Gestational PFHxS exposure at environmentally relevant levels is associated with adult hepatic steatosis and PERK/SREBP1 pathway activation

Perfluorohexane sulfonate (PFHxS), an increasingly detected environmental pollutant, poses potential metabolic health risks, yet its developmental toxicity at environmentally relevant doses remains poorly understood. Here, we investigated the long-term effects of PFHxS exposure on the hepatic development using a mouse model with oral administration of 0.03 and 0.3 μg/kg/day throughout pregnancy. Our findings demonstrated that gestational PFHxS exposure induced persistent hepatic oxidative stress and was associated with the activation of the endoplasmic reticulum stress response (PERK/eIF2α/ATF4 pathway) in adults. These molecular alterations were accompanied by the upregulation of sterol regulatory element-binding protein 1 (SREBP1) and the transcriptional activation of key lipogenic enzymes (ACC, FASN, SCD1), culminating in hepatic lipid accumulation, inflammation, and fibrosis. Notably, these pathological changes exhibited sex-specific characteristics. These findings revealed, for the first time, that gestational PFHxS exposure at environmental levels may contribute to adult hepatic steatosis, potentially through mechanisms involving PERK/SREBP1-mediated lipogenesis. This study provided critical insights into the emerging health risks of replacement PFAS compounds. • Gestational PFHxS exposure induced persistent hepatic steatosis and fibrosis in adulthood. • Gestational PFHxS exposure promoted lipogenic gene expression via ER stress-mediated PERK/SREBP1 activation. • Oxidative damage sustained from fetal life through adulthood culminated in ER stress. • Findings highlighted the need to incorporate gestational exposure as a critical window into PFHxS risk assessment.