多氯联苯（PCBs）暴露对非酒精性脂肪肝的影响及相关分子机制研究

Epidemiological studies have showed that long-term exposure to Polychlorinated biphenyls (PCBs) are closely associated with Nonalcoholic fatty liver disease (NAFLD). However, there are few studies on the potential toxicity of NAFLD induced by exposure to PCBs. The possible mechanisms of NAFLD induced by exposure are not clear. In our previous studies, we found that a mixture of PCBs exposure in ApoE-/- mice enhanced NAFLD. On the base of this, our project will use C57BL/6 mice and HepG2 cells as in vivo and in vitro NAFLD experiment models to study different types of PCBs exposure whether worsen NAFLD and structure-activity relationship of PCBs. Furthermore, we will get the expression profiling of mRNA and microRNA by the use of gene chip technology. To determine the potential signaling pathways and miRNAs, we selected mRNAs and miRNAs that only expressed in the effected group of PCBs using the DAVID, Gene Ontology and Ingenuity Pathway Analysis software and database. Finally, by blocking or activating signal pathway and overexpression of miRNAs, our studies will be performed to study potential regulation signaling pathways and microRNAs in NAFLD induced by exposure to PCBs. This project is to study the toxic effect of PCBs in different layers and levels and will be provided theoretical basis for relevant control benchmark of pollutants and molecular targets for slow down the NAFLD caused by exposure to PCBs.

流行病学调查显示长期暴露于多氯联苯与非酒精性脂肪肝（NAFLD）密切相关，然而目前对多氯联苯诱导NAFLD及其潜在分子作用机制尚无明确认识。我们前期研究发现多氯联苯混合物暴露能诱导ApoE-/-小鼠NAFLD的发病。在此基础上，本项目将系统进行不同结构的多氯联苯单体暴露，比较暴露后对C57BL/6小鼠和HepG2细胞的NAFLD诱导情况，筛选出起作用的多氯联苯，明确其构效关系；通过基因芯片技术和GO、IPA等软件分析多氯联苯效应组小鼠肝脏mRNA、miRNA的表达变化及潜在调控信号通路和miRNAs；并通过激活或阻断信号通路以及miRNA过表达探讨潜在信号通路和miRNAs在多氯联苯暴露诱导NAFLD中的调控作用，结合体内外模型初步阐明相关分子作用机制。本项目从多个层次和水平阐明多氯联苯的毒性效应，可为制定多氯联苯的控制基准提供理论依据，并为有效减缓多氯联苯造成的NAFLD提供分子靶标。

非酒精性脂肪肝(Nonalcoholic fatty liver disease，NAFLD)在我国发病率已高达15%，由于它与失代偿期肝硬化、肝功能衰竭和原发性肝癌密切相关，已经成为严重危害人类健康的三大肝病之一。多氯联苯（Polychlorinated biphenyls ，PCBs）是一类典型的持久性有机污染物（POPs），研究证实在我国多个地区生物体和环境中均可检测到PCBs的存在，其对生态环境和人类健康可造成严重的影响。近年来，多篇流行病学研究显示PCBs暴露能够增加部分人群患NAFLD的风险，部分研究也已经证实PCBs与NAFLD具有显著相关性。然而，目前在国际范围内关于PCBs诱导NAFLD的研究报道依然很少，对于其分子机制的研究尚处于初步阶段。因此本项目使用体内和体外细胞模型筛选出起作用的PCBs， 通过组学技术探讨了其潜在分子作用机制。本研究结果表明：（1）共面多氯联苯PCB156暴露能显著诱导HepG2和HL7702细胞脂质蓄积；（2）PCB156（55mg/kg）长期暴露（12周）能够加剧高脂喂养的C57BL/6小鼠NAFLD的发病；（3）PCB156暴露可显著影响的HL7702细胞基因表达谱，包括628个差异表达的lncRNAs 和222差异表达的mRNAs，分析结果表明差异基因主要参与调控炎症信号通路和脂质代谢通路。