Developmental Programming: Mechanisms of Early Exposure to Real-Life Chemicals in Biosolids on Offspring Ovarian Dynamics†.

Abstract

Female reproductive capacity is shaped by ovarian reserve and patterns of follicle development. Ovarian reserve depletion occurs by follicle activation and atresia, which can be affected by environmental chemicals (ECs). Because humans are simultaneously exposed to hundreds of ECs, real-life exposure models are essential to assess patterns of atresia after EC exposure. Previous findings demonstrate maternal preconceptional and gestational ECs exposure via biosolids-treated pasture (BTP) increases activation rate and reduces primordial follicle pool in juveniles, but not adults. We hypothesized that this shift involves changes in death and proliferative pathways that impact follicle atresia from juvenile to adult life. Ovaries were collected from juvenile (9.5 weeks) and adult (2.5 years) offspring from ewes grazed on either BTP or inorganic fertilizer-treated pasture (Control). Follicular atresia was assessed through morphological characteristics and molecular death pathways, including expression of markers for apoptosis (CASP3), autophagy (LC3), and ferroptosis (GPX4) and proliferation (Ki67). There were higher levels of apoptosis and autophagy, and lower proliferation, in juvenile BTP offspring compared to controls. In adult BTP offspring, apoptosis and proliferation did not differ, autophagy was lower, and ferroptosis was higher compared to controls. Apoptosis was lower and ferroptosis higher in adults than in juveniles, regardless of treatment. Adult BTP offspring had lower autophagy and similar proliferation levels to juvenile BTP. These findings suggest that lower autophagy and lack of decrease in proliferation contribute to normalization of activation rate and ovarian pool in BTP adults and supportive of lasting impacts of gestational EC exposure on offspring follicular health.