**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 pituitaryovarian 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 [84–86].

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

*Endocrine Disruptors and Infertility DOI: http://dx.doi.org/10.5772/intechopen.104403*

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 [99–102]. 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 estrogensendocrine 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].
