Open access peer-reviewed chapter - ONLINE FIRST

Endocrine Disruptors and Infertility

Written By

Selma Yazar

Submitted: December 21st, 2021 Reviewed: March 8th, 2022 Published: April 7th, 2022

DOI: 10.5772/intechopen.104403

IntechOpen
The Toxicity of Environmental Pollutants Edited by Daniel Dorta

From the Edited Volume

The Toxicity of Environmental Pollutants [Working Title]

Dr. Daniel Dorta and Prof. Danielle Palma De Oliveira

Chapter metrics overview

17 Chapter Downloads

View Full Metrics

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).

Keywords

  • endocrine disruptors
  • infertility
  • pesticides
  • heavy metal
  • cosmetics

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), viainhalation, 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.

Advertisement

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 viavarious 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 vitroand in vivostudies 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.

Advertisement

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 vitroand 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 vitroand 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].

Advertisement

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.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Kelishadi R. Environmental pollution: Health effects and operational implications for pollutants removal. Journal of Environmental and Public Health. 2012;2012:1-2. DOI: 10.1155/2012/341637
  2. 2. Kabir ER, Rahman MS, Rahman I. A review on endocrine disruptors and their possible impacts on human health. Environmental Toxicology and Pharmacology. 2015;40:241-258. DOI: 10.1016/j.etap.2015.06.009
  3. 3. Canipari R, Santis L, Cecconi S. Female fertility and environmental pollution. International Journal of Environmental Research and Public Health. 2020;17:8802. DOI: 10.3390/ijerph17238802
  4. 4. Leisegang K, Dutta S. Do lifestyle practices impede male fertility? Andrologia. 2020;00:e13595. DOI: 10.1111/and.13595
  5. 5. Keith LH. Environmental endocrine disruptors. Pure and Applied Chemistry. 1998;70(12):2319-2326
  6. 6. Di Nisio A, Foresta C. Water and soil pollution as determinant of water and food quality/contamination and its impact on male fertility. Reproductive Biology and Endocrinology. 2019;17(1):4. DOI: 10.1186/s12958-018-0449-4
  7. 7. Marques-Pinto A, Carvalho D. Human infertility: Are endocrine disruptors to blame? Endocrine Connections. 2013;2:R15-R29. DOI: 10.1530/EC-13-0036
  8. 8. Giudice L. Environmental toxicants: Hidden players on the reproductive stage. Fertility and Sterility. 2016;106(4):791-794. DOI: 10.1016/j.fertnstert.2016.08.019
  9. 9. Balabanič D, Klemenčič AK. Endocrine-disrupting chemicals and male reproductive health: A review. Zdravstveni Vestnik. 2018;87(1-2):69-80. DOI: 10.6016/ZdravVestn.2456
  10. 10. Lagos-Cabre R, Moreno RD. Contribution of environmental pollutant to male infertility: A working model of germ cell apoptosis induced by plasticizer. Biological Research. 2012;45:5-14. DOI: 10.4067/S0716-97602012000100001
  11. 11. Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiological Reviews. 2017;97:995-1043. DOI: 10.1152/physrev.00018.2016
  12. 12. Hess RA, Cooke PS. Estrogen in the male: A historical perspective. Biology of Reproduction. 2018;99(1):27-44. DOI: 10.1093/biolre/ioy043
  13. 13. Daston GP, Gooch JW, Breslin WJ, Shuey DL, Nikiforov AI, Fıco TA, et al. Environmental estrogens and reproductive health: A discussion of the human and environmental data. Reproductive Toxicology. 1997;11(4):465-481. DOI: 10.1016/s0890-6238(97)00014-2
  14. 14. Fucic A, Galea KS, Duca RC, Yamani ME, Frery N, Godderis L, et al. Potential health risk of endocrine disruptors in construction sector and plastics industry: A new paradigm in occupational health. International Journal of Environmental Research and Public Health. 2018;15:1229. DOI: 10.3390/ijerph15061229
  15. 15. Kumar N, Sing AK. Trends of male factor infertility, an important cause of infertility: A review of literature. Journal of Human Reproductive Sciences. 2015;8(4):191-196. DOI: 10.4103/0974-1208.170370
  16. 16. Marić T, Fučić A, Aghayanian A. Environmental and occupational exposures associated with male infertility. Arhiv za higijenu rada i toksikologiju. 2012;72:101-113. DOI: 10.2478/aiht-2021-72-3510
  17. 17. Krzastek SC, Farhi J, Gray M, Smith RP. Impact of environmental toxin exposure on male fertility potential. Translational Andrology and Urology. 2020;9(6):2797-2813. DOI: 10.21037/tau-20-685
  18. 18. Petersen KU, Balkiss AM, Hærvig KK, Bonde JPE, Hogaard KS, Toft G, et al. Use of personal care product and semen quality: A cross-sectional study in young Danish men. Toxics. 2020;8(62):1-13. DOI: 10.3390/toxics8030062
  19. 19. Rocca CL, Tait S, Guerrati C, Busani L, Ciardo F, Bergamasco B, et al. Exposure to endocrine disruptors and nuclear receptors gene ezpression in infertile and fertile men from Italian areas with different environmental features. International Journal of Environmental Research and Public Health. 2015;12:12426-12445. DOI: 10.3390/ijerph121012426
  20. 20. Arena AC, Fernandez CD, Porto EM, Bissacot DZ, Pereira OCM, Kempinas WG. Fenvalarate, a pyrethroid insecticide, adversely affects sperm production and storage in male rats. Journal of Toxicology and Environmental Health, Part A: Current Issues. 2008;71:1550-1158. DOI: 10.1080/15287390802392024
  21. 21. Fisch H, Braun SR. Trends in global semen parameter values. Asian Journal of Andrology. 2013;15:169-173. DOI: 10.1038/aja.2012.143
  22. 22. Carlsen E, Giwecman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ. 1992;305:609-613. DOI: 10.1136/bmj.305.6854.609
  23. 23. Kumar M, Sarma DK, Shubham S, Kumawat M, Verma V, Prakash A, et al. Environmental endocrine-disrupting chemical exposure: Upcoming global health burden. Frontiers in Public Health. 2020;8:549. DOI: 10.3389/fpubh.2020.553850
  24. 24. Dobrakowski M, Kaletka Z, Machoń-Grecka A, Kasperczyk S, Horak S, Birkner E, et al. The role of oxidative stress, selected metals, and parameters of the ımmune system in male fertility. Oxidative Medicine and Cellular Longevity. 2018;2018:6249536. DOI: 10.1155/2018/6249536
  25. 25. Bhatt RV. Environmental influence on reproductive health. International Journal of Gynecology & Obstetrics. 2000;70:69-75
  26. 26. Roeleveld N, Bretveld R. The impact of pesticides on male fertility. Current Opinion in Obstetrics & Gynecology. 2008;20:229-233. DOI: 10.1097/GCO.0b013e3282fcc334
  27. 27. Amir S, Shah STA, Mamoulakis C, Docea AO, Kalantzi O-I, Zachatiou A, et al. Endocrine disruptors acting on estrogen and androgen pathways cause reproductive disorders through multiple mechanism: A review. International Journal of Environmental Research and Public Health. 2021;18:1464. DOI: 10.3390/ijerph18041464
  28. 28. Lifeng T, Shoulin W, Junmin J, Xuezhao S, Yannan L, Qianli W, et al. Effects of fenvalarate exposure on semen quality among occupational workers. Contraception. 2006;73:92-96. DOI: 10.1016/j.contraception.2005.06.067
  29. 29. Toshima H, Suziki Y, Imai K, Yoshinaga J, Shiraishi H, Mizumoto Y, et al. Endocrine disrupting chemicals in urine of Japanese male partners of subfertie couples: A pilot study on exposure and semen quality. International Journal of Hygiene and Environmental Health. 2012;215:502-506. DOI: 10.1016/j.ijheh.2011.09.005
  30. 30. Sinclair S. Male infertility: Nutritional and environmental considerations. Alternative Medicine Review. 2000;5(1):28-38
  31. 31. Chowdhury AR. Recent advances in heavy metals induced effect on male reproductive function-a retrospective. Al Ameen Journal of Medical Sciences. 2009;2(2):37-42
  32. 32. Wu HM, Lin-Tan DT, Wang ML, Huang HY, Lee CL, Wang HS, et al. Lead level in seminal plasma may affect semen quality for men without occupational exposure to lead. Reproductive Biology and Endocrinology. 2012;10:91. DOI: 10.1186/1477-7827-10-91
  33. 33. Ma Y, He X, Qi K, Wang T, Qi Y, Cui L, et al. Effects of environmental contaminants on fertility and reproductive health. Journal of Environmental Sciences. 2018;77:210-217. DOI: 10.1016/j.jes.2018.07.015
  34. 34. Jamalan M, Ghaffari MA, Zeinali M. Human sperm quality and metal toxicants: Protective effects of some flavonoids on male reproductive function. International Journal of Fertility and Sterility. 2016;10(2):215-223. DOI: 10.22074/ijfs.2016.4912
  35. 35. Kiziler AR, Aydemir B, Onaran I, Alici B, Ozkara H, Gulyasar T, et al. High levels of cadmium and lead in seminal fluid and blood of smoking men are associated with high oxidative stress and damage in infertile subjects. Biological Trace Element Research. 2007;120:82-91. DOI: 10.1007/s12011-007-8020-8
  36. 36. He Y, Zou L, Luo W, Yi Z, Yang P, Yu S, et al. Heavy metal exposure, oxidative stress and semen quality: Exploring associations and mediation effects in reproductive-aged men. Chemosphere. 2020;244:125498. DOI: 10.1016/j.chemosphere.2019.125498
  37. 37. Kahraman S, Hass H, Karatas A, Ilgın H. The effect of blood and seminal plasma heavy metal and trace element levels on sperm quality. Journal of Medical Sciences. 2012;32(6):1560-1568. DOI: 10.5336/medsci.2011-26578
  38. 38. Kasperczky A, Dobrakowski M, Czuba ZP, Horak S, Kasperczyk S. Environmental exposure to lead induces oxidative stress and modulates the function of the antioxidant defense system and the immune system in the semen of males with normal semen profile. Toxicology and Applied Pharmacology. 2015;284(3):339-344. DOI: 10.1016/j.taap.2015.03.001
  39. 39. Shabani K, Hosseini S, Khani AGM, Moghbelinejad S. The effects of semen parameters and age on semen motility of Iranian men. Global Journal of Fertility and Research. 2017;2(1):024-029. DOI: 10.17352/gjfr.000008
  40. 40. Li C, Cao M, Ma L, Ye X, Song Y, Pan W, et al. Pyrethroid pesticide exposure and risk of primary ovarian insufficiency in Chinese women. Environmental Science & Technology. 2018;52(5):3240-3248. DOI: 10.1021/acs.est.7b06689
  41. 41. Li P, Zhong Y, Jiang X, Wang C, Zuo Z, Sha A. Seminal plasma metals concentration with respect to semen quality. Biological Trace Element Research. 2012;148(1):1-6. DOI: 10.1007/s12011-012-9335-7
  42. 42. Famurewa AC, Ugwuja EI. Association of blood and seminal plasma cadmium and lead levels with semen quality in non-occupational exposed infertile men in Abakaliki, south East Nigeria. Journal of Family & Reproductive Health. 2017;11(2):97-103
  43. 43. Vigeh M, Smith DR, Hsu PC, PC. How does lead induce male infertility? Iran. The Journal of Reproductive Medicine. 2011;9(1):1-8
  44. 44. Ji G, Xia Y, Gu A, Shi X, Long Y, Song L, et al. Effects of non-occupational environmental exposure to pyrethroids on semen quality and sperm DNA integrity in Chinese men. Reproductive Toxicology. 2011;31:171-176. DOI: 10.1016/j.reprotox.2010.10.005
  45. 45. Sengupta P, Banerjee R. Environmental toxins: Alarming impacts of pesticides on male fertility. Human & Experimental Toxicology. 2014;33(10):1017-1039. DOI: 10.1177/0960327113515504
  46. 46. Xia Y, Han Y, Wu B, Wang S, Gu A, Lu N, et al. The relation between urinary metabolite of pyrethroid insecticides and semen quality in humans. Fertility and Sterility. 2008;89:1743-1750. DOI: 10.1016/j.fertnstert.2007.05.049
  47. 47. Song L, Wang YB, Sun H, Yuan C, Hong X, Qu JH, et al. Effects of fenvalarate and cypermethrin on rat sperm motility patterns in vitro as measured by computer-assisted sperm amalysis. Journal of Toxicology & Environmental Health Part A: Current Issues. 2008;5:325-332. DOI: 10.1080/15287390701738517
  48. 48. Mehrpour O, Karrari P, Zamani N, Tsatsakis AM, Abdollahi M. Occupational exposure to pesticides and consequences on male semen and fertility: A review. Toxicology Letters. 2014;230:146-156. DOI: 10.1016/j.toxlet.2014.01.029
  49. 49. Martenies SE, Perry MJ. Environmental and occupational pesticide exposure and human sperm parameters: A systematic review. Toxicology. 2013;307:66-73. DOI: 10.1016/j.tox.2013.02.005
  50. 50. Pan C, Liu YP, Li YF, Hu JH, Zhang JP, Wang HM, et al. Effects of cypermethrin on the ligand-independent interaction between androgen receptor and steroid receptor coactivator-1. Toxicology. 2012;299:160-164. DOI: 10.1016/j.tox.2012.05.022
  51. 51. Pan C, Wang Q , Liu YP, Xu LF, Li YF, Hu JX, et al. Anti-androgen effects of the pyrethroid pesticide cypermethrin on interactions of androgen receptor with corepressors. Toxicology. 2013;311:178-183. DOI: 10.1016/j.tox.2013.06.011
  52. 52. O’Hara L, Smith LB. Androgen receptor roles in spermatogenesis and infertility. Best Practice & Research. Clinical Endocrinology & Metabolism. 2015;29:595-605. DOI: 10.1016/j.beem.2015.04.006
  53. 53. Zhang J, Zhu W, Zheng Y, Yang J, Zhu X. The antiandrogenic activity of pyrethroid pesticides cyfluthrin and ß-cyfluthrin. Reproductive Toxicology. 2008;25:491-496. DOI: 10.1016/j.reprotox.2008.05.054
  54. 54. Du G, Shen O, Sun H, Fei J, Lu C, Song L, et al. Assessing hormone receptor activities of pyrethroid ınsecticides and their metabolites in reporter gene assays. Toxicological Sciences. 2010;116(1):58-66. DOI: 10.1093/toxsci/kfq120
  55. 55. Xu LC, Sun H, Chen JF, Bian Q , Song L, Wang XR. Androgen receptor activities of p,p-DDE, fenvalerate and phoxim detected by androgen receptor reporter gene assay. Toxicology Letters. 2006;160(2):151-157. DOI: 10.1016/j.toxlet.2005.06.016
  56. 56. Tang W, Wang D, Wang J, Wu Z, Li L, Huang M, et al. Pyrethroid pesticide residues in the global environment: An overview. Chemosphere. 2018;191:990-1007. DOI: 10.1016/j.chemosphere.2017.10.115
  57. 57. Kim KB, Barlett MG, Anand SS, Bruckner JV, Kim HJ. Rapid determination of the synthetic pyrethroid insecticide deltamethrin, in rat plasma and tissues by HPLC. Journal of Chromatography B. 2006;834:141-148. DOI: 10.1016/j.jchromb.2006.02.039
  58. 58. Wu HM, Tan DTL, Wang ML, Huang HY, Wang HS, Soong YK, et al. Cadmium level in seminal plasma may affect the pregnancy rate for patients undergoing infertility evaluation and treatment. Reproductive Toxicology. 2008;25:481-484. DOI: 10.1016/j.reprotox.2008.04.005
  59. 59. Xu LC, Liu L, Ren XM, Zhang MR, Cong N, Xu AQ , et al. Evaulation of androgen receptor transcriptional activities of some pesticides in vitro. Toxicology. 2008;243:59-65. DOI: 10.1016/j.tox.2007.09.028
  60. 60. Han Y, Xia Y, Han J, Zhou J, Wang S, Zhu P, et al. The relationship of 3-PBA pyrethroids metabolite and male reproductive hormones among non-occupational exposure males. Chemosphere. 2008;72:785-790. DOI: 10.1016/j.chemosphere.2008.03.058
  61. 61. Wang Q , Shen JY, Zhang R, Hong JW, Li Z, Ding Z, et al. Effects and mechanisms of pyrethroids on male reproductive system. Toxicology. 2020;438:152460. DOI: 10.1016/j.tox.2020.152460
  62. 62. Meeker JD, Barr DB, Hauser R. Pyrethroid insecticide metabolites are associated with serum hormone levels in adult men. Reproductive Toxicology. 2009;27:155-160. DOI: 10.1016/j.reprotox.2008.12.012
  63. 63. Meeker JD, Rossano MG, Protas B, Diamond MP, Puscheck E, Daly D, et al. Cadmium, lead, and other metals in relation to semen quality: Human evidence for molybdenum as a male reproductive toxicant. Environmental Health Perspectives. 2008;116(11):1473-1479. DOI: 10.1289/ehp.11490
  64. 64. Sikka SC, Wang R. Endocrine disruptors and estrogenic effects on male reproductive axis. Asian Journal of Andrology. 2008;10(1):134-145. DOI: 10.1111/j.1745-7262.2008.00370.x
  65. 65. Oehninger S, Kruger TF. Sperm morphology and its disorders in the context of infertility. F&S Reviews. 2021;2(1):75-92. DOI: 10.1016/j.xfnr.2020.09.002
  66. 66. Merzenich H, Zeeb H, Blettner M. Decreasing sperm quality: A global problems? BMC Public Health. 2010;10:24. DOI: 10.1186/1471-2458-10-24
  67. 67. Alam MF, Akhter M, Mazumder B, Ferdous A, Hossain MD, Dafader NC, et al. Assessment of some heavy metals in selected cosmetics commonly used in Bangladesh and human health risk. Journal of Analytical Science and Technology. 2019;10:1-8. DOI: 10.1186/s40543-018-0162-0
  68. 68. Wang J, Pan L, Wu S, Lu L, Xu Y, Zhu Y, et al. Recent advances on endocrine disrupting effects of UV filters. International Journal of Environmental Research and Public Health. 2016;13:782. DOI: 10.3390/ijerph13080782
  69. 69. Witorsch RJ, Thomas JA. Personal care products and endocrine disruption: A critical review of the literature. Critical Reviews in Toxicology. 2010;40(S3):1-30. DOI: 10.3109/10408444.2010.515563
  70. 70. Giokas DL, Salvador A, Chisvert A. UV filters: From sunscreens to human body and the environment. Trends in Analytical Chemistry. 2007;26:360-374. DOI: 10.1016/j.trac.2007.02.012
  71. 71. Louis GMB, Kannan K, Sapra KJ, Maisong J, Sundaram R. Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples fecundity. American Journal of Epidemiology. 2014;180(12):1168-1175. DOI: 10.1093/aje/kwu285
  72. 72. Frederiksen H, Krause M, Jørgensen N, Rehfeld A, Skakkebaek N, Andersson AM. UV filters in matched seminal fluid-, urine-, and serum samples from young men. Journal of Exposure Science & Environmental Epidemiology. 2020;31:345-355. DOI: 10.1038/s41370-020-0209-3
  73. 73. Nicolopoulou-Stamati P, Hens L, Sasco AJ. Cosmetics as endocrine disruptors: Are they a health risk? Reviews in Endocrine & Metabolic Disorders. 2015;16:373-383. DOI: 10.1007/s11154-016-9329-4
  74. 74. Schiffer C, Müller A, Egeberg DL, Alvarez L, Brenker C, Rehfeld A, et al. Direct action of endocrine disrupting chemicals on human sperm. EMBO Reports. 2014;15(7):758-765. DOI: 10.15252/embr.201438869
  75. 75. Ren D, Navarro B, Perez G, Jackson AC, Hsu S, Shi Q , et al. A sperm ion channel required for sperm motility and male fertility. Nature. 2001;413:603-609. DOI: 10.1038/35098027
  76. 76. Rehfeld A, Dissing S, Skakkebaek NE. Chemical UV filters mimic the effect of progesterone on Ca2+ signaling in human sperm cells. Endocrinology. 2016;157(11):4297-4308. DOI: 10.1210/en.2016-1473
  77. 77. Rehfeld A, Egeberg DL, Almstrup K, Petersen JH, Dissing S, Skakkebaek NE. EDC impact: Chemical UV filters can affect human sperm function in progesterone-like manner. Endocrine Connections. 2018;7:16-25. DOI: 10.1530/EC-17-0156
  78. 78. Adoamnei E, Mendiola J, Moñino-García M, Vela-Soria F, Iribarne-Durán LM, Fernández MF, et al. Urinary concentrations of benzophenone-type ultra violet lights filters and reproductive paramaters in young men. International Journal of Hygiene and Environmental Health. 2018;221(3):531-540. DOI: 10.1016/j.ijheh.2018.02.002
  79. 79. Louis GMB, Chen Z, Kim S, Sapra KJ, Phil M, Bae J, et al. Urinary concentrations of benzophenone–type ultraviolet light filters and semen quality. Fertility and Sterility. 2015;104(4):989-996. DOI: 10.1093/aje/kwu285
  80. 80. Chen M, Tang R, Fu G, Xu B, Zhu P, Qiao S, et al. Association of exposure to phenols and idiopathic male infertility. Journal of Hazardous Materials. 2013;250-251:115-121. DOI: 10.1016/j.jhazmat.2013.01.061
  81. 81. Joffe M. Infertility and environmental pollutants. British Medical Bulletin. 2003;68:47-70. DOI: 10.1093/bmb/ldg025
  82. 82. Craig ZR, Wang W, Flaws JA. Endocrine-disrupting chemicals in ovarian function: Effects on steroidogenesis, metabolism and nuclear receptor signaling. Reproduction. 2011;142(5):633-646. DOI: 10.1530/REP-11-0136
  83. 83. Gibson DA, Saunders PTK. Endocrine disruption of oestrogen action and female reproductive tract cancers. Endocrine-Related Cancer. 2014;21(2):T13-T31. DOI: 10.1530/ERC-13-0342
  84. 84. Chang SH, Cheng BH, Lee SL, Chuang HY, Yang CY, Sung FC, et al. Low blood lead concentration in association with infertility in women. Environmental Research. 2006;101:380-386. DOI: 10.1016/j.envres.2005.10.004
  85. 85. Lee S, Min JY, Min KB. Female infertility associated with blood lead and cadmium levels. International Journal of Environmental Research and Public Health. 2020;17:1794. DOI: 10.3390/ijerph17051794
  86. 86. Georgescu B, Georgescu C, Dărăban S, Bouaru A, Passcalău S. Heavy metals acting as endocrine disruptors. Journal of Animal Science and Biotechnology. 2011;44(2):89-93
  87. 87. Silberstein T, Saphier O, Paz-Tal O, Trimarch JR, Gonzalez L, Keefe DL. Lead concentrates in ovarian follicle compromises pregnancy. Journal of Trace Elements in Medicine and Biology. 2006;20:205-207. DOI: 10.1016/j.jtemb.2006.05.001
  88. 88. Lei HL, Wei HJ, Ho HY, Liao KW, Chien LC. Relationship between risk factors for infertility in women and lead, cadmium, and arsenic blood levels: A cross-sectional study from Taiwan. BMC Public Health. 2015;15:1220. DOI: 10.1186/s12889-015-2564-x
  89. 89. Tang N, Zhu ZQ. Adverse reproductive effects in female workers of lead battery plants. International Journal of Occupational Medicine and Environmental Health. 2003;16(4):359-361
  90. 90. Gerhard I, Monga B, Waldbrenner A, Runnebaum B. Heavy metals and fertility. Journal of Toxicology & Environmental Health Part A: Current Issues. 1998;54(8):593-611. DOI: 10.1080/009841098158638
  91. 91. Srivastava V, Dearth RK, Hiney JK, Ramirez LM, Bratton GR, Dees WL. The effects of low-level Pb on steroidogenic acute regulatory protein (StAR) in the prepubertal rat ovary. Toxicological Sciences. 2004;77:35-40. DOI: 10.1093/toxsci/kfg249
  92. 92. Tanrıkut E, Karaer A, Celik O, Celik E, Otlu B, Yilmaz E, et al. Role of endometrial concentrations of heavy metals (cadmium, lead, mercury and arsenic) in the aetiology of unexplained infertility. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2014;179:187-190. DOI: 10.1016/j.ejogrb.2014.05.039
  93. 93. Marettova E, Maretta M, Legath J. Effect of pyrethroids on female genital system. Review. Animal Reproduction Science. 2017;184:132-138. DOI: 10.1016/j.anireprosci.2017.07.007
  94. 94. Jurewicz J, Radwan P, Wielgomas B, Radwan M, Karwacka A, Kaluzny P, et al. Exposure to pyrethroid pesticides and ovarian reserve. Environment International. 2020;144:106028. DOI: 10.1016/j.envint.2020.106028
  95. 95. Monteiro C d S, Xavier EB d S, Caetano JPJ, Marinho RM. A critical analysis of the impact of endocrine disruptors as a posisible etiology of primary ovarian insufficiency. JBRA Assisted Reproduction. 2020;24(3):324-331. DOI: 10.5935/1518-0557.20200005
  96. 96. Whitworth KW, Baird DD, Steiner AZ, Bornman RMS, Travlos GS, Wilson RE, et al. Anti-Müllerian hormone and lifestyle, reproductive, and environmental factors among women in rural South Africa. Epidemiology. 2015;26:429-435. DOI: 10.1097/eDe.0000000000000265
  97. 97. Li C, Cao M, Ma L, Ye X, Song Y, Pan W, et al. Pyrethroid pesticide exposure and risk of primary ovarian insufficiency in Chinese women. Environmental Science & Technology. 2018;52(5):3240-3248. DOI: 10.1021/acs.est.7b06689
  98. 98. Hu Y, Ji L, Zhang Y, Shi R, Han W, Tse LA, et al. Organophosphate and pyrethroid pesticide exposure measured before conception and associations with time to pregnancy in Chinese couples enrolled in the Shanghai birth cohort. Environmental Health Perspectives. 2018;126(7):1-9. DOI: 10.1289/EHP2987
  99. 99. Schlumpf M, Kypke K, Wittassek M, Angerer J, Mascher H, Mascher D, et al. Exposure patterns of UV filters, fragrances, parabens, phthalates, organochlor pesticides, PBDEs, and PCBs in human milk: Correlation of UV filters with use of cosmetics. Chemosphere. 2010;81:1171-1183. DOI: 10.1016/j.chemosphere.2010.09.079
  100. 100. Jimenez-Diaz I, Molina-Molina JM, Zafra-Gomez A, Ballesteros O, Navalon A, Real M, et al. Simultaneous determination of the UV- filters benzyl salicylate, phenyl salicylate, octyl salicylate, homosalate, 3-(4-methylbenzylidene) camphor and 3- benzylidene camphor in human placental tissue by LC-MS/MS. assessment of their invitro endocrine activity. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2013;936:80-87. DOI: 10.1016/j.jchromb.2013.08.006
  101. 101. Zhang T, Sun H, Qin X, Wu Q , Zhang Y, Ma J, et al. Benzophenone-type UV filters in urine and blood from children, adults, and pregnant women in China: Maternal and fetal cord blood. Science of the Total Environment. 2013;1(461-462):49-55. DOI: 10.1016/j.scitotenv.2013.04.074
  102. 102. Janjua NR, Mogensen B, Andersson AM, Petersen JH, Henriksen M, Skakkebaek NE, et al. The Journal of Investigative Dermatology. 2004;123:57-61. DOI: 10.1111/j.0022-202X.2004.22725.x
  103. 103. Waring RH, Harris RM. Endocrine disruptors: A human risk? Molecular and Cellular Endocrinology. 2005;244:2-9. DOI: 10.1016/j.mce.2005.02.007
  104. 104. Kunisue T, Chen Z, Louis GMB, Sundaram R, Hediger ML, Sun L, et al. Urinary concentrations of benzophenone-type UV filters in U.S. women and their association with endometriosis. Environmental Science & Technology. 2012;46(8):4624-4632. DOI: 10.1021/es204415a
  105. 105. Faass O, Schlumpf M, Reolon S, Henseler M, Maerkel K, Durrer S, et al. Female sexual behavior, estrous cycle and gene expression şn sexually dimorphic brain regions after pre-and postnatal exposure to endocrine active UV filters. Neurotoxicology. 2009;30:249-260. DOI: 10.1016/j.neuro.2008.12.008

Written By

Selma Yazar

Submitted: December 21st, 2021 Reviewed: March 8th, 2022 Published: April 7th, 2022