Hepatotoxicity assessment investigations on PFASs targeting L-FABP using binding affinity data and machine learning-based QSAR model.
Hepatotoxicity assessment investigations on PFASs targeting L-FABP using binding affinity data and machine learning-based QSAR model.
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DOI：
10.1016/j.ecoenv.2023.115310
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发表时间：
2023-07
影响因子：
6.8
通讯作者：
Jiayi Zhao;Xiaoyue Shi;Zhiqin Wang;Sijie Xiong;Yongfeng Lin;Xiaoran Wei;Yanwei Li;Xiaowen Tang-Xiaowen
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文献类型：
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作者：
Jiayi Zhao;Xiaoyue Shi;Zhiqin Wang;Sijie Xiong;Yongfeng Lin;Xiaoran Wei;Yanwei Li;Xiaowen Tang-Xiaowen
全氟烷基物质和多氟烷基物质 (PFAS) 是持久性有机污染物，已在各种环境介质和人血清中检测到，但其安全评估仍然具有挑战性。 PFAS 可能在肝组织中积聚，并通过与肝脂肪酸结合蛋白 (L-FABP) 结合而引起肝毒性。因此，评估 PFAS 与 L-FABP 的结合亲和力对于评估潜在的肝毒性作用至关重要。本研究对L-FABP的两个结合位点进行了评估，结果表明，外部位点对多氟烷基硫酸盐具有高亲和力，内部位点更倾向于全氟烷基磺酰胺，总体而言，L-FABP的内部位点对PFASs更敏感。 PFAS 与 L-FABP 的结合亲和力数据被用作训练集，开发基于机器学习模型的定量构效关系 (QSAR)，以有效预测潜在危险的 PFAS。进一步的贝叶斯核机器回归 (BKMR) 模型揭示了灵活性作为 PFAS 诱导的肝毒性的决定性分子特性。它可以通过直接影响结合构象（个体效应）以及与其他分子特性的整合（联合效应）来影响 PFAS 与靶蛋白的亲和力。我们目前的工作使人们对 PFAS 的肝毒性有了更多的了解，这对于 PFAS 的肝毒性分级、给药指导和更安全的替代品开发具有重要意义。
Per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants that have been detected in various environmental media and human serum, but their safety assessment remains challenging. PFASs may accumulate in liver tissues and cause hepatotoxicity by binding to liver fatty acid binding protein (L-FABP). Therefore, evaluating the binding affinity of PFASs to L-FABP is crucial in assessing the potential hepatotoxic effects. In this study, two binding sites of L-FABP were evaluated, results suggested that the outer site possessed high affinity to polyfluoroalkyl sulfates and the inner site preferred perfluoroalkyl sulfonamides, overall, the inner site of L-FABP was more sensitive to PFASs. The binding affinity data of PFASs to L-FABP were used as training set to develop a machine learning model-based quantitative structure-activity relationship (QSAR) for efficient prediction of potentially hazardous PFASs. Further Bayesian Kernel Machine Regression (BKMR) model disclosed flexibility as the determinant molecular property on PFASs-induced hepatotoxicity. It can influence affinity of PFASs to target protein through affecting binding conformations directly (individual effect) as well as integrating with other molecular properties (joint effect). Our present work provided more understanding on hepatotoxicity of PFASs, which could be significative in hepatotoxicity gradation, administration guidance, and safer alternatives development of PFASs.