Endocrine Disruptors and Infertility

Abstract

Endocrine-disrupting chemicals (EDC) are known to interfere the body’s endocrine system. EDCs can also be considered as industrial chemicals namely pesticides, cleaning materials, plastics, heavy metals, and cosmetics. Most of these compounds particularly at low doses, occurring in complex mixtures, have been reported as emerging contaminants. EDCs are currently present in environment (water, diet, food contact materials, personal care products, etc). The adverse effects of exposure to EDCs have already been extensively described such as infertility, cancers, disrupted thyroid function, neurological disorders, obesity, metabolic syndrome. EDCs may be blamed for increasing the human reproductive disorders especially infertility. This is a serious public health problem that should not be ignored. This chapter aims to summarize the major scientific advances in human infertility associated with exposure to EDCs with epidemiological and experimental evidence. The chemicals covered in this chapter are heavy metals (lead), pesticides (pyrethroids), and cosmetics (UV filters).

1. Introduction

Industrialization and the development of technology make our lives easier, but they also bring negative effects on our health. Particularly, the reproductive health is the system most affected by these modern living conditions and environmental factors. In recent years, many environmental polluting chemicals have been shown to have the ability to interfere with the functioning of the body’s hormone, which have been classified as endocrine-disrupting chemicals (EDCs). An EDC is defined by the United States Environmental Protection Agency (EPA) as, “an exogenous chemical substance or mixture that alters the structure or function(s) of the endocrine system and causes adverse effects at the level of the organism, its progeny, and populations or (sub)populations” [1, 2, 3, 4].

These EDCs are extremely heterogeneous and can be divided into three groups;

1. Pharmaceuticals—(e.g., diethylstilbestrol, ethinyl oestradiol, naproxen, acetaminophen),

2. Natural and synthetics hormones—(e.g., phytoestrogens, 3-omegafatty acids; synthetic such as oral contraceptives).

3. Environmental EDCs—(e.g., polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers heavy metals, pesticides, detergents, plasticizers, solvents, dioxin and cosmetics) [5, 6].

EDCs have been by far the biggest focus due to their widespread use and wide exposure. The major route of human exposure to these chemicals is through ingestion of contaminated water and food (e.g., meat, fish, dairy products, and vegetables), via inhalation, and through the skin. These chemicals are easily released into the environment for example through leaching into the soil and water. Some EDCs (such as some organochlorine pesticides, polychlorinated biphenyl, biphenol-A, phthalates, heavy metals) are known as persistent organic pollutants due to their high lipophilicity. These substances pass into the systemic circulation, can be metabolized to compounds that are more toxic than the parent chemicals, and are potentially eliminated through pathways such as urine, semen, and breast milk [6, 7, 8, 9].

EDCs include different groups of chemicals such as persistent organic pollutants, industrial compounds, children’s products (containing lead, phthalates, cadmium), food contact materials (e.g., bisphenol A, phthalates, linings of cans, or plastic bottles containing phenol), pesticides, chemical substances that are widely used in cosmetics such as phthalates, ultraviolet (UV) filter constituents, and parabens, as well as several heavy metals, polybrominated diphenyl ethers that are flame retardants used in agriculture, and many household and industrial products [2, 8].

Most EDCs have the potential to markedly affect the development of the steroid hormone dependent human reproductive system. EDCs can interfere with the normal secretion, synthesis, production, metabolism, transport, or effect of hormones. EDCs can alter cellular processes by different mechanisms, by binding to steroid hormone nuclear receptors and activating genomic and non-genomic pathways, activating ion channels, inducing proinflammatory cytokines and chemokines, promoting oxidative stress, and altering cell proliferation and differentiation [7, 8]. EDCs may contain a large number of molecules capable of inducing estrogenic or antiandrogenic effects. They may mimic the sex hormones estrogen or androgen or they may block the activities of estrogen or androgen. (i.e., be antiestrogens or antiandrogens) [4, 5, 10]. EDCs can indirectly produce an estrogenic response by a number of different mechanisms, such as increasing estrogen synthesis (e.g., peroxisome proliferators inducing aromatase activity, thus increasing circulating estradiol levels), facilitating estrogen receptor binding, or altering the estrogen ratio. Estrogens are a group of chemicals of similar structure primarily responsible for female reproduction but the existence of estrogen in men has been known for over 90 years. However, our knowledge of the general role of estrogens in the male reproductive and non-reproductive organs is clearly far behind that in females. In addition, exposure to exogenous estrogens, especially developmentally, has recently been shown to have deleterious effects on the male reproductive system in men [11, 12].

Estrogens are mainly produced by the ovaries, but also by the adrenal glands and adipose tissue. Estradiol is most potent member of the class of steroid hormones produced primarily by the ovaries [11, 13]. For instance, in either sex, androgens give rise to estrogens, through aromatase, so together they play a vital role in homoeostasis. In addition, EDCs can exert an antiestrogenic effect by preventing endogenous estrogens from interacting with their receptors and thus inhibiting their action. In general, estrogenic compounds promote the development of female sexual characteristics; antiestrogens inhibit the development of female characteristics, but not necessarily male characteristics [7, 13].

It is well known that chemicals interfering with hormonal pathways can seriously affect human reproductive disorders such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality, and/or function [5, 6, 9, 14]. A growing body of scientific evidence indicates that reproductive health, and ultimately reproductive capacity, is under pressure globally. Unfortunately, relatively few studies have addressed the impact of environmental exposures on human reproductive function. It has been reported that the number of families applying to infertility clinics to have a child with the assisted reproductive techniques has increased significantly in recent years [4, 8, 15]. Infertility is defined as “a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse.” It affects 10–15% of all couples and varies between countries and geographic regions. Idiopathic infertility accounts for approximately 44% of male infertility cases and is the most common individual diagnosis [3, 16, 17].

The current chapter discusses the detrimental effects of EDCs exposure on male/female infertility, by providing an overview of experimental studies on humans and by reporting epidemiological studies in humans. The present section will focus on the relationship between hormone disruptors and female infertility. Specifically, pesticides pyrethroids, heavy metal such as lead as well as commonly used cosmetics like UV filters will be discussed.

2. Male infertility

The psychological, social, and economic consequences of reduced male capacity to have children are often severe and extend beyond individuals to entire families and society at large. The previously discussed subject of decline in male fertility is no longer controversial because many studies over the past 10 years have shown a decrease in semen quality [4, 17, 18, 19]. EDCs affect the maturation, function, and viability of sperm by acting directly on the sperm or altering the function of the epididymis as well as the sperm’s ability to fertilize an egg. In normal human males, the number of sperm is close to what is normally required for fertility. While acute exposure can cause significant changes in spermatogenesis, it appears to occur with low-dose, chronic exposures to EDCs that impair spermatogenesis [5, 17, 20]. Therefore, even a small decrease in daily sperm production can cause infertility. Semen parameters are used to measure sperm quality and they are very important because they can be used to predict male infertility [5, 20]. However, for many reason, semen may be the least understood body fluid in terms of the distribution of its normal values in the general population. Since it is difficult to obtain semen fluid, men are not included in the study, therefore not many studies can be conducted to reveal the relationship between semen quality and chemical substances [21].

About 15% of couples worldwide are infertile and half is the male factor. Male infertility is considered as primary cause of infertility in 20% of couples and a contributing factor in 30–40% of cases. Infertility is caused by changes in the hypothalamic-pituitary-gonadal (HPG) axis or by direct effects on sperm and other semen parameters [4, 17]. Men with sperm parameters below the values specified in WHO are considered to have male factor infertility. The most important of these are low sperm concentration (oligospermia), poor sperm motility (asthenospermia), and abnormal sperm morphology (teratospermia). Other factors less correlated with infertility include semen volume and other seminal markers [15].

In a large review of international studies conducted by authors, it is reported that the average sperm count in men decreased from 113 million/mL to 66 million/mL and significant anomalies in sperm morphology/motility in 50 years (1940–1990) in the world [7, 22].

Sperm function is affected by reactive oxygen species (ROS) produced during the metabolism of these chemicals, which is another possible effect of infertility including EDCs. Oxidative stress plays an important role in the mechanism of male infertility. Oxidative stress is a balance between the production of ROS and the natural antioxidant defense of semen. Increased ROS levels can be due to many factors such as environmental pollutants and lifestyle factors [23, 24].

The effect of EDCs in testicles is mediated mainly by the nuclear estrogen receptors (ESR1 and ESR2) expressed by Sertoli and germ cells. These cells secrete masculinizing hormones that regulate sperm production, [6, 10, 25]. Because hormones tightly control the male reproductive system, anti-androgens or EDCs that mimic estrogens can interfere with spermatogenesis and have a profound effect on healthy sperm production [16]. Men exposed to estrogenic EDCs may reduce fertility and develop female secondary sex characteristics such as gynecomastia [13].

Different mechanisms of action related to the hormone-disrupting effects of pesticides are discussed, but the most common mention is the interaction with the recognition and binding of reproductive hormone receptors. Most EDCs are substances with estrogenic/anti-androgenic activity that act by interfering with the estrogen receptors (ER) or the androgen receptor (AR), which are commonly found in male reproductive tissues [26, 27]. For the last been, it has focused on the estrogenic effect of EDCs and it has been determined that many substances are “environmental estrogens.” It is though that increased exposure to estrogens not only causes prenatal testicular damage, but may also contributes to postpartum inhibition of testicular function and spermatogenesis. Environmental estrogens affect fetal development by inhibiting the development of Sertoli cells, which determine the lifetime capacity of sperm production. These estrogens can also inhibit enzymes in testosterone synthesis and directly affect testosterone production [28, 29, 30].

2.1 Heavy metal (LEAD-Pb)

Rapid industrialization and over-growing urbanization and the toxic effects of heavy metals on the male reproductive system have become an important public health all over the world. Reproductive problems in males due to metal exposure are one of the most important areas of concern in toxicology [31]. In epidemiological and clinical studies, it has been found to be associated with impaired semen quality as a result of the direct effect of heavy metals on testicular function or hormonal changes. One of the heavy metals of greatest concern is lead (Pb). Lead exposure can cause toxicity to both the male and female reproductive systems. Pb is a natural compound and is regularly used in mining, smelting, refining, leaded gasoline (petrol), lead-acid batteries, paints, jewelry, children’s products, and many other products. The general population is exposed to Pb through contaminated food and water and inhalation of airborne Pb. Lead in seminal plasma may increase with environmental pollutions, and industrial and dietary exposure [6, 32, 33].

In toxicology studies, it is argued that the determination of heavy metal levels in the seminal fluid may better indicate exposure, due to the accumulation of these substances in the male reproductive organs, rather than the determination of heavy metal levels in the blood [31, 32]. At low levels of occupational exposure in smelting industry workers, lead has been associated with reduced semen concentration, motility, and viability. Heavy metals cause toxicity by affecting the HPG axis, testicular function, spermatogenesis, and steroidogenic processes either directly or through the endocrine system [17, 31, 34].

Strong evidences confirm that male infertility in metal-exposed humans is mediated via various mechanisms such as production of reactive oxygen species (ROS). It is known that smoking causes oxidative stress by increasing oxidant levels or decreasing antioxidant levels in seminal plasma [34, 35]. Kiziler et al. [35] investigated Pb levels in blood and seminal plasma of the infertile and fertile groups. Pb levels in seminal plasma and blood were significantly higher in infertile men than those in fertile groups. It was revealed that sperm count, motility, and morphology were significantly decreased in infertile smokers than in non-smoker infertile and fertile men. He et al. [36] investigated whether oxidative stress is an intermediate mediator in regulating the associations between heavy metal exposure and impaired semen quality. A significant inverse relationship was found between Pb exposure and the percentage of normal sperm morphology [36], and a negative correlation was detected with the sperm count and motility [37]. Lead levels of non-occupational lead exposure in 341 infertile men were investigated by Wu et al. [32]. The research results showed a significant inverse correlation between the lead concentration in seminal plasma and the sperm count. These results showed a negatively correlation with standard semen parameters and biomarkers of sperm function. Therefore, the authors postulate that unexplained male infertility may be due to increased Pb levels [38].

It is known that semen quality has an effect on sperm motility, which is one of the most important factors in infertility [39]. Sperm motility depends on the synchronized movements proteins, sugars, ions, and small organic molecules. It is one of the main factors that facilitate the journey of sperm toward the egg and the subsequent fertilization process. Defects in sperm motility are a common reason for infertility in humans [34]. Li et al. [40] examined the positively relationship between increased blood Pb levels and low semen quality. Li et al. [41] also found a negative correlation between Pb concentrations and sperm motility. Therefore, authors suggest that among the semen parameters, sperm motility can be a sensitive indicator of semen quality.

It has been reported that 90% of male infertility problems are related to sperm count, and there is also a positive relationship between sperm count and semen parameters [15]. Famurewa and Ugwuja [42] found that seminal plasma Pb was significantly (p < 0.05) higher in oligospermic and normospernic men than in azospermic men. Significant inverse associations (p < 0.01) were found between blood lead and sperm count.

In conclusion, lead shows its effect on reproductive hormones by changing the reproductive hormone axis and hormonal control over spermatogenesis rather than having a direct toxic effect on the seminiferous tubules of testicles [43]. The overall results of these studies indicate that even considerably low levels of blood and seminal plasma Pb might reduce the human semen quality, it potentially reduces male fertility; however, more infertility studies are needed to show that lead has a direct effect on male infertility [42].

2.2 Pyrethroids

The most widely used group among pesticides is the group of synthetic pyrethroids. General population exposure to pyrethroids can occur primarily through dietary residues and inhalation or ingestion of contaminated house dust after indoor application. Because of high performance and low toxicity of pyrethroids, these chemicals are widely used both in agriculture and at home as a substitute for organochlorine insecticides [44, 45]. In recent years, hormone disruptors such as pyrethroids have been discussed with studies showing the male infertility relationship [28, 29]. It is suggested that pyrethroids can cross the blood testicular barrier, reach the nucleus of spermatogenetic cells, and affect sperm function, due to their hydrophobic and small molecular structure. Although associations between occupational exposure to pyrethroids and altered semen quality are generally reported, there are limited epidemiological data on the potential effects of non-occupational exposure to pyrethroids on male reproductive function [44]. In recent years, studies have reported that pyrethroid pesticides can reduce sperm count and motility, change sperm morphology, increase abnormal sperm count, cause sperm DNA damage, and also affect sex hormone levels [46, 47, 48, 49]. It is emphasized that these findings may be of particular concern for male infertility due to increased use of pyrethroids and widespread human exposure. As a result, it is reported that these substances play an important role in reproductive toxicity [45].

The number of environmental pollutants such as pyrethroids determined to have anti-androgenic effects is increasing day by day. However, recently the relationship between androgenic/antiandrogenic effects of these substances and male infertility has been discussed [28, 29, 50, 51]. Androgens, like testosterone, are steroid hormones essential for normal male reproductive development and function and play a very important role in spermatogenesis, in adulthood [52]. Androgenes belong to the steroid superfamily and are mainly involved in gonadal development. Androgens are present in different levels in both men and women [27]. The differentiation of the male reproductive system depends on fetal testicular androgen production. In addition, disruption estrogen exposure in the fetal period may cause reproductive abnormalities by disrupting the sensitive androgen-estrogen balance [7, 27]. Anti-androgenic pyrethroids interfere with the androgen receptor signaling pathway by interacting with androgen receptors [51]. In recent years, cypermethrin, deltamethrin, fenvalarate, bifenthrin, permethrin, lambda cyholothrin, cyfluthrin are the most used pyrethroids in many countries, and the anti-androgenic effect of these substances has been reported [53, 54, 55, 56, 57, 58, 59]. Therefore, the identification of these chemicals is very important in many fields, including food production, reproductive toxicology, and risk assessment [57]. Although it has been suggested that some pyrethroids act as androgen receptor antagonists, more studies are needed to determine the mechanisms underlying the antagonism [50].

As a result of exposure to pyrethroids in different ways, it has been shown that these substances are rapidly metabolized in human by hydrolytic cleavage of the ester bond followed by oxidation [60]. Because of the rapid metabolism of pyrethroids, determination of their urinary metabolities is preferred for the estimation of pyrethroid exposures. 3-phenoxybenzoic acid (3-PBA) is a general metabolite of many pyrehroids (cypermethrin deltamethrin, permethrin, and others) and is a metabolite with the highest rate in non-occupational exposure. Therefore, determination of this metabolite in urine may indicate environmental exposure to different pyrethroids [44, 60]. In the literature, there are not many studies on the infertility relationship of anti-androgenic pyrethroids/metabolites [28, 29, 44, 46, 61]. In infertility studies, exposure to non-persistent pyrethroid metabolities has been associated with changes in reproductive hormones in men [62], as well as decreased semen quality and increased sperm DNA damage due to urinary metabolities of pyrethroid insecticides [29, 44, 63]. Han et al. [60] found an association between serum hormone levels and urinary 3PBA levels (between 3-BPA and LH and E2 hormones), in infertile men, as result of their investigation. The detrimental effect of pesticides such as pyrethroids on sperm concentration, motility, and morphology may result from impaired spermatogenesis due to various hormonal changes [64]. The information provided by examining sperm morphology in a complete semen analysis is becoming increasingly important clinically for infertility and fertility [65]. Abnormal sperm morphology due to secretory dysfunction of Leydig and Sertoli cells impairs sperm fertilization capacity. Sperm parameters such as sperm concentration, sperm motility, and sperm morphology are related to each other. The factors that cause deterioration in any of these parameters generally affect the others. It is reported that the best indicator of infertility is sperm concentration after sperm motility [64, 66]. More studies are needed to better elucidate the effects of exposure to potential endocrine-disrupting pyrethroid pesticides on semen parameters.

2.3 Cosmetics (UV filters)

Cosmetics include all non-pharmaceutical substances consumed or applied to improve personal health, hygiene, or appearance. These products contain many components such as phthalates, parabens, UV filters, polycylic musks, antimicrobials, formaldehyde, which are used different purposes. In addition, many cosmetic products contain heavy metals such as lead, cadmium, antimony, chromium, arsenic, mercury, nickel as ingredient or impurities [18, 67]. The main route of exposure is through the skin and through inhalation. The main endpoint of exposure is endocrine disruption. This is because of the many substances in cosmetics and UV filters that have endocrine active properties that affect directly damaging the testicular tissue. Recently, Peterson et al. [18] investigated the cosmetic exposure and associations with measures of semen quality in young Danish men. Despite the widespread use of multiple products, they found little an association with semen quality.

UV filters are used not only in cosmetic products such as skin lotion, beauty creams, lipsticks, and hair sprays, but also as additives in plastics, printing inks, shampoos, perfumes, and other products. Although UV filters are applied to the body surface, there is information that they are absorbed, metabolized, bio accumulated, and/or excreted from the skin. There is not much information about the metabolism of the UV filter in humans in the literature [68, 69, 70].

UV filters are new environmental pollutants that could potentially affect a large proportion of the population [71]. Men’s exposure to these substances is likely due to contact with products containing these chemicals [72]. In fact, in vitro and in vivo studies in different species of mammals showed that some of these UV filters exhibit hormonal activity and are able to interact with estrogen, androgen, and thyroid signaling [68]. However, epidemiological studies on the relationship between hormone-disrupting effects of organic UV filters and infertility are very limited. Therefore, more research is needed to determine the health risks of these substances [73]. Frederiksen et al. [72] investigated the degree of exposure of human spermatozoa to UV filters in Danish men. They found that almost half of the men had measurable concentrations in their seminal fluid of at least one of the selected UV filters.

In recent studies, the mechanism of action of UV filters on sperm has been evaluated. Some processes in sperm depend on calcium ion channels opened in the cell membrane. CatSper ion channel, which is specifically expressed in spermatozoa, controls intracellular Ca2+ concentration and sperm motility. CatSper activation mediates an increase in intracellular Ca2+ levels in the sperm tail. The presence of an inactive CatSper protein in male mice has been reported to cause infertility [74, 75]. Schiffer et al. [74] investigated the effect of 96 different EDCs including UV filters (4-MBC, BP3, 3-BC, HMS, OD-PABA) on human sperm. Researchers reported that structurally diverse EDCs activate the sperm-specific CatSper channel, thereby inducing intracellular Ca2+ increase, motility response, and acrosomal exocytosis. Rehfeld et al. [76] also revealed that organic UV filters have been shown to induce a Ca2+ influx through CatSper. As a result, authors argue that EDCs (selected UV filters) interfere with various sperm functions and thus may impair human fertility. Sperm cell dysfunction is a common cause of infertility. Progesterone is a known inducer of acrosomal reaction in sperm cells, and suboptimal induction of acrosomal reaction in response to progesterone is correlated with fertility. Rehfeld et al. [77] examined the effects of organic UV filters on the human sperm cell function acrosomal reaction, sperm penetration into a viscous medium and hyperactivation, as well as on sperm viability. The result of these study showed that selected UV filters mimic the effects of progesterone on the activation of the CatSper Ca2+ channel in human spermatozoa.

Adoamnei et al. [78] investigated whether there are associations between urinary concentrations of BP-type UV filters and semen quality and reproductive hormone levels in young men. They found a significant positive association between urinary BP-type (BP1 and BP3) concentrations and some reproductive hormones (FSH, T/E2). They suggest that further research is needed in other male populations. When the relationship between semen parameters and reproductive hormones is evaluated in other studies with BP-type UV filters, it is reported that there is a significant relationship [79] and found no association between urinary concentrations of BP3 and idiopathic male infertility [80]. As a result, human exposure to these organic UV filters can interfere with sperm and impair fertility.

3. Female infertility

EDCs are thought to affect women’s menstrual cycle, estrogen deficiency, infertility, and are also associated with diseases such as polycystic ovary syndrome (PCOS) and endometriosis, spontaneous abortions, birth defects, endometriosis, breast cancer, premature ovarian failure [23, 25]. Female are at a greater risk than men, especially with the rise in environmental estrogens. However, since research on these exposures often tends to focus on male fertility, it is unlikely that EDCs will answer questions about female fertility [25, 81]. Because females are relatively sensitive to estrogens and are heavily exposed to environmental estrogens, women will also be most affected by EDCs. The origin of endocrine disruption hypothesis was related to exposure to estrogens. Literature data also show that long-term and combined exposure to environmental estrogens will have an impact on female fertility. Although it has long been known that female fertility is impaired by estrogen exposure, there are limited data on whether long-term low-dose exposure to environmental pollutants with weak estrogenic effect causes problems such as infertility in women [81].

There is little epidemiological information about trends in female infertility. Data on the effects of EDCs on the female reproductive system and fertility are insufficient. However, it has been suggested that there is a relationship between exposure to EDCs and their long-term effects [7, 81].

The most common direct or indirect causes of female infertility are endocrine problems. EDCs alter endocrine function through various mechanisms. One of these mechanisms is that these substances directly bind to estrogen receptors and increase aromatase activity, thereby increasing estrogen sensitivity. Another mechanism is that EDCs indirectly lead to an increase in endogenous estrogen production and exert their effects through both receptor-dependent and receptor-independent mechanisms through their effects on gonadotropin-releasing hormone. Both mechanisms result in altered ovarian function by altering endocrine signaling with several processes in ovary and the other reproductive organs [3, 33, 82].

EDCs act on female reproductive hormones and receptors through estrogenic, anti-estrogenic, androgenic, and anti-androgenic mechanisms [23, 25]. Estradiol (E2) plays a very important role in female fertility. The functions of estrogens are mediated primarily by two estrogen receptors: ESR1 (ERalfa) and ESR2 (ERbeta), both of which are widely expressed in cells throughout the female reproductive system [83]. Most EDCs interfere with female reproductive function by activating or inhibiting ESRs. EDCs have different binding affinities to ESRs and therefore exert different effects in ovary. In ovary, the main function of ESR1 is to regulate steroidogenesis in theca cells. On the other hand, the function of ESR2 is granulosa cell differentiation toward FSH, follicle maturation, and ovulation. Many EDCs interfere with female reproductive function by activating or inhibiting ESRs. Different EDCs exert different effects in the ovary depending on their binding affinity to different ESRs [82, 83].

The sensitivity of the developing female reproductive system to estrogens raises the question of whether exposure to EDCs with estrogenic activity (such as heavy metals, pesticides, and cosmetics) can affect the female fertility [81].

3.1 Heavy metal (LEAD-Pb)

Lead is known to be one of potential female reproductive toxins. However, there are few studies on whether low Pb exposure causes female infertility compared with male infertility. Lead is a potent disruptor of adrenal and ovarian steroidogenesis and inhibits progesterone synthesis and activity in dose-dependent manner. The effects of lead on 17-β-estradiol, testosterone, and cortisol may cause stimulant effects after low-level exposure, while inhibiting effects after high-level exposure. Exposure to Pb causes impaired fertility in women, two key proteins in the function of the pituitary-ovarian axis. Both P-450 aromatase and ER-β-activity in granulosa cells of ovarian follicles have been shown to be strongly inhibited in women exposed to Pb [84, 85, 86].

It is known that Pb can concentrate, impair cellular processes, and cause harmful results in terms of reproductive health. Lee et al. [85] found that low blood lead level was positively associated with infertile women. It has been suggested that even low blood lead levels may be detrimental to female fertility. Silberstein et al. [87] compared lead levels in blood and follicular fluid from nine patients undergoing IVF treatment. Lead levels in follicular fluid were found to be significantly higher in non-pregnant patients compared with pregnant patients. The results of this study show that high concentrations of lead negatively affect female fertility [87]. Another researcher investigated the association between blood concentrations of Pb and risk factors for infertile or pregnant women in Taiwan. The concentration of Pb was significantly higher in the blood of infertile women than in that of pregnant women. Particularly, frequent use of Chinese herbal medicine by infertile women has been associated with elevated blood Pb levels. It is suggested that the risk-benefit of Chinese herbal medicine intake should be evaluated by women of childbearing age [88].

With the increase in the female workforce of more women in Pb production in developing countries, more women are exposed to potential reproductive hazards. In a study by Tang and Zhu [89], it was shown that Pb causes reproductive toxicity and female infertility as a result of occupational exposure (lead battery plants). In this study, it was observed that the menstrual cycle, that is, the hormonal balance of female workers exposed to lead was disturbed [89]. On the other hand, Gerhard et al. [90] investigated whether the urinary heavy metal excretion is associated with different factors of infertility. They found that accumulation of heavy metals in the ovary disturbs the production of estradiol and progesterone. The study by Srivastava et al. [91] also supports that pubertal women exposed to low levels of lead maternally have suppressed levels of both luteinizing hormone (LH) and estradiol (E2). Maternal Pb exposure changes only LH, not FSH secretion.

Endometriosis affects 10% of women of childbearing age and causes infertility in about half of these women. Recently, it has been reported that exposure to EDCs is associated with endometriosis [7]. Tanrıkut et al. [92] determined the role of endometrial concentrations of heavy metals including Pb in the unexplained infertility. Lead levels were detected in 15 and 3% of 33 infertile and 32 fertile women, respectively. Further population-based studies are needed to determine the reproductive toxicity of low-level Pb exposure [85].

3.2 Pyrethroids

Although in vitro and experimental animal studies show that pyrethroids may affect ovarian function, epidemiological studies in this direction are scarce. Since pyretroids are rapidly metabolized in mammals, their toxicity is reported to be very limited [93, 94]. Marettova et al. [93] reviewed the effect of pyrethroids on female reproductive system. In vitro and experimental animal studies have shown that pyrethroids can inhibit female endocrine functions. It has been determined that pyrethroids such as fenvalarate, deltamethrin, and cypermethrin cause morphometric and structural changes in female genital organs. It has been determined that the negative effect of toxic substances on the ovary may be caused by decreased gonadotropin secretion, impaired follicular growth, or enzymatic interaction, which may lead to decreased sex steroid hormone synthesis. As a result, it has been reported that pyrethroids/metabolities may impair the structure and function of female reproductive organs [93].

Women are normally exposed to estrogen, but the effects of ECDs on women are more difficult to monitor due to the large differences in the estrogen cycle and circulating hormone concentrations during different phases of the cycle. The presence of estrogen-mimicking compounds in adult women can interfere with natural hormone cycles, impairing reproductive capacity, potentially making women unable to conceive, or maintaining a pregnancy [5]. If fertilization does not occur or pregnancy does not occur, the corpus luteum undergoes a process of cell death known as luteolysis or corpus luteum regression. Disruption of the process of folliculogenesis and corpus luteum formation leads to adverse reproductive outcomes such as anovulation, infertility, decreased fertility, estrogen deficiency, and premature ovarian failure (POF). The POF is one of the mechanisms leading to female infertility [82, 95]. Anti-Mullerian hormone (AMH) is a marker of ovarian reserve. Whitworth et al. [96] investigated the relationship between residential spraying pyrethroid exposure and AMH levels in African women. The authors reported that pyrethroids reduce the level of AMH, one of the predictors of female fertility. In another non-occupational exposure study in Chinese women, a positive correlation was found between increased urinary 3-PBA concentration and FSH and LH levels, and a negative correlation between AMH and 3-PBA [97]. Hu et al. [98] researched the effects of preconception exposure pyrethroids on gestational duration and infertility in the general population of couples planning to conceive in China. They found that the urinary 3-PBA concentrations in the highest quartile were correlated with longer time to pregnancy and infertility in women.

These limited study data highlight that this may be of concern due to the increasing use of pyrethroids causing non-occupational exposure among the general population and the lack of epidemiological studies.

3.3 Cosmetics (UV filters)

Residues of UV filters were also studies biological samples such as urine, breast milk, placenta, plasma, fetal cord blood, semen, and tissues [99, 100, 101, 102]. Considering the chronic toxic effects of UV filters in terms of both their residual values and their hormone-disrupting effects, there are serious warnings in the literature. In particular, there are studies showing that organic UV filters, called “environmental estrogens-endocrine disruptors,” have estrogenic and antiandrogenic activity as much as other industrial chemicals [69, 103]. Recent studies dealing with organic UV filters are mostly focused on their effect on endocrine damage. Wang et al. [68] reviewed the potential endocrine disruptors of typical UV filters including benzophenones (BPs), camphor derivatives, and cinnamate derivatives.

It has been shown that there is statistically significant relationship between exposure to endocrine-disrupting UV filters and estrogen-mediated diseases. Kunisue et al. [104] assessed the relationship between exposure to BPs and endometriozis. The association of urine concentrations of BPs with an increased probability of being diagnosed with endometriozis was studied in 600 women. Significant regional variations were found for 2OH-4MeO-BP and 2,4OH-BP urine concentrations, and monthly variations (higher concentrations in July and August) were determined based on female use. When these results are evaluated, it is reported that there may be a relationship between exposure to high 2,4OH-BP levels and endometriozsis, considering that 2,4OH-BP has a higher estrogenic activity than 2OH-4MeO-BP [104]. The most used group of UV filters is benzophenone (BP) and it has about 29 compounds. Considering the wide use of BPs in sunscreen and personal care products, as well as their estrogenic and antiandrogenic activities, BPs are reported to be a public health concern. Given the widespread use of UV filters, concerns have arisen about their potential impact on human health, including infertility [71]. Thus, further studies are needed to clarify associations between exposures to these chemicals.

Faass et al. [105] examined the pre- and postnatal effects of 4-MBC and 3-benzylidene camphor (3-BC) that are sunscreens with endocrine-disrupting properties, in rat and dog. It was observed that these UV filters disrupted female sex behaviors, estrus cycle, and gene expression of sex hormones in brain. Screening the data from this point of view, in rat exposed to endocrine-disrupturing UV filters in low doses, it was observed that these chemicals have an influence on the sexual behaviors and gene expression of sex hormones. In this study, it was additionally found that the difference is not so high when residual values of organic UV filters are compared with those in humans. It is obviously underlined that this could be a potential risk namely for women [105].

However, human data evaluating the effects of hormone disruptors of these substances are very limited and studies have been carried out recently. BP-3, which is a UV filter used in sunscreens and cosmetic products, has been detected in almost all individuals and not only during the summer season. Louis et al. [71] investigated the effects of 5 UV filters, which are most commonly used in sunscreen products and personal care products, and whose residues were detected in human urine samples, on the duration of conception. Urine samples were collected from 501 couples who stopped using contraceptives to become pregnant until they achieved pregnancy. The effect of five UV filters BP3 (its metabolites BP1, BP8), BP2, and 4-OH-BP on the duration of conception was evaulated. The results show that male exposure to selected UV filters (BP2 and 4-hydoxybenzophenone) can reduce couple’s fertility, resulting in a longer time to pregnancy [71].

4. Conclusions

In general, it is being observed that the most important harmful effects of exposure to endocrine-disrupting environmental pollutants such as heavy metals, pesticides, and cosmetics are on the reproductive system in humans. Infertility is both clinical and social problems that affect the couple’s life, health services, and social environment. With the awareness of these important issues, factors that increase the risk of infertility can be prevented. Further toxicological studies are needed to further understand the risk and mechanisms of action of these substances on male and especially female reproductive function, and to identify and characterize new EDCs.

Conflict of interest

The authors declare no conflict of interest.