Prenatal exposure to diethylstilbestrol has multigenerational effects on folliculogenesis

Diethylstilbestrol (DES) is an estrogenic endocrine disrupting chemical (EDC) that was prescribed to millions of pregnant women worldwide, leading to increased rates of infertility in the exposed offspring. We have previously demonstrated that this reduced fertility persists for multiple generations in the mouse. However, how altered ovarian function contributes to this infertility is unknown. Therefore, this study sought to determine if DES exposure promotes two common ovarian disorders, primary ovarian insufficiency (POI) and polycystic ovary syndrome, contributing to the reduced fertility in DES offspring. Moreover, we investigated if these impacts are transgenerational. Gestating mice were exposed to 100 µg/kg DES, and ovarian morphology was observed in F1-F3 female descendants. F1 females trended towards fewer primordial and more secondary follicles and similarly, F2 females had fewer primordial and significantly more secondary follicles compared to controls. No differences in follicle proportions were observed in the F3. Moreover, DES exposure did not increase follicular cysts. These results show that DES accelerates folliculogenesis, indicative of a POI phenotype and that this is likely contributing to the reduced fertility observed in DES descendants. Moreover, this study highlights the ability of estrogenic EDCs to disrupt folliculogenesis, which may exacerbate the onset of POI in women already at risk.