多氯联苯/多溴二苯醚的人类和小鼠孕烷X受体活性的差异分子机理和预测新方法研究

项目名称： 多氯联苯/多溴二苯醚的人类和小鼠孕烷X受体活性的差异分子机理和预测新方法研究

项目编号： No.21277074

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 环境科学、安全科学

项目作者： 杨旭曙

作者单位： 南京医科大学

项目金额： 80万元

中文摘要： 多氯联苯(PCBs)/多溴二苯醚(PBDEs)激活孕烷X受体(PXR)可能会产生内分泌干扰等毒性。而PCBs/PBDEs的PXR受体活性在人类和小鼠之间存在显著差异性，这将直接影响到PCBs/PBDEs生态风险评价的准确性。本申请拟对PCBs/PBDE与人类和小鼠PXR受体进行三维分子模拟和分子对接，并结合定点突变，从微观角度揭示影响PCBs/PBDEs对人类和小鼠PXR受体不同活性的配体和受体分子的关键结构特征，从分子结构角度阐明人类和小鼠PXR受体介导的PCBs/PBDEs不同活性的微观分子机理；同时发展基于配体活性构象和受体结构的PCBs/PBDEs活性预测新方法。本研究成果将为发展PCBs/PBDEs的风险评价体系提供理论基础和方法学，为科学制定PCBs/PBDEs的相关环境质量标准、实现PCBs/PBDEs的有效控制与科学管理提供理论依据。

中文关键词： 全氟/多氟化合物；孕烷X受体；分子对接；定点突变；模型预测

英文摘要： PCBs and PBDEs can exert endocrine disrupting effects by binding to the pregnane X receptor (PXR). PXR exhibits differences between human and mouse in its response to PCBs and PBDEs, which is unfavorable to accurately assessing the risk that PCBs and PBDEs throw on the ecosystem. This project plans to employ the three-dimensional molecular stimulation,docking and site-directed mutagenesis to explore the interaction between PCBs/PBDEs and hPXR/mPXR with the aim to discover the key structural features of liands and receptors, which have a great effect on difference between hPXR and mPXR in responds to PCBs/PBDEs. As a result, the molecular mechanism of differences that PXR exhibits between human and mouse in its response to PCBs and PBDEs can be revealed. In addition, a novel method based on the structure of both liand and receptor can be developed to predict the activity of PCBs/PBDEs mediated by hPXR/mPXR. The achievement we will gain in this reseach can contribute to the development of theoretical basis and methodology to assess the ecology risk of PCBs/PBDEs. The achievement may also provide a theoretical foundation for scientific formulation of environmental quality standards for PCBs/PBDEs and for effective control and scientific administration of PCBs/PBDEs.

英文关键词： poly- and perfluorinated compounds (PFCs)；pregnane X receptor (PXR)；molecular docking；site-directed mutagenesis；QSAR model