**5. Summary**

Phthalates are commonly used as plasticizers in the manufacturing of flexible polyvinyl chloride products. Little information is available on the effects of phthalates on neonatal ovary. These compounds have been actually shown to affect germ cell nest breakdown and primordial follicle assembly in cultured newborn mouse ovaries [84]. In addition, early postnatal treatment with diethylhexyl phthalate accelerated folliculogenesis by decreasing the number of primordial follicles and increasing the number preantral and antral follicles in mice [85]. The decrease in primordial follicle pool indicated estrogenic action of these compounds.

ICI 182,780 is a widely used anti-estrogen that can bind to both ERα and ERβ with very high affinity and completely antagonize the effect of estrogens [86]. It was found that ICI 182,780 in combination with estradiol allowed oocytes cyst breakdown neonatal rat ovaries [87]. On the other hand, Wang and Roy [46] revealed that ICI 182,780 significantly increased apoptosis and caused a modest reduction in primordial follicle formation in neonatal hamster ovary. Likewise, ICI 182,780 accelerated primordial follicles formation from oocyte nests in the neonatal pig. However, the initial follicle recruitment marked by the number of growing was delayed [69].

The compounds that exert both estrogenic and anti-estrogenic properties are parabens, which are widely used as anti-microbial agents in the cosmetic and pharmaceutical industries. Parabens inhibited the early phase of folliculogenesis and steroidogenesis in the ovaries of neonatal rats [88]. Moreover, it appears that parabens through inhibition of transcriptional

Methoxychlor (MXC) is an organochlorine pesticide metabolized predominantly to 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl) ethane (MOH) and the bisphenolic compound 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl) ethane (HPTE) in the organism [89]. MXC along with its metabolites acts through ERs and possesses estrogenic, anti-estrogenic, and anti-androgenic activities depending on the receptor subtype [90]. In a variety of experimental studies, MXC administration in early pregnancy or during the prenatal and neonatal periods has been shown to cause adverse abnormalities in adulthood of female rats, such as reduced ovarian functions and ovulatory rates, as well as pregnancy outcome [1]. Uzumcu et al. [91] demonstrated that MXC administration during the primordial-to-primary follicle transition period in mice (postnatal days 3–10) inhibited follicular development and reduced antral follicle numbers. In addition, MXC treatment increased the level of AMH protein production, which in turn inhibited folliculogenesis within the ovary. Another research suggested that exposure to MXC during fetal and neonatal ovarian development led to adult ovarian dysfunction, including an increase in the number of preantral and early antral follicles and a reduced number of corpora lutea and female infertility in rats [92]. Furthermore, there are several reports suggesting the role of MXC in the induction of epigenetic modifications within the ovary. Rats exposed to MXC (20 or 100 μg/kg body weight) between embryonic day 19 and postnatal day 7 revealed altered methylation pattern in the promoter region of ERα that suppressed the ERα expression and caused ovarian dysfunction. Developmental exposure to MXC led to significant hypermethylation in the ERβ promoter regions, whereas the ERα

repressor Foxl2, regulated the levels of steroidogenic enzymes [88].

**4.3. EACs with mixed properties**

210 Selected Topics in Neonatal Care

promoter was unaffected [93].

The plausible link between EACs exposure during critical periods of early development and risk of chronic diseases in adulthood, including premature ovarian failure and PCOS, has been reported. The harmful effects of compounds with androgenic, anti-androgenic, estrogenic, and anti-estrogenic activities during neonatal window may occur with exposure to lower doses than those harmful for adults. These chemicals have been shown to target the ovary of neonates and adversely affect oocyte survival, follicle formation, and growth, as well as steroidogenic functions. There is a concern over EACs due to their common use and persistence within the modern living environment. The better cognition of mechanisms underlying the long-term consequences of the neonatal EACs exposure may in future lead to an understanding of human health risks and developing prevention strategies.
