Prenatal acephate exposure induces uterine proliferative remodeling and PI3K/Akt/mTOR-associated oxidative stress, apoptosis, and autophagy in rats.

Abstract

Prenatal exposure to organophosphate pesticides has been increasingly associated with long-term reproductive failure; nevertheless, their effects on uterine developmental programming are still little understood. This study examined whether in utero exposure to acephate causes lasting uterine damage in female rat progeny and analyzed the associated molecular processes. Pregnant Wistar rats were administered oral acephate (14 or 28 mg/kg) from gestational days 6 to 21, and uterine tissues from female progeny were analyzed at postnatal day 28. Prenatal exposure to acephate caused significant histopathological changes, including endometrial glandular hyperplasia. Oxidative stress was indicated by increased malondialdehyde and protein carbonyl levels, alongside substantial decreases in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Molecular investigations revealed elevated expression of LC3 and caspase-3 at both the mRNA and protein levels, corroborated by immunofluorescence, signifying the activation of autophagy and apoptosis. Acephate altered PI3K/Akt/mTOR signaling in a dose-dependent manner, exhibiting suppression of PI3K/mTOR at lower doses and compensatory Akt activation despite ongoing mTOR inhibition at higher doses. These findings collectively indicate that prenatal exposure to acephate alters uterine development via oxidative stress-induced, dysregulation of PI3K/Akt/mTOR signaling, leading to autophagy, apoptosis, and abnormal proliferative remodeling that could jeopardize long-term female reproductive health.