P-630 Implications of a Combined Perinatal Exposure to BPA and BP-3 for Offspring Gonadal Function and Reproductive Health in Mice

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Abstract Study question Does a pre- and postnatal exposure to two widespread EDCs, bisphenol A (BPA) and benzophenone-3 (BP-3), affect offspring gonadal function in mice? Summary answer Combined pre- and postnatal exposure to BPA and BP-3 affects gonadal function in mice with possible long-term implications for fertility in both sexes. What is known already Endocrine disrupting chemicals (EDCs) are found ubiquitously in the environment and are used in many products of everyday life. Exposure to EDCs at environmental concentrations can pose significant risks to male and female health and fertility. EDCs have estrogen-like, antiestrogenic or antiandrogenic properties that can affect reproductive and immune function in multiple ways. Especially during sensitive developmental periods and at reproductive age, continuous exposure to EDCs and EDC-mixtures poses long-term risks for reproductive health. Given that the number of medically assisted reproduction patients is increasing in many countries, there is need to understand the effects of EDCs to reproductive health. Study design, size, duration We exposed pregnant mice from gestation day 0 to postnatal day (P) 21 to BPA (oral), BP-3 (dermal), both BPA and BP-3, or control substances (10 animals/group) at concentrations relevant for environmental exposure. Ten female offspring/group underwent superovulation by pregnant-mare serum gonadotropin and human chorionic gonadotropin (hCG) treatment at P28 and P30, respectively. Females were dissected 13 h after hCG-treatment, males (10 per group) were sacrificed on P56 and P100 to retrieve tissues for analysis. Participants/materials, setting, methods After dissection, ovaries were embedded in paraffin, sectioned and stained with hematoxylin/eosin to count healthy and atretic follicles and measure corpus luteum development. Flow cytometry was used to determine immune cells in the ovaries and gene expression of different ovarian markers was analyzed by qPCR. Ovulated oocytes were counted in hCG-treated females by microscopy. Male offspring testes were dissected to determine epididymal sperm count by light-microscopy and gene expression of testicular markers by qPCR. Main results and the role of chance In female offspring, we observed significantly fewer secondary follicles following BPA, BP-3 and BPA+BP-3 exposure (P < 0.05), and an increase in atretic follicles (P < 0.05) when exposed to BP-3 and BPA+BP-3 compared to controls. BPA+BP-3 exposure also caused an increase in ovarian NK cell number (P < 0.05), and altered ovarian estrogen receptor 1 and 2 (P < 0.05 and < 0.0001), androgen receptor (P < 0.05), and hormone-metabolizing enzyme Cyp11a1 (P < 0.05) gene expression. Ovarian response to exogenous gonadotropins (PMSG and hCG) was impaired leading to significantly fewer oocyte-cumulus-complexes in BPA (P < 0.05) and BPA+BP-3 (P < 0.05) exposed females. In male offspring on P56, total sperm count was altered (P < 0.05) and gene expression of androgen-metabolizing enzymes Cyp11a1 (P < 0.01), Cyp17a1 and Cyp19a1 (P < 0.05) in the testis was significantly decreased following BPA+BP-3 exposure compared to controls. On P100, these differences in sperm count and gene expression were no longer observed between BPA-BP-3 exposed offspring and controls. Limitations, reasons for caution Our study provides insights into effects of EDCs for male and female reproduction in a model organism that need verification in human epidemiology and in vitro studies. Further studies are needed to determine the long-term consequences for reproduction and underlying mechanisms in mice and humans. Wider implications of the findings The results suggest that low, environmentally relevant concentrations of widespread EDCs significantly affect male and female reproductive organs following pre- and postnatal exposure. Especially EDC mixtures have not been studied in great detail and may be a significant risk for reproductive health. Trial registration number No

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