Date of Award

8-1-2019

Degree Name

Doctor of Philosophy

Department

Molecular, Cellular, and Systemic Physiology

First Advisor

Hayashi, Kanako

Abstract

Bisphenol (BP) A is a common manufacturing chemical in polycarbonate plastics and has been widely used in plastics, epoxy resin liners of canned foods, dental materials, and thermal receipts. Human exposure to BPA is associated with a negative impact on human health including the development and function of the reproductive system due to its action as an endocrine-disrupting chemical (EDC). Numerous experimental studies have demonstrated that BPA impairs both male and female reproductive function, despite the variation in study paradigms such as dose, exposure route, timing, and outcomes measured. Due to the toxicological effects of BPA, BPA analogues such as BPS have been used as alternatives for BPA. However, recent evidence has suggested these BPA analogues can induce similar or even more severe toxic effects as BPA, and health risks of exposure to replacement bisphenols need to be considered. Therefore, my study was designed to examine whether prenatal exposure to BPE and BPS negatively impacts on male and female reproductive function in mice. Pregnant females were orally administrated corn oil (control), BPA, BPE, and BPS (0.5, 20, or 50mg/kg/day) from gestational day 11 (the presence of vaginal plug=1) to birth, and reproductive tissues in F1 mice were collected and analyzed in both neonatal and adult mice. In males, I observed reduced sperm counts and quality, disrupted stages of spermatogenesis in adults and increased germ cell apoptosis in neonatal testis following prenatal BPA, BPE or BPS exposure. Particularly, I found the expression of methyltransferases for DNA methylation and histone modification was also affected by prenatal exposure to BPA, BPE, or BPS in neonatal testis, suggesting a potential of epigenetic alterations in F1 males. In females, prenatal exposure to BPE and BPS accelerated the onset of puberty, disrupted estrous cyclicity, and caused several fertility problems especially in aged mice. In the neonatal ovaries, I also observed that BPE and BPS inhibit germ cell nest breakdown comparable to BPA. These results suggest that prenatal exposure to BPE and BPS with physiologically relevant doses affects male and female reproductive function probably due to germ cell development defects in the developing gonads. Finally, to understand their complete impact on male and female fertility, a study of transgenerational effects of BPE and BPS is performed to examine the transgenerational effects of prenatal exposure to BPA, BPE and BPS on reproductive function in F3 offspring. To be called transgenerational, expression of the specific phenotype will be continued at least across three generations. As described in previous studies, the direct exposure of a pregnant female (F0 generation) results in the exposure of the embryos (F1 generation) and the germline that will generate the next generation (F2 generation). Thus, I orally exposed to control treatment (corn oil), BPA, BPE or BPS (0.5 or 50 μg/kg/day) from gestational day 7 to birth in pregnant females (F0). Mice from F1 and F2 offspring were used to generate the F3 generation. In F3 males, prenatal exposure to BPA, BPE, and BPS induces persistence and even more severe phenotypes in sperm counts and motility in the F3 generation than in the F1 offspring. The expression of DNA and histone methyltransferases were transgenerationally increased by BPA, BPE and BPS exposure in both neonatal and adult testis. In F3 females, prenatal exposure to BPA, BPE, and BPS accelerated the onset of puberty and exhibited abnormal estrous cyclicity, and those females exhibited similar fertility problems as those in the F1 generation. However, BPA, BPE and BPS exposure did not affect neonatal follicular development such as germ cell nest breakdown or follicle numbers in the ovary on postnatal day 4. Taken together, our results suggest that prenatal exposure to BPA analogues, BPE and BPS, have transgenerational effects on male and female reproductive function in mice. Our findings suggest the hypothesis that transgenerational epigenetic alterations in germ cells may lead to reproductive disorders/dysfunction in the F3 generation.

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