Oxidative stress, apoptosis and proliferation in uterus of piglets fed by sow or formula after ex vivo endocrine compound exposure.

Endocrine-active compounds (EACs) derived from anthropogenic activities and bioactive components in maternal milk influence neonatal development, a critical period for postnatal uterine morphogenesis. Here, using an ex vivo model, we investigated whether neonatal exposure to the antiandrogen 2-hydroxyflutamide, the environmental estrogen 4-tert-octylphenol, and the organochlorine insecticide metabolite HPTE (which exhibits estrogenic, antiestrogenic, and/or antiandrogenic activity) induces oxidative stress and alters proliferation and apoptosis in uterine explants from 10-day-old piglets. Additionally, we assessed whether natural feeding provides protection against the adverse effects of EACs. We found that EACs disrupting androgen or estrogen signaling increased ROS/RNS production, enhanced specific antioxidant enzyme activity, and/or induced apoptosis exclusively in sow-fed piglets, suggesting a compensatory mechanism to maintain cellular homeostasis. Its absence in formula-fed piglets may indicate a reduced capacity to activate protective mechanisms against EACs, potentially due to delayed development. In contrast, EAC-induced alterations in uterine cell proliferation occurred in both feeding groups in a cell type- and feeding-dependent manner. These findings suggest that natural feeding does not fully protect against EAC-induced uterine development disruption, which may have long-term reproductive consequences. Moreover, they reinforce the notion that the neonatal period is a critical window of uterine development, highly sensitive to endocrine disruptors.