Neurotoxicity mechanisms of per- and polyfluoroalkyl substances: An integrated study of network toxicology, molecular docking, and Mendelian randomization

Background Observational studies have shown that exposure to per- and polyfluoroalkyl substances can lead to neurotoxicity. We focus on whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) affect brain morphology and the potential molecular mechanisms of toxicity. Methods Causal relationship between PFOA/PFOS exposure and brain morphology was explored based on Mendelian randomization (MR), and the toxic molecular mechanism was investigated by using network toxicology. Results MR analysis indicated PFOA exposure reduced brain volume in left parahippocampal (p = 0.018) and right rostral anterior cingulate (p = 0.007), while PFOS exposure decreased volume in left middle temporal (p = 0.036), paracentral (p = 0.022), postcentral (p = 0.014), posterior cingulate (p = 0.002), rostral middle frontal (p = 0.040), superior frontal (p = 0.027), superior parietal (p = 0.033), and right inferior parietal (p = 0.017), superior frontal (p = 0.030), superior parietal (p = 0.025), and caudal middle frontal (p = 0.041). GO/KEGG analyses revealed 161 targets linked to PFOA/PFOS-induced neurotoxicity, primarily associated with fatty acid metabolism, GABA signaling, neurotransmitter receptor activity, ferroptosis, and PPAR pathways. Molecular docking verified key targets (PPARG, FASN, SCD, CD36, GOT2) underlying the toxicity mechanism. Conclusions Exposure to PFOA and PFOS leads to reduced brain volume - neurotoxicity at the macroscopic level. PPARG, FASN, SCD, CD36 and GOT2, at the molecular level, are the key targets involved in the pathology of brain damage caused by PFOA/PFOS.