环境中PPCPs对妊娠期肝内胆汁淤积症（ICP）的致病性的理论研究

Intrahepatic cholestasis of pregnancy (ICP) is one of the important diseases during pregnancy. When a pregnancy gets ICP disease, her fetus will suffer an extremely high fetal mortality. Nowadays, PPCPs which are widespread using in women have become a new type of pollutants. However, there is no clear evidence to concern a relationship between PPCPs and the existence of ICP, and there is no literature reported how PPCPs influence the ICP. Investigating ICP pathogenesis is very significant study and it is benefit to reduce pregnant woman the risk of getting the ICP disease. Till now, pathogenic mechanism in experimental research data couldn’t be effectively obtained, so we intend to apply computer-aided drug design approach to environmental pollutants’ etiology research..This project intends to systematically construct multiple evaluation methods by using both chemometrics and bioinformatics methods, in order to theoretically explore the pathogenicity of PPCPs on the ICP. In PPCPs, the main components of commonly used care-products and drug molecules were taken as the object of study. Hepatic cell line cytotoxicity is used as in vitro activity, and serum glycocholic acid concentration and hemorheology change are used as in vivo pathological activity. Then the structure-activity multivariate models will be constructed with molecular descriptors and these activities. The active target enzyme (bile Acid receptor TGR5 and bile acid transporter ASBT, et al.) are selected to access and analyze the molecular interactions and explain the mechanism by using molecular docking and molecular dynamics simulation. This method includes toxicity data collection, ICP activity and toxicity database building, QSAR modeling, 3D toxicity group model (pharmacophore model) screening, and molecular dynamics simulation analysis. Data collection is a key step with the stoichiometry and biological informatics combining method, data filtering, validation, and integration. Both stoichiometry and biological informatics are used as descriptors in this QSAR model. And 3D toxicity group model (pharmacophore model) and molecular dynamics simulation will be combined analysis for PPCPs pathogenic assessment of ICP pathogenicity. This project will provide a new method for the study of the pathogenicity of environmental pollutants, provide theoretical support for the reasonable discharge and management of PPCPs, and provide effective and basic data and a potential method to carry out health toxicology and risk assessment on environmental chemicals.

妊娠期肝内胆汁淤积症（ICP）是孕期重要疾病之一，胎儿致死率极高。然而，女性广泛使用的PPCPs已渐成新型污染物，PPCPs对ICP是否存在关联及如何影响，目前仍无报道，因此探索PPCPs对ICP的致病性机理，从源头上控制得病风险具有重要意义。在实验研究仍无法解释其影响机制的前提下，本项目拟将化学计量学和生物信息学相结合来系统地构建多重评价方法，理论探索PPCPs对ICP的致病性：以PPCPs中常用护理品主要成分和药物小分子为考察对象，以肝细胞系细胞毒性为体外活性，以血清甘胆酸浓度、血液流变学变化等为病理活性，利用机器学习方法，综合分子化学信息和生物信息构建结构-活性多元综合模型；采用活性靶酶（胆汁酸膜受体TGR5和胆汁酸转运体ASBT等）辅助分析分子相互作用，合理解释机理。以期为环境污染物的致病性研究提供新的方法指导，为深入开展环境化学品健康毒理研究与风险评价提供基础数据和新方法支持。

医药品与个人护理品(PPCPs)是生活中容易被大众忽略的典型、新型污染物，通过环境残留接触，在体内代谢残存或长期富集后，以致对人类健康存在高风险性。妊娠期肝内胆汁淤积症（ICP）是孕期重要疾病之一，胎儿致死率极高。然而，女性广泛接触和使用的PPCPs对ICP是否存在关联及如何影响，目前国内外环境毒理学研究仍无报道。. 本项目针对环境污染物PPCPs是否对ICP有致病性，以及如何影响机体致病的问题，将计算机辅助药物设计方法应用到环境污染物的致病性研究中来，以常见PPCPs分子为主要研究对象，以肝细胞系细胞毒性等为体外活性，以ICP疾病相关基因为重点考察因素，利用化学信息学和生物信息学方法为分析手段，结合人类交互组网络和分子动力学模拟分析，构建多元参数-活性关系模型，综合评价PPCPs对ICP的致病性机理。.本项目主要以环境中PPCPs，尤其是临床常用药物小分子为考察对象，建立并优化了临床常用药物对ICP的致病性的大数据回顾性分析预测方法，预测得Omeprazole，Lansoprazole和Amoxicillin对ICP有较高风险；应用蛋白-蛋白互作网络分析方法，完成了ICP相关靶标的疾病模块定义方法的建立和完善；通过从药物分子靶标出发结合ICP疾病模块分析，获得了药物分子与ICP疾病网络相关的拓扑参数，建立起药物分子的ICP致病性的网络拓扑参数的预测模型，准确预测得Omeprazole，Lansoprazole和Amoxicillin三种分子高致病风险；对三分子的网络拓扑参数进行生物信息学基因富集分析，考察了每个分子的ICP致病性机理，并合理解释。同时，借助活性靶酶（OCT3、TGR5和ASBT等）应用分子模拟分析分子相互作用，进一步阐释三分子致病机理。. 本项目将化学计量学和生物信息学相结合来系统地构建和完善了多重评价方法，预测并合理解释了部分PPCPs的ICP致病性。在建立小分子对ICP致病性的多种预测的新方法的基础上，进一步借助系统生物学，离散数学和网络分析，在我们的未来研究中有望形成一种新的网络毒理学计算方法来分析环境污染物的毒性和副作用。