Mercury exposure as a determinant of female infertility: Mechanistic insights and reproductive outcomes

Introduction

Mercury is the third-ranking element detrimental to human health according to the United States Agency for Toxic Substances and Disease Registry. It is characterized as a persistent, bio-accumulative and toxic contaminant [4] . It exists in various physical and chemical forms, primarily elemental mercury and cationic forms, namely mercurous and mercuric ions. Elemental mercury exists as a liquid at room temperature while the mercuric form is the most prevalent cationic form of mercury in occupational and environmental settings. Methylmercury, formed by the methylation of inorganic (mercuric) forms of mercury by microorganisms in soil and water is recognized as the most commonly encountered organic mercuric compound in the environment [55] . Mercury, when released into the environment, contaminates the air, water, and soil, affecting the global food chain [7] . It persistently bioaccumulates and biomagnifies within the ecosystem [38] . The global mercury assessment in the year 2018 revealed that mining operations are the primary contributors to atmospheric mercury emissions, followed by stationary industrial facilities fueled by fossil fuels and fixed domestic burning. Additionally, other sources of mercury include cement production, non-ferrous metal production, large-scale gold production, vinyl-chloride monomer, biomass burning, iron and steel production, chlor-alkali production, oil refining and waste incineration [46] . Mercury fumes and mercury-laden dust in electronics waste and lamp recycling sectors also present a risk of exposure to elemental mercury through inhalation by workers [59] . In addition to thermometers, thermostats, and dental amalgam, old paint supplies and certain fungicides contain mercury compounds [45] . Pharmaceuticals, such as mercurochrome and merthiolate, as well as algaecides and childhood vaccines are additional potential sources of mercury toxicity [54] .

Health Implications of Mercury Exposure in Females

Environmental mercury exposure has been found to have profound cellular, cardiovascular, haematological, renal, pulmonary, immunological, neurological, reproductive, genotoxicity, embryotoxicity, endocrine disruption, cancer promotion, pregnancy and reproductive system damage in humans [53,68] . Mercury and its forms, even in small doses, affect the nervous, respiratory, and cardiovascular systems. It can cause disorders such as cancers, endothelial dysfunction, gastric and vascular disorders, hormonal imbalances, miscarriages, and reproductive disorders, skin lesions, vision damage and even death [6] . The brain and kidney are the target organs for longterm exposure to mercury [49] . Mercury has negative effects on fertility in both men and women [40] . Individuals consuming substantial amounts of fish may have low-level and long-term exposure to methylmercury (MeHg), leading to a considerable public health concern. Such chronic exposure to MeHg in utero by infants leads to the dysfunction of the central nervous system (CNS), especially the cerebral and cerebellar cortex [29] . In addition to female infertility, mercury exposure is linked with conditions like polycystic ovary syndrome, premenstrual syndrome, dysmenorrhea, amenorrhea, early menopause, endometriosis, benign breast cancers, and galactorrhea [71,28,47] . High mercury levels in women's blood are correlated with infertility. Similar studies have shown that 80% of infertile women and 68% of pregnant women had hair methylmercury levels above the reference dose of 1 mg/kg set by the US Environmental Protection Agency, which also correlated with their daily methylmercury exposure [24] . Women inhabiting the Gangetic plains of Bihar had blood, urine and breast milk mercury levels above the WHO permissible limits. This depicts that women infants fed via breastfeeding by such women are likely at health risk. Their infants' urine had higher mercury contamination with complete accumulation of mercury in their bodies [34] .

Effect of Mercury on Fertility and Pregnancy Outcomes

In recent years, infertility has emerged as a significant medical and social concern.

A variety of health conditions, including women's age, tubal disease, ovulation disorders, and uterine abnormalities, in conjunction with lifestyle factors such as the consumption of alcohol and smoking, as well as environmental stressors, have significantly increased the prevalence of infertility on a global scale [50] . Multiple toxicants contribute to the impact on fertility; however, the primary factor is widely regarded as stemming from exposure to heavy metals, particularly mercury. Elevated mercury levels have been associated with infertility and decreased fertility [22] . Mercury acts as an endocrine disruptor affecting the hypothalamus, pituitary gland, ovary, adrenal gland, thyroid gland, etc. [62,26] . Prenatal mercury exposure may influence pregnancy or its outcome, and this effect seems to be contingent upon the dose, duration, and timing of exposure. The nutritional status of an exposed individual might also influence the impact of mercury [35] . The administration of nearly all chemical forms of mercury during and even before gestation resulted in reproductive problems, such as stillbirths, spontaneous abortion, congenital malformations, infertility, disturbances in the menstrual cycle, inhibition of ovulation and behavioural effects in the offspring [33,66,67] . Furthermore, occupational mercury vapour exposure is hazardous to pregnant female workers, increasing the risk of adverse reproductive outcomes, especially congenital anomalies [48] . Mercury vapours can cross the placental barrier, so pregnant women exposed to mercury vapour are at an increased risk of adverse reproductive outcomes [16,42,9] . Mercury exposure causes damage to ovarian follicles and diminishes ovarian reserve due to oxidative stress. Pregnant women exposed to methylmercury (MeHg) mainly via diet and or inhalation, the absorbed MeHg crosses the placenta and accumulates in fetal tissues, causing neural tube defects, craniofacial malformations, and delayed fetal growth [73] .

Effect of Mercury on Oogenesis and Ovarian Function

Mercury exposure negatively impacts reproductive health by altering oogenesis and ovarian function. In rat ovaries, mercury has been reported to be deposited particularly in macrophages of atretic young and mature ovarian follicles and corpora lutea, within granulosa cells of atretic follicles and in the lutein cells of freshly formed corpora lutea [61] . In animal models, inorganic mercury exposure causes anovulation in hamsters [11] , prolonged diestrus up to 10 days in rats, with evidence of mercury accumulation in the ovaries [61] . Similarly, high doses of mercury cause adverse effects on the mouse ova [36] . Mercuric chloride (HgCl 2 ) has been found to delay the meiosis of mouse ova in vitro [27] . Female hamsters subcutaneously injected with very high doses of HgCl 2 (6.4 and 12.8 mg/kg) showed a slight increase in the incidence of chromosome aberrations in bone marrow, inhibition of ovulation, despite a low HgCl 2 concentration in the ovaries, and an increase in the number of degenerated oocytes after 12.8 mg/kg injection [65] . Additionally, mercury has been documented to alter female gonadal function in fish, mice, and hamsters. Studies on fish subjected to mercurycontaminated water have demonstrated a decline in gonadal steroidogenesis and pituitary gonadotropinreleasing levels, inhibition of ovarian maturation, a reduction in ovarian weight, and a decrease in both the quantity and size of oocytes. However, the process of meiosis in ova was impacted by mercury in both mice and hamsters [43,51,75] . Methylmercury chloride (MMC) markedly decreases oocyte maturation during in vitro cultivation of mouse oocytes. The defects in oocyte maturation induced by MMC exposure can be attributed to impaired cytoskeleton dynamics and DNA damage [14] . Additionally, in vivo studies in mice revealed that mercury exposure impairs oocyte maturation due to the hyperactivation of mitochondrial autophagy via the monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signal pathway induced by mitochondrial dysfunction [23] .

Mercury-induced Molecular Signalling Pathways in Females

Methylmercury alters intracellular calcium concentration by disrupting the regulation of calcium from the intracellular calcium pool and increasing the permeability of the plasma membrane to Ca 2+ [2] . Mercury has also been shown to have calcium-mimetic effects [20] and to alter intracellular calcium homeostasis [3] . Mercury influences the binding of hormones by their receptors. Mercuric chloride (HgCl 2 ) has been shown to inhibit estradiol binding to rat uterine nuclear receptors, and the presence of divalent ions enhanced the binding [30] . Toxic effects of mercury and mercury-containing xenobiotics occur through interference with cellular and molecular mechanisms, leading to oxidative stress, DNA damage, mitochondrial damage, apoptosis, epigenetic alterations, and impaired signalling pathways [44] . Female rats exposed to mercuric chloride (HgCl 2 ) exhibit histological alterations in the uterine epithelium like vacuolation in uterine epithelial cells, cystic dilatation of uterine glands, and degeneration of the epithelial lining along with ovarian changes [52] . Female Wistar rats orally exposed to mercury (5, 50 and 500μg/L in drinking water) for 28 days have been shown to increase receptor-dependent (PGF2αinduced) and receptor-independent (calcium chloride-induced and high K+-depolarizing solution-induced) myometrial contractions coupled with a corresponding increase in the uterine calcium levels at 5μg/L mercury concentration significantly. These results suggest that mercury at low levels (5μg/L) has a detrimental effect on myometrial activity by altering calcium entry into the smooth muscle and/or the release of calcium from intracellular stores without causing any apparent systemic toxicity in rats [31] . In vitro exposure to HgCl 2 interacts with muscarinic receptors and activates calcium signalling cascades involving calcium channels, Rhokinase, protein kinase-C, and phospholipase-C pathways to exert uterotonic effects in rat myometrium [32] .

Endocrine Disruptive Effects of Mercury

Mercury possesses an endocrine-disruptive potential affecting the hypothalamus, pituitary, thyroid, adrenal gland and gonads (testis and ovary) in laboratory animals as well as in humans [70] . Its acute, subacute, or chronic exposure disrupts the hypothalamic-pituitary-adrenal and hypothalamic-gonadal axes, which negatively affect reproductive functions. This predominantly interferes with hormones such as FSH and LH, further altering steroids such as estrogens, progesterone, and androgens. Mercury primarily inhibits 21alpha hydroxylase, affecting adrenal function and hormone production. It also has impacts on reproductive organs, including gonad size and gamete production [58,56] . Chronic ingestion of low levels of mercuric chloride in female rats lowers the progesterone level, increases LH and FSH levels, indicating that mercuric chloride has a disruptive effect in the corpora lutea, which manifests itself after ovulation [21] . Methyl mercury (20 mg/l) in the drinking water of adult rats has been reported to be deposited in the pituitaries [41] . Similarly, it is found to be deposited in the hypothalamus of rats on exposure to mercury in any form [18] . Mercuric chloride is a weak estrogen mimic and depending on its concentration and exhibits estrogen receptor agonistantagonist properties. It does not affect the binding of estradiol to estrogen receptor (ER). It exhibits estrogen-like effects through binding and activating ER rather than binding to ER by competing with estradiol [74] . However, as is the case with estradiol, mercury stimulates Erk1/2 activation that is dependent on mobilization of intracellular Ca 2+ , suggesting similar signalling mechanisms [37] . In MCF-7 cells, the estrogenicity of HgCl 2 has been examined stimulating both estrogen receptor-dependent transcription and an increase in proliferation of MCF-7 cells [8] .

Molecular Mechanisms Involved in Mercury-Induced Oxidative Stress

A cell maintains redox homeostasis under physiological conditions through well-regulated systems, including enzymatic antioxidants (e.g., superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPx) and nonenzymatic scavengers (e.g., glutathione, vitamin E) [39] . Reactive oxygen species (ROS), such as superoxide (O 2 • -) and hydrogen peroxide (H 2 O 2 ), act as signalling molecules at low levels modulating metabolic and vascular functions [60] . Mercury causes redox imbalances that lead to oxidative stress through both direct and indirect pathways. The direct pathways include direct generation of reactive oxygen species (ROS) by altering the mitochondrial respiratory chain. The indirect pathway is characterized by the accumulation of ROS resulting from the interference of mercury in the biochemical reactions of antioxidants [63,12,10] . The adverse health effects of mercury exposure occur through the disruption of redox homeostasis, primarily caused by alterations in microtubule assembly. Mercury-induced toxicity associated genes/proteins expressed can be identified by several comprehensive analyses of transcriptomics, proteomics, and metabolomics [29] . Several oxidative stress-related genes are modulated by mercury-induced cytotoxicity and genotoxicity in rat lungs [13] . Adult Wistar rats treated with mercury (II) thiocyanate (Hg(SCN) 2 ) at a dose rate of 0.001 mg/L ad libitum for 65 days show altered oxidative stress biomarkers: superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), and hydrogen peroxide (H 2 O 2 ) in blood and tissue samples with evident cellular alterations [1] . Similarly, fresh tissue homogenates and body fluids from the liver, kidney, lung, testis, and serum in rats exhibit enhanced lipid peroxidation after parenteral administration of mercuric chloride (HgCl 2 ) at a dose rate of 5 mg/kg body weight (subcutaneously). Elevated levels of malondialdehyde (MDA) suggest that lipid peroxidation is one of the molecular mechanisms for cell injury in acute HgCl 2 poisoning [25] . Mercury exposure affects the fertility of both sexes; however, due to the fixed and non-renewable pool of germ cells in the ovaries, it has a more severe impact on females than males [5] . The ovary is a crucial organ in the female reproductive system, as it performs both reproductive and endocrine functions. The production of excessive ROS can cause severe damage to the ovary. Mercury exposure causes oxidative stress in the ovaries through both direct and indirect mechanisms, altering signal transduction pathways. The detrimental effects of mercury on the ovaries include follicular atresia and decreased estrogen production, causing premature ovarian insufficiency in women [69] . The ROS accumulation triggers oxidative damage and apoptosis via the hypoxia-inducible factor-1α (HIF-1α) vascular endothelial growth factor (VEGF) signalling pathway leading to follicular atresia with age [72] . and causing DNA damage in oocytes [64] . Methylmercury (MeHg) exhibits a high affinity for selenohydryl groups, sulfhydryl groups, and selenides, which directly activate the antioxidant Keap1/Nrf2 signalling pathway, leading to the impairment of antioxidant enzymes and proteins and ultimately disrupting the antioxidant systems [19] . In laying hens, oxidative stress and ovarian disorders are caused by impeding the Nrf2/Keap1 signalling pathway after mercury exposure [15] . Mercury diminishes the viability of the human ovarian granulosa cell line in a concentrationdependent manner. It significantly reduces cellular ATP levels, mitochondrial membrane potential, oxygen consumption rates, and lactate production, increases membrane fluidity, promotes mitochondrial swelling and enhances the permeability of the inner mitochondrial membrane. Consequently, the bioenergetic disruption may represent a key cause of mercury-induced ovarian dysfunction [17] .

Conclusion

Mercury and its compounds' toxicity continues to remain a paramount global issue, impacting human and animal health. Its versatile effects interfere with multiple organ systems with profound effects on fertility and reproductive processes through several molecular pathways. Mercury exposure at low concentrations for a longer period of time in females adversely affects fertility and pregnancy outcomes by altering oogenesis and ovarian function, as a limited non-replenishable source of ova is available. Mercury acts as an endocrine disruptor, interferes with cellular and molecular mechanisms, leading to oxidative stress, apoptosis, epigenetic alterations, and impaired signalling pathways in the female reproductive system. Thus, the toxicological impact of mercurial compounds on female reproductive systems highlights the need for preventive measures and comprehensive research to understand and mitigate the mechanisms of toxicity and associated female reproductive health risks.

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