Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring

Abstract

Di-(2-Ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) present significant environmental endocrine-disrupting chemical properties. Although studies have implied reproductive impairment from exposure to BPA and DEHP, no study to date has shown the effect and mechanism of hepatic function after gestational and lactational co-exposure to DEHP and BPA in offspring. A total of 36 perinatal rats were randomly divided into four groups, DEHP (600 mg/kg/day), BPA (80 mg/kg/day), DEHP combined with BPA (600 mg/kg/day + 80 mg/kg/day), and control. Notably, 11 chemical targets were screened after identifying eight substances associated with chemically-induced hepatic damage. Molecular docking simulations revealed a high-scoring combination of eight metabolic components and targets of the PI3K/AKT/FOXO1 signaling pathway. The DEHP and BPA combination disrupted hepatic steatosis, ultimately affecting systemic the glucose and the lipid metabolic homeostasis with significant toxicity. Mechanistically, co-exposure to DEHP and BPA causes liver dysfunction and hepatic insulin resistance via PI3K/AKT/FOXO1 pathway in offspring. This is the first study of the hepatic function and mechanism of co-exposure to DEHP and BPA that combines metabolomics, molecular docking, and traditional toxicity assessment methods.