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多溴联苯醚和全氟烷基酸的分子毒理机制研究

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任肖敏, 张连营, 郭良宏. 多溴联苯醚和全氟烷基酸的分子毒理机制研究[J]. 环境化学, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
引用本文: 任肖敏, 张连营, 郭良宏. 多溴联苯醚和全氟烷基酸的分子毒理机制研究[J]. 环境化学, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
shu
REN Xiaomin, ZHANG Lianying, GUO Lianghong. Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids[J]. Environmental Chemistry, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
Citation: REN Xiaomin, ZHANG Lianying, GUO Lianghong. Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids[J]. Environmental Chemistry, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
shu

多溴联苯醚和全氟烷基酸的分子毒理机制研究

  • 1.

    中国科学院生态环境研究中心, 北京, 100085

Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids

  • 1.

    State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Centre for Eco-environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China

  • 摘要: 多溴联苯醚(PBDEs)和全氟烷基酸(PFAAs)是两类使用量大、环境污染广泛、人体暴露严重的新型有机污染物,2009年已纳入《斯德哥尔摩公约》持久性有机污染物 (POPs) 名单,但其毒性效应及作用机制并不明确.本文综述了本课题组近几年针对多溴联苯醚PBDEs和全氟烷基酸PFAAs的分子毒理机制研究工作,主要集中在这两类污染物对甲状腺系统、雌激素系统和肝脏脂肪酸代谢系统干扰效应的分子机制研究.本文分别从分子、细胞和活体三个层面,研究了污染物与核受体的直接结合作用、结合后受体的构象变化、细胞内受体的转录活性、以及活体暴露后受体调控基因的表达变化,由此阐明了污染物通过与受体直接作用导致细胞和活体生物功能改变的分子机制.同时结合计算模拟,探讨了污染物生物效应与其化学结构之间的关系,发现污染物的受体活性取决于它们与受体结合的空间构型,而其活性强度基本与二者的结合能力一致,主要受疏水作用和氢键的影响.此外,还通过研究污染物与天然配体转运蛋白的相互作用,明确了各个污染物与转运蛋白的结合能力,探讨了其构效关系,并评估了污染物对天然配体在体内转运过程的潜在干扰效应.通过上述研究工作,提出了多层面、多靶点研究环境污染物分子毒理机制的新思路,建立和引进了研究污染物与生物靶分子相互作用的新方法,发现了PBDEs、PFAAs与TR、ER、PPARγ核受体结合的新模式,为深入了解这些污染物的分子毒理机制提供了有用的信息和有效的研究手段.
    Abstract: Polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl acids (PFAAs) are two groups of persistent organic pollutants (POPs) which are widely used, broadly existing in the environment, and frequently detected in humans. In 2009 they were added to the POPs list of the Stockholm Convention. However, the toxicological effects and mechanisms of PBDEs and PFAAs are still not well understood. This review summarizes our recent work on the studies of molecular toxicological mechanisms of PBDEs and PFAAs, focusing on their disruption effects on thyroid hormone system, estrogen system and hepatic fatty acid metabolism system. From the molecular, cellular and in vivo level, we investigated the direct binding interaction of these chemicals with hormone nuclear receptors, receptor conformational change after ligand binding, receptor mediated transcriptional activity in cells, and change of gene expression in experimental animals. Based on the results, we established a direct link between receptor binding and change of biological functions in cells and in vivo. Using molecular docking, we investigated the structural basis for the observed agonistic or antagonistic activity. It was found that their activity was determined by the binding geometry with the receptor, and their potency depended on the binding affinity with the protein, which were dominated by the hydrophobic and hydrogen-bond interactions. We also studied the binding interaction of these chemicals with transport proteins, and estimated their potential disruption effect on the in vivo transport of endogenous substances. Through these studies, we put forward a multi-level, multi-target strategy for the investigation of molecular toxicological mechanisms of POPs, established and introduced new methods for the study of POPs interactions with biological macromolecules, identified new binding modes of PBDEs and PFAAs with ER, TR and PPARγ nuclear receptors. Our work has provides new information on the molecular toxicological mechanisms of PBDEs and PFAAs, and also new tools for the study of other POPs.
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  • 收稿日期:  2014-05-26
任肖敏, 张连营, 郭良宏. 多溴联苯醚和全氟烷基酸的分子毒理机制研究[J]. 环境化学, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
引用本文: 任肖敏, 张连营, 郭良宏. 多溴联苯醚和全氟烷基酸的分子毒理机制研究[J]. 环境化学, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
shu
REN Xiaomin, ZHANG Lianying, GUO Lianghong. Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids[J]. Environmental Chemistry, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
Citation: REN Xiaomin, ZHANG Lianying, GUO Lianghong. Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids[J]. Environmental Chemistry, 2014, 33(10): 1662-1671. doi: 10.7524/j.issn.0254-6108.2014.10.012
shu

多溴联苯醚和全氟烷基酸的分子毒理机制研究

  • 1. 中国科学院生态环境研究中心, 北京, 100085
  • 收稿日期:  2014-05-26

摘要: 多溴联苯醚(PBDEs)和全氟烷基酸(PFAAs)是两类使用量大、环境污染广泛、人体暴露严重的新型有机污染物,2009年已纳入《斯德哥尔摩公约》持久性有机污染物 (POPs) 名单,但其毒性效应及作用机制并不明确.本文综述了本课题组近几年针对多溴联苯醚PBDEs和全氟烷基酸PFAAs的分子毒理机制研究工作,主要集中在这两类污染物对甲状腺系统、雌激素系统和肝脏脂肪酸代谢系统干扰效应的分子机制研究.本文分别从分子、细胞和活体三个层面,研究了污染物与核受体的直接结合作用、结合后受体的构象变化、细胞内受体的转录活性、以及活体暴露后受体调控基因的表达变化,由此阐明了污染物通过与受体直接作用导致细胞和活体生物功能改变的分子机制.同时结合计算模拟,探讨了污染物生物效应与其化学结构之间的关系,发现污染物的受体活性取决于它们与受体结合的空间构型,而其活性强度基本与二者的结合能力一致,主要受疏水作用和氢键的影响.此外,还通过研究污染物与天然配体转运蛋白的相互作用,明确了各个污染物与转运蛋白的结合能力,探讨了其构效关系,并评估了污染物对天然配体在体内转运过程的潜在干扰效应.通过上述研究工作,提出了多层面、多靶点研究环境污染物分子毒理机制的新思路,建立和引进了研究污染物与生物靶分子相互作用的新方法,发现了PBDEs、PFAAs与TR、ER、PPARγ核受体结合的新模式,为深入了解这些污染物的分子毒理机制提供了有用的信息和有效的研究手段.

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