M.; Vidal-Jordana, A.; Sastre-Garriga, J. Treatment of multiple sclerosis-success from bench to bedside. Nat. Rev. Neurol. 2019, 15, 53–58. [Google Scholar] [CrossRef]
  347. Yang, Y.; Wei, S.; Zhang, B.; Li, W. Recent Progress in Environmental Toxins-Induced Cardiotoxicity and Protective Potential of Natural Products. Front. Pharmacol. 2021, 12, 699193. [Google Scholar] [CrossRef]
Figure 1. (a) The antioxidant effects of resveratrol against BPA and high-fat-diet-induced developmental programming of hypertension through the AhR signaling pathways [160]. (b) The molecular mechanisms involved in the anti-apoptotic effects of Pistacia integerrima against BPA exposure-induced toxicity in heart tissue [157]. AhR: aryl hydrocarbon receptor; Cyp1a1: cytochrome P450 Cyp1a1; Cyto C: cytochrome C; PUMA: P53 upregulated modulator of apoptosis; Drp1: dynamin-related protein 1; Ubc13: ubiquitin-conjugating enzyme variant.
Figure 1. (a) The antioxidant effects of resveratrol against BPA and high-fat-diet-induced developmental programming of hypertension through the AhR signaling pathways [160]. (b) The molecular mechanisms involved in the anti-apoptotic effects of Pistacia integerrima against BPA exposure-induced toxicity in heart tissue [157]. AhR: aryl hydrocarbon receptor; Cyp1a1: cytochrome P450 Cyp1a1; Cyto C: cytochrome C; PUMA: P53 upregulated modulator of apoptosis; Drp1: dynamin-related protein 1; Ubc13: ubiquitin-conjugating enzyme variant.
Molecules 27 05384 g001
Figure 4. Schematic diagram showing the various NPs evaluated for their potential ameliorating roles against specific BPA-induced toxicity.
Figure 4. Schematic diagram showing the various NPs evaluated for their potential ameliorating roles against specific BPA-induced toxicity.
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Table 1. Summary of experimental studies evaluating the ameliorative potential of natural products and natural compounds against BPA exposure-induced toxicity.
Table 1. Summary of experimental studies evaluating the ameliorative potential of natural products and natural compounds against BPA exposure-induced toxicity.
Author; YearAnimal ModelBPA DoseNatural Product/Natural Compound and Its DoseBPA Induced ToxicityMechanism of Actions
Ishtiaq et al., 2020 [157]Sprague Dawley rats100 µg/kg B.wt/dayPistacia integerrima
200 mg/kg B.wt/day
CardiotoxicityNeutralizing the oxidative stress through Ubc13/p53 pathway
Kaur, S., and Sadwal, S. 2020 [171]Mice (BALB/c)1 mg/kg B.wt/dayFenugreek seed extract—200 mg/
kg B.wt/day
Testicular damage-Antioxidant effects
Friques et al., 2020 [174]Wistar rats 100 μg/kg B.wt/dayKefir—0.3 mL/100 g B.wt/dayHypertension and vascular toxicity-Antioxidant effects
-Increasing NO bioavailability
Abdou et al., 2022 [179]Wistar rats50 mg B.wt/day/kgGrape seed
proanthocyanidins—200 mg/kg B.wt/day
Neurotoxicity-Anti-inflammatory effects
-Antioxidant effects
Zaid et al., 2021 [190]Sprague Dawley rats10 mg/kg B.wt/dayFicus deltoidea—100 mg/kg B.wt/dayFemale reproductive toxicity (Uterus)NA
Zaid et al., 2018 [191]Sprague Dawley rats10 mg/kg B.wt/dayFicus deltoidea—100 mg/kg B.wt/dayFemale reproductive system (ovary)NA
Revathy et al., 2017 [193]Sprague Dawley rats200 mg/kg B.wt/dayIpomoea batatas—400 mg/kg B.wt/dayMale reproductive toxicityNA
Kazmi et al., 2018 [199]Sprague Dawley rats25 mg/kg B.wt/dayQuercus dilatata Lindl. ex Royle—300 mg/kg B.wt/dayHepatotoxicityAntioxidant effects
Mohamad Zaid et al., 2015 [204]Sprague Dawley rats10 mg/kg B.wt/day Tualang honey—200 mg/kg B.wt/dayUterine toxicity-Normalizing ERα, ERβ, and C3 expression and distribution
-Reducing lipid peroxidation
Zaid et al., 2014 [205]Sprague Dawley rats10 mg/kg B.wt/day Tualang honey—200 mg/kg B.wt/dayOvarian toxicityAntioxidant effects
Eweda et al., 2020 [209]Albino Wistar rats30 mg/kg B.wt/daySesame lignans—20 mg/kg B.wt/dayHepatotoxicity and cardiotoxicity-Antioxidant effects
-Improving lipid profile
Abo et al., 2020 [210]Sprague Dawley rats25 and 50 mg/kg B.wt/daySesame oil—10 mL/kg B.wt/day CardiotoxicityAntioxidant effects
Soliman et al., 2021 [216]Albino rats500 mg/kg B.wt/dayPropolis—50 mg/kg B.wt/dayLung injuryAnti-inflammatory and antioxidant effects
Sujan et al., 2019 [220]Swiss albino mice50 mg/kg B.wt/dayNigella Sativa oil—
1 mL/kg B.wt/day
Hyperlipidemia and obesityAntioxidant effects
Sujan et al., 2020 [221]Swiss albino mice50 mg/kg B.wt/dayNigella Sativa oil—
1 mL/kg B.wt/day
Blood and reproductive organAntioxidant effects
Fadishei. et al., 2021 [222]Albino Wistar rats10 mg/kg B.wt/dayNigella Sativa oil—
21, 42, 84 μL/kg B.wt/day
Thymoquinone—0.5, 1, 2 mg/kg B.wt/day
Metabolic disorderAntioxidant effects
Abdel-Wahab et al., 2014 [223]Sprague Dawley (SD) rats 10 mg/kg B.wt/dayThymoquinone—10 mg/kg B.wt/day Hepatoxicity Antioxidant effects
Mohsenzadeh et al., 2021a [230]Wistar rats 10 mg/kg B.wt/dayGreen tea—
25, 50, and 100 mg/kg B.wt/day
Epigallocatechin gallate—10, 20, and 40 mg/kg/day
Vascular toxicityAntioxidant effects
Mohsenzadeh et al., 2021b [231]Albino Wistar rats10 mg/kg B.wt/dayGreen tea—
25, 50, and 100 mg/kg B.wt/day
Epigallocatechin gallate—10, 20, and 40 mg/kg/day
Metabolic disorders-Anti-inflammatory effects
-Regulating the metabolism of lipids
-Improving insulin signaling pathways
Veissi et al., 2018 [234]NMRI mice100 μg/kg B.wt/daySoy extract—
60, 150 mg/kg B.wt/day
Metabolic disorderAntioxidant effects
Patisaul et al., 2012 [235]Wistar rats1 mg/LSoy rich dietAnxiogenic behaviorEstrogen receptor beta, melanocortin receptors, oxytocin/vasopressin signaling pathways
Fawzy et al., 2018 [238]Swiss albino mice50 mg/kg B.wt/dayPumpkin seed oil—1 mL/kg B.wt/dayDNA damage in the liver and testes Decreasing DNA damage
El Tabaa et al., 2017 [245]Wistar rats250 mg/kg B.wt/dayGinkgo biloba extract— mg/kg B.wt/dayNeurotoxicity-Increasing biogenic amines release
-Antioxidant effects
adiponectin pro-secretory effects
Lee et al., 2020 [253]CD-1 mice200 mg/kg B.wt/dayKorean red ginseng—1.2 g/kg/dayInflammation in liver and uterus Anti-inflammatory effects
Park et al., 2020 [254]ICR mice 800 mg/kg B.wt/dayKorean red ginseng—1.2 g/kg/dayIncreased lipid profile Regulating lipid metabolic process-related genes
Saadeldin et al., 2018 [255]Albino rats150 mg/kg B.wt/dayGinseng—200 mg/kg B.wt/dayReproductive toxicityModulating mRNA transcripts of STAR, HSD17B3, and CYP17B, via AKT/PTEN pathway
Kaur et al., 2020 [261]BALB/c mice1 mg/kg B.wt/dayMurraya koenigii—200 mg/kg B.wt/dayTesticular toxicity -Antioxidant effects
-Antiapoptotic effects
Poormoosavi et al., 2018 [100]Wistar rats 10 mg/kg B.wt/dayAsparagus officinalis
200 mg/kg B.wt/day
Hepatic and renal toxicityAntioxidant effects
Behmanesh et al., 2018 [269]Wistar rats 20 μg/kg B.wt/dayAloe vera gel—300 mg/kg B.wt/dayTesticular toxicity Antioxidant effects
Munir et al., 2017 [273]Sprague Dawley rats25 mg/kg B.wt/dayTribulus terrestris L. —20 mg/kg B.wt/dayTesticular toxicityNA
Sirasanagandla et al., 2022 [155]Apo E mice1 μg/mlResveratrol—20 mg/kg B.wt/dayAtherosclerosisAutophagy modulation
Rameshrad et al., 2018 [182]Albino Wistar rats35 mg/kg B.wt/dayResveratrol—100 mg/kg B.wt/day
Grape Seed Extract—3, and 12 mg/kg B.wt/day
Vascular toxicity Antioxidant effects
Rameshrad et al., 2019 [183]Wistar rats35 mg/kg B.wt/dayResveratrol—25, 50, and 100 mg/kg B.wt/day
Grape seed extract—3, 6, 12 mg/kg B.wt/day
Metabolic syndrome and insulin resistance-Promoting insulin signaling
-Increasing ABCG8 expression in the liver
-Antioxidant activity
Shih et al., 2021 [278]Sprague Dawley rats50 μg/kg B.wt/dayResveratrol butyrate esters—
30 mg/kg B.wt/day
ObesityModulatory activity in intestinal microbiota
Fouad et al., 2021 [279]Wistar rats20 mg/kg B.wt/dayResveratrol—
20 mg/kg B.wt/day
Uterine damage-Antioxidant activity
-Antiapoptotic effects
Cetin et al., 2021 [280]Wistar albino rats130 mg/kg B.wt/dayResveratrol—100 and 200 mg/kg/day
Apigenin—100 and 200 mg/kg B.wt/day
Salivary gland cytotoxicity-Antioxidant effects
-Antiapoptotic effects
Bordbar et al., 2021 [281]Sprague Dawley rats50 mg/kg B.wt/dayResveratrol—100 mg/kg B.wt/dayHepatotoxicityNA
Hsu et al., 2019 [160]Sprague Dawley rats50 μg/kg B.wt/dayResveratrol—50 mg/LDevelopmental programming of hypertension-Increasing NO bioavailability
-Antioxidant effects
-Suppressing the AHR signaling pathway
Liao et al., 2021 [284]Sprague Dawley rats50 μg/kg B.wt/dayResveratrol butyrate esters—30 mg/kg B.wt/dayHepatic toxicity -Antioxidant effects
-Modulating gut microbiota
Rahmani-Moghadam et al., 2022 [286]Sprague Dawley rats 50 mg/kg B.wt/dayResveratrol—100 mg/kg B.wt/dayOral mucosa and tongue toxicityNA
Alekhya Sita al., 2019 [293]Wistar rats250 mg/kg B.wt/day Luteolin—100 and 200 mg/kg B.wt/dayNephron toxicityNrf2/
antioxidant response element (ARE)/HO-1 pathway regulation
Adesanoye et al., 2020 [294]Drosophila melanogaster (Canton-S strain)0.05 mMLuteolin—150 and 300 mg/kg B.wt/dayOxidative stress, locomotor deficit,
reduction in offspring emergence rate, cell viability, inhibition of acetylcholinesterase activity
-Antioxidant and chemo-preventive properties
Faheem et al., 2021 [299]Albino Wistar rats 50 mg/kg B.wt/dayLycopene—10 mg/kg B.wt/dayLung injury-Anti-inflammatory effects
-Antioxidant effects
-Antiapoptotic effects
Abdel-Rahman et al., 2018 [300]Wistar rats 10 mg/kg B.wt/dayLycopene—10 mg/kg B.wt/dayHepatotoxicity -Antioxidant effects
-Antiapoptotic effects
Ma et al., 2018 [301]Kunming mice 500 mg/kg B.wt/dayLycopene—20 mg B.wt/day/kgReproductive toxicityNA
Elgawish et al., 2020 [302]Wistar rats 10 mg/kg B.wt/dayLycopene—10 mg/kg B.wt/dayMetabolic syndrome-Antioxidant effects
-Anti-inflammatory effects
El Morsy et al., 2020 [303]Albino rats 50 mg/kg B.wt/dayLycopene—10 mg/kg B.wt/dayHippocampal neurotoxicity and defective memory function-Antioxidant effects
-Activation of MAPK/ERK pathway
-Antiapoptotic effects
Essawy et al., 2021 [304]Sprague Dawley rats125 mg/kg B.wt/dayAstragaloside IV—80 mg/kg B.wt/day
A. spinosus saponins-100 mg/kg B.wt/day
DNA damage and Neurotoxicity -Antioxidant effects
-Anti-inflammatory and anti-apoptotic effects
-Reducing DNA damage
-Regulating the BDNF and NR2A and NR2B gene expression
Abd Elkader et al., 2021 [310]Sprague Dawley rats125 mg/kg B.wt/dayAstragaloside IV—80 mg/kg B.wt/day
A. spinosus saponins-100 mg/kg B.wt/day
Long-lasting anxiety-like behavior and depression in schizophrenia -Neuroprotective activity
Khodayar et al., 2020 [314]Wistar rats 50 mg/kg B.wt/day Naringin—40, 80, and 160 mg/kg B.wt/dayCardiotoxicity-Lipid-lowering
-Antioxidant effects
-Decreasing lipid peroxidation
Mahdavinia et al., 2019 [315]Wistar rats50 mg/kg B.wt/day Naringin—40, 80, and 160 mg/kg B.wt/dayCognitive impairment and oxidative damage-Antioxidant and neuroprotective effects
Rezaee-Tazangi et al., 2020 [321]NMRI mice 0.8 mmol/mL Taurine—5, 10, 30, and 50 µmol/LMitochondrial toxicity and impaired sperm qualityAntioxidant effects
Mahdavinia et al., 2019 [108]Wistar rats250 mg/kg B.wt/dayQuercetin—75 mg/kg B.wt/dayHepatotoxicity (liver)-Antioxidant effects
-Preventing mitochondrial damage
Pradhan et al., 2021 [322]Zebrafish 17.52 μMTaurine—63.9233 μMNeurotoxicity Antioxidant effects
Shirani et al., 2019 [326]Wistar rats 250 mg/kg B.wt/dayQuercetin—75 mg/kg B.wt/dayNephrotoxicity (through uric acid and creatinine)Antioxidant effects
Jahan et al., 2016 [327]Sprague Dawley rats50 mg/kg B.wt/dayQuercetin—50 mg/kg B.wt/dayTesticular toxicity NA
Sahoo et al., 2020 [328]Zebrafish 17.52 μMQuercetin—2.96 μMNeurotoxicityAntioxidant effects
Sangai et al., 2014 [330]Swiss albino mice120 and 240 mg/kg B.wt/dayQuercetin—60 mg/kg B.wt/dayHepatotoxicity and nephrotoxicity Antioxidant effects
Bernardo et al., 2015 [333]Sprague Dawley rats25 and 250 μg/kg B.wt/dayGenistein—
5.5 mg/kg B.wt/day
Reproductive organsAntitumor effects
Betancourt et al., 2014 [335]Sprague Dawley rats250 μg/kg B.wt/dayGenistein—
250 mg/kg B.wt/day
CancerAnticancer and chemoprotective effects
Uzunhisarcikli and Aslanturk, 2019 [341]Wistar rats130 mg/kg B.wt/dayCurcumin—100 mg/kg/day
Taurine—100 mg/kg B.wt/day
HepatotoxicityAntioxidant effects
Panpatil et al., 2020 [342]Wistar NIN (WNIN) rats0, 50 and 100 ug/kg B.wt/dayTurmeric in diet 3% (wt/wt)Liver and kidney Decreasing DNA migration and genotoxicity
Apaydin et al., 2019 [343]Albino rats130 mg/kg B.wt/dayCurcumin—100 mg/kg B.wt/day
Taurine—100 mg/kg B.wt/day
Cardiotoxicity Antioxidant effects
Kalender et al., 2019 [344]Wistar rats130 mg/kg B.wt/dayCurcumin—100 mg/kg B.wt/day
Taurine—100 mg/kg B.wt/day
Testicular toxicity Antioxidant effects
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Sirasanagandla, S.R.; Al-Huseini, I.; Sakr, H.; Moqadass, M.; Das, S.; Juliana, N.; Abu, I.F. Natural Products in Mitigation of Bisphenol A Toxicity: Future Therapeutic Use. Molecules 2022, 27, 5384.

AMA Style

Sirasanagandla SR, Al-Huseini I, Sakr H, Moqadass M, Das S, Juliana N, Abu IF. Natural Products in Mitigation of Bisphenol A Toxicity: Future Therapeutic Use. Molecules. 2022; 27(17):5384.

Chicago/Turabian Style

Sirasanagandla, Srinivasa Rao, Isehaq Al-Huseini, Hussein Sakr, Marzie Moqadass, Srijit Das, Norsham Juliana, and Izuddin Fahmy Abu. 2022. "Natural Products in Mitigation of Bisphenol A Toxicity: Future Therapeutic Use" Molecules 27, no. 17: 5384.

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