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 early-life PFHxS exposure induced persistent hepatic oxidative stress and activated the endoplasmic reticulum stress response (PERK/eIF2α/ATF4 pathway) in adult. These molecular alterations subsequently upregulated sterol regulatory element-binding protein 1 (SREBP1) expression, leading to transcriptional activation of key lipogenic enzymes (ACC, FASN, SCD1) and ultimately resulting in hepatic lipid accumulation, inflammation, and fibrosis. Notably, these pathological changes exhibited sex-specific characteristics in both male and female. These findings revealed, for the first time, that early-life 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.