Chronic PFOA and PFOS Exposure Triggers Cellular Oxidative Stress and Alters Lipid Levels as Revealed through Multi-omics Analysis

Per- and polyfluoroalkyl substances (PFAS), or "forever chemicals," are linked to metabolic, immune, and neurotoxic disorders, yet their long-term cellular effects remain unclear. Using a 24-week chronic exposure model with non-transformed human epithelial cells, we examined responses to low, environmentally relevant concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). Integrated transcriptomic and lipidomic analyses revealed that despite minimal cellular accumulation, molecular changes emerged around week 17, marked by transcriptional signatures indicative of oxidative stress responses, cell survival pathways, and lipid metabolism. Our data suggests a multi-faceted model in which long-term PFOA and PFOS exposure induces oxidative stress mediated by SESN2 and SOD3 , increases lipid biosynthesis via SREBP pathway, and causes compound-specific disruptions of membrane lipids. These findings highlight the importance of multi-omic, time-resolved approaches in uncovering the mechanisms of chronic low-dose chemical exposure and provide a foundation for future in vivo studies.