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

## TL;DR

This study shows that neonatal piglets fed by formula may be more vulnerable to endocrine disruptors than those fed by their mothers, affecting uterine development and potentially reproductive health.

## Contribution

The study introduces an ex vivo model to assess how endocrine disruptors affect uterine development in neonatal piglets, comparing the protective effects of natural versus formula feeding.

## Key findings

- EACs increased oxidative stress and apoptosis in sow-fed piglets, suggesting a compensatory mechanism.
- Formula-fed piglets showed reduced capacity to activate protective mechanisms against EACs.
- EACs altered uterine cell proliferation in both feeding groups, indicating disrupted development.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-025-09895-y.