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Some per- and polyfluoroalkyl substances (PFASs) tend to be accumulated in liver and cause hepatotoxicity. However, the difficulty to directly measure liver concentrations of PFASs in humans hampers our understanding of their hepatotoxicity and mechanisms of action. We investigated the partitioning of 11 PFASs between liver and blood in male CD-1 mice. Although accumulation of the perfluoroalkanesulfonic acids (PFSAs) in mice serum was higher than their carboxylic acids (PFCAs) counterparts as expected, the liver-blood partition coefficients (R L/S) of PFSAs were lower than the PFCAs R L/S, implying a competition between liver and blood. The in vitro experiments further indicated that the partitioning was dominantly determined by their competitive binding between human liver fatty acid binding protein (hL-FABP) and serum albumin (HSA). The binding affinities (K d) of PFASs to both proteins were measured. The correlations between the R L/S and log K d (hL‑FABP)/log K d (HSA) were stronger than those with log K d (hL‑FABP) alone, magnifying that the partitioning was dominantly controlled by competitive binding between hL-FABP and HSA. Therefore, the liver concentrations of the selected PFASs in humans could be predicted from the available serum concentrations, which is important for assessing their hepatotoxicity.

Food is a major source of human exposure to per- and polyfluoroalkyl substances (PFASs), yet little is known about their bioavailability in food matrices. Here, the relative bioavailability (RBA) of PFASs in foods was determined using an in vivo mouse model. Pork, which had the highest lipid content, exhibited the greatest effect on bioavailability by increasing the RBAs of perfluoroalkyl acids (PFAAs) while reducing those of fluorotelomer phosphate diesters (diPAPs). During intestinal digestion of lipids, the bioaccessibility of PFAAs increased due to their greater partition into the stable mixed micelles. However, diPAPs were more likely to partition into the undigested oil phase due to their strong hydrophobicity. Both in vitro incubation and molecular docking results indicated that the PFAAs exhibited stronger binding affinities with mouse blood chylomicrons (CMs) than with diPAPs. Collectively, both lipid digestion in the intestine and the carrier effect of CMs played important roles in modulating the bioavailability of PFASs in food. More attention should be given to further evaluating the health risks of PFASs associated with the intake of high-lipid foods.

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.

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