Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation: Experimental and Computational Approaches
Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation: Experimental and Computational Approaches
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筛选减少肝脏生物蓄积的潜在 PFOS 替代品：实验和计算方法。
DOI：
10.1021/acs.est.8b05564
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发表时间：
--
影响因子：
11.4
通讯作者：
Liang Yong
中科院分区：
文献类型：
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作者：
Cao Huimin;Zhou Zhen;Wang Ling;Liu Guangliang;Sun Yuzhen;Wang Yawei;Wang Thanh;Liang Yong
全氟辛烷磺酸(PFOS)是一种持久性有机污染物，在肝脏组织中具有显著的生物蓄积潜力。暴露于全氟辛烷磺酸可导致肝脏重量增加，诱发肝脏腺瘤，并导致肝脏肿大。可以设计和合成全氟辛烷磺酸的替代品，使其具有显著较低的肝脏生物蓄积。在这项研究中，我们进行了动物暴露实验，以调查14种全氟烷基和多氟烷基物质的组织积累。相关分析表明，化合物在大鼠肝脏中的积累与其与肝脏脂肪酸结合蛋白(LFABP)的结合亲和力有很强的相关性。因此，我们将定量构效关系模型与分子动力学(MD)模拟相结合，开发了计算模型来预测两个新合成的替代品--全氟十氢-2-磺酸和N-二氟丁酸的LFABP结合亲和力。阐述了LFABP的全氟辛烷磺酸替代物的结合特性，以探索不同的分子结构修饰如何影响潜在的结合机制。随后的动物实验表明，基于MD模拟的结合自由能计算提供了一个很好的指标来反映在相同暴露剂量和持续时间下全氟辛烷磺酸替代品的相对肝脏蓄积程度。我们的实验暴露和计算模型相结合的发现可以为设计具有弱LFABP结合能力和低肝蓄积的全氟辛烷磺酸的潜在替代品提供有用的信息。
Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant with significant bioaccumulation potential in liver tissues. Exposure to PFOS could cause increase of liver weight, induce adenomas of the liver, and cause hepatomegaly. Alternatives of PFOS might be designed and synthesized that have significantly lower liver bioaccumulation. In this study, we conducted animal exposure experiments to investigate tissue accumulations of 14 per- and polyfluoroalkyl substances. Correlation analysis demonstrated that accumulation of the compounds in rat liver had strong correlations with their binding affinities of liver fatty acid binding protein (LFABP). Thus, we combined a quantitative structure–activity relationship model with molecular dynamics (MD) simulations to develop computational models to predict the LFABP binding affinities of two newly synthesized alternatives, perfluorodecalin-2-sulfonic acid andN-diperfluorobutanoic acid. The binding characteristics of the PFOS alternatives for LFABP were elaborated to explore how the different structural modifications of molecules influenced the underlying binding mechanisms. Subsequent animal experiments demonstrated that the binding free energy calculations based on the MD simulations provided a good indicator to reflect the relative degree of liver accumulation of the PFOS alternatives in the same exposure doses and durations. Our findings from the combination of experimental exposure and computational model can provide helpful information to design potential alternatives of PFOS with weak LFABP binding capability and low liver accumulation.