Hepatotoxicity and lipid metabolism disorders of 8:2 polyfluoroalkyl phosphate diester in zebrafish: In vivo and in silico evidence

8:2 polyfluoroalkyl phosphate diester (8:2 diPAP) has been shown to accumulate in the liver, but whether it induces hepatotoxicity and lipid metabolism disorders remains largely unknown. In this study, zebrafish embryos were exposed to 8:2 diPAP for 7 d. Hepatocellular hypertrophy and karyolysis were noted after exposure to 0.5 ng/L 8:2 diPAP, suggesting suppressed liver development. Compared to the water control, 8:2 diPAP led to significantly higher triglyceride and total cholesterol levels, but markedly lower levels of low-density lipoprotein, implying disturbed lipid homeostasis. The levels of two peroxisome proliferator activated receptor (PPAR) subtypes (ppar alpha and ppar gamma) involved in hepatotoxicity and lipid metabolism were significantly upregulated by 8:2 diPAP, consistent with their overexpression as determined by immunohistochemistry. In silico results showed that 8:2 diPAP formed hydrogen bonds with PPAR alpha and PPAR gamma. Among seven machine learning models, Adaptive Boosting performed the best in predicting the binding affinities of PPAR alpha and PPAR gamma on the test set. The predicted binding affinity of 8:2 diPAP to PPAR alpha (7.12) was higher than that to PPAR gamma (6.97) by Adaptive Boosting, which matched well with the experimental results. Our results revealed PPAR - mediated adverse effects of 8:2 diPAP on the liver and lipid metabolism of zebrafish larvae.