Chemical speciation significantly shapes the neurotoxicity of perfluoroalkyl acids

Perfluoroalkyl acids (PFAAs) are a group of prevalent pollutants in aquatic environments, raising substantial concerns about ecological health. Previous research has indicated that chemical speciation can significantly alter the health risks posed by PFAAs. To further verify the importance of chemical speciation and support a more accurate risk assessment, this study conducted a five-month chronic exposure of adult zebrafish to typical PFAAs and their salts, namely perfluorooctanoic acid (PFOA), perfluorobutane carboxylic acid (PFBA), and perfluorobutanesulfonic acid (PFBS). Following exposure, the variations in neurotoxic risks were comprehensively explored and compared based on chemical speciation. The results showed that PFAAs were more prone to accumulation in the brain than their salt counterparts, regardless of the sex. From a neurotoxicological standpoint, PFAAs, particularly PFOA, imposed significantly higher neurotoxic potency. They were more effective at inhibiting acetylcholinesterase (AChE) activity, causing acetylcholine neurotransmitter accumulation, and downregulating the transcription of key cholinergic and neural genes in the zebrafish brains. The estimation of systemic Integrated Biomarker Response version 2 (IBRv2) indices confirmed the combined influences of chemical speciation, carbon chain length, and terminal acid group on the risk outcomes of PFAAs, with the order of potency being: PFOA > PFBS > PFOA salt > PFBS salt > PFBA > PFBA salt. Biolayer interferometry monitoring and molecular docking simulation consistently demonstrated that PFAAs had a higher binding affinity with AChE recombinant protein than their respective salts. High-throughput brain proteomics provided insights into the neurotoxic mechanisms, revealing universal disturbances in cholinergic neurotransmission and synaptic organization. Overall, these findings further substantiate the critical role of chemical speciation in driving the health risks of PFAAs. It is therefore highly necessary to prioritize the control of PFAAs in application and discharge processes and establish form-specific management strategies.