Beyond Traditional PFAS: Potent Neurotoxicity of 6:2 Cl-PFESA Through Lipidomic Dysregulation

Per- and polyfluoroalkyl substances (PFASs) are a class of highly persistent synthetic chemicals that have raised significant environmental and health concerns due to their stability and bioaccumulation potential. 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA), a novel alternative to traditional PFASs like perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), has been increasingly used in various industries. However, its neurotoxic effects remain poorly understood. In this study, we compared the neurotoxic impacts of 6:2 Cl-PFESA with those of PFOS and PFOA in PC12 cells. Our findings revealed that while all three PFASs induced dose-dependent neurotoxicity, 6:2 Cl-PFESA exhibited the most potent effects, causing significantly greater reductions in cell viability and higher rates of apoptosis. Lipidomic analysis further demonstrated that high-dose exposure (100 μM) to all three chemicals profoundly altered lipid profiles, perturbing broad neurotoxicity-related networks including phosphoinositide (PI) metabolism, MAPK, and BDNF-TrkB signaling. Crucially, 6:2 Cl-PFESA uniquely induced lipidomic disruptions even at a low dose (0.025μM) reflecting human exposure levels, specifically triggering pathways such as phospholipid biosynthesis and ferroptosis. Our study underscores the urgent need to evaluate the neurotoxic risks of emerging PFAS alternatives, especially considering their widespread environmental distribution and potential to covertly impair neuronal signaling pathways.