Obiako_2025_Chemosphere_387_144678

Perfluoroalkyl substances (PFAS) induced neurotoxicity is an emerging concern, with evidence increasingly linking it to the dysregulation of neurotransmission pathways. This study investigates the effects of three different PFAS, namely perfluorooctanoic acid (PFOA), perfluorobutanoic acids (PFBA), and undecafluoro-2-methyl-3-oxahexanoic acid (GenX), on catecholamine neurotransmitter release (dopamine, noradrenaline, and adrenaline) and neurotransmission-regulating enzymes (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). Neurotransmitter release assays revealed that PFAS exposure in neuronal cells increased dopamine and noradrenaline levels but reduced adrenaline levels. Cholinesterase activity was assessed in cell-free conditions and human neuronal cells (SH-SY5Y), revealing PFAS-induced enzymatic perturbations characterized by decreased AChE activity and increased BChE activity. Fluorescence and synchronous fluorescence spectroscopy highlighted differential enzyme-PFAS interactions, which were corroborated by molecular docking results and revealed compound-specific interactions with amino acid residues. Of the substances tested, PFOA exhibited the strongest binding interaction. (19)F nuclear magnetic resonance (NMR) spectroscopy also demonstrated differential binding interactions among the PFAS and AChE or BChE. This study provides mechanistic insights into PFAS-induced neurotoxicity, highlighting their potential to disrupt neurotransmitter and enzymatic dynamics crucial for neurological health.