This study investigated the tissue-specific accumulation and biotransformation of 6:6 and 8:8 perfluoroalkyl phosphinic acids (PFPiA) in common carp (Cyprinus carpio) during 90 d exposure and 30 d depuration in water in the laboratory. Both 6:6 and 8:8 PFPiAs could quickly accumulate in the carp, and 6:6 PFPiA displayed higher bioaccumulation potential than 8:8 PFPiA. The highest concentrations of PFPiAs were observed in the blood, while the lowest were found in the muscle. The equilibrium dialysis experiment indicated that both PFPiAs had higher binding affinities with the proteins in the fish serum than in liver, which was supported by the molecular docking analysis. The results also indicated that 6:6 PFPiA had higher binding affinities with the serum and liver proteins than 8:8 PFPiA. These results suggested that the tissue-specific distribution of PFPiAs was highly dependent on the binding affinities with the specific proteins. Both in vivo and in vitro experiments consistently indicated that PFPiAs experienced biotransformation and produced perfluoroalkyl phosphonic acids (PFPAs), and biotransformation of 8:8 PFPiA was more active than 6:6 PFPiA. It was worth noting that perfluorohexanonate and perfluorooctanoic acids were identified in fish as metabolites after long-term exposure to PFPiAs for the first time.

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As alternatives to traditional per-and polyfluoroalkyl substances, perfluoroalkyl phosphonic acids (PFPiAs) are frequently detected in aquatic environments, but the neurotoxic effects and underlying mechanisms remain unclear. In this study, male zebrafish were exposed to 6:6 PFPiA (1 and 10 nM) for 28 days, which exhibited anxiety-like symptoms. Gut microbiome results indicated that 6:6 PFPiA significantly increased the abundance of Gram-negative bacteria, leading to enhanced levels of lipopolysaccharide (LPS) and inflammation in the gut. The LPS was delivered to the brain through the gut− brain axis (GBA), damaged the blood−brain barrier (BBB), stimulated neuroinflammation, and caused apoptosis as well as neural injury in the brain. This mechanism was verified by the fact that antibiotics reduced the LPS levels in the gut and brain, accompanied by reduced inflammatory responses and anxiety-like behavior. The BBB damage also resulted in the enhanced accumulation of 6:6 PFPiA in the brain, where it might bind strongly with and activate aryl hydrocarbon receptor (AhR) to induce brain inflammation directly. Additionally, as the fish received treatment with an inhibitor of AhR, the inflammation response and anxiety-like behavior decreased distinctly. This study sheds light on the new mechanisms of neurotoxicity-induced 6:6 PFPiA due to the interruption on GBA.