Jiangsu Province Engineering Research Center for Marine Bio-resources Sustainable Utilization, College of Oceanography, Hohai University, Nanjing 210024, China; Key Laboratory of Integrated Regulation and Resources Development of Shallow Lakes of Ministry of Education, Hohai University, Nanjing 210024, China.
Jiangsu Province Engineering Research Center for Marine Bio-resources Sustainable Utilization, College of Oceanography, Hohai University, Nanjing 210024, China.
J Hazard Mater. 2024 May 5;469:133807. doi: 10.1016/j.jhazmat.2024.133807. Epub 2024 Feb 16.
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 (pparα and pparγ) 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 PPARα and PPARγ. Among seven machine learning models, Adaptive Boosting performed the best in predicting the binding affinities of PPARα and PPARγ on the test set. The predicted binding affinity of 8:2 diPAP to PPARα (7.12) was higher than that to PPARγ (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.
8:2 聚氟烷基磷酸二酯（8:2 diPAP）已被证明在肝脏中积累，但它是否会引起肝毒性和脂质代谢紊乱在很大程度上尚不清楚。在这项研究中，将斑马鱼胚胎暴露于 8:2 diPAP 中 7 天。暴露于 0.5ng/L 8:2 diPAP 后，观察到肝细胞肥大和核溶解，表明肝脏发育受到抑制。与水对照组相比，8:2 diPAP 导致甘油三酯和总胆固醇水平显著升高，而低密度脂蛋白水平显著降低，表明脂质稳态失调。两种参与肝毒性和脂质代谢的过氧化物酶体增殖物激活受体（PPAR）亚型（pparα 和 pparγ）的水平被 8:2 diPAP 显著上调，与免疫组织化学测定的过表达一致。计算机模拟结果表明，8:2 diPAP 与 PPARα 和 PPARγ 形成氢键。在七种机器学习模型中，自适应增强在预测 PPARα 和 PPARγ 在测试集上的结合亲和力方面表现最佳。自适应增强预测的 8:2 diPAP 与 PPARα 的结合亲和力（7.12）高于与 PPARγ 的结合亲和力（6.97），与实验结果吻合较好。我们的结果揭示了 8:2 diPAP 通过 PPAR 对斑马鱼幼虫肝脏和脂质代谢的不良影响。
