Effects of mixed exposure to PFAS on adolescent non-alcoholic fatty liver disease: Integrating evidence from human cohorts, toxicogenomics, and animal models to uncover mechanisms and potential target sites.

Extensive evidence suggests a correlation between environmental pollutants, specifically perfluoroalkyl and polyfluoroalkyl substances (PFAS) and non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the association and underlying mechanisms of PFAS-induced NAFLD in adolescents by employing a comprehensive approach of population-based studies, toxicogenomics, and animal models. A total of 2014 freshmen from Dali University were recruited for this study, with 1694 participants undergoing serum testing for PFAS exposure. Additionally, Comparative Toxicogenomics Database analysis and PFAS exposure experiments were conducted by orally administering PFAS to 8-week-old adult C57/6 J mice for 28 days. Epidemiological analysis of the adolescent cohort revealed that perfluorohexanesulfonic acid and perfluorooctanoic acid are significant risk factors for NAFLD in adolescents. Toxicogenomic analysis revealed that the negative regulation of gap junction assembly and glutathione derivative biosynthesis contributes to NAFLD development. Animal model studies further demonstrated that combined PFAS exposure led to pathological changes in hepatocytes, including inflammation and steatosis, elevated liver enzymes, cholestasis, and bile canalicular blockage. This study reveals that PFAS exposure serves as a significant risk factor for hepatic steatosis/NAFLD in adolescents. The activation of cytochrome P4502E1 and glutathione S-transferase A1 signaling highlights new molecular targets for PFAS-induced disruptions in hepatic lipid metabolism.