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.

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.

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