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题名	POPs暴露对动脉粥样硬化的影响及其相关分子机制的研究
作者	单秋丽
学位类别	博士
答辩日期	2014-05
授予单位	中国科学院研究生院
授予地点	北京
导师	杜宇国
关键词	POPs Aroclor1254 TCDD 动脉粥样硬化 POPs Aroclor1254 TCDD atherosclerosis
其他题名	Study on Molecular Mechanism for atherosclerosis effected by POPs exposure
学位专业	环境科学
中文摘要	持久性有机污染物，是一类具有长期残留性、生物蓄积性、半挥发性和高毒性，能够在大气环境中长距离迁移并能沉积回地球，对人体健康和环境具有严重危害的天然和人工合成的有机污染物。越来越多的流行病学研究结果显示持久性有机污染物与动脉粥样硬化的发生发展呈现显著的相关性。然而，其中的分子机制和作用靶点还很不清楚。因此本课题选择具有共面结构的2种PCBs（PCB77，PCB126）和具有非共面结构的2种PCBs(PCB153，PCB104)、TCDD、PBDEs（BDE47，BDE209）和Aroclor1254（一种PCB的混合物）这8种POPs，探讨POPs与动脉粥样硬化的关系。       本研究通过使用ApoE-/-小鼠作为实验模型，发现Aroclor1254和TCDD联合暴露能显著加剧ApoE-/-小鼠动脉粥样硬化的形成并可同时诱导炎性因子MCP-1、RIG-I的表达。结果表明，Aroclor1254和TCDD联合作用导致ApoE-/-小鼠的动脉粥样硬化和炎症反应密切相关。        非酒精性脂肪肝是心血管疾病的病因之一。因此，从我们的实验结果中，同样发现Aroclor1254和TCDD联合作用可以加重ApoE-/-小鼠非酒精性脂肪肝的形成、肝脏坏死和炎症。Aroclor1254和TCDD单独或者协同作用均能诱导芳香烃受体的表达，但是，两者协同作用和单独作用相比并不具有显著差异。我们进一步采用基因芯片技术，探讨具体的致病机理，发现Aroclor1254和TCDD联合作用可显著激活ApoE-/-小鼠肝组织的Nrf2氧化应激信号通路。        miRNA在疾病的调控中起着重要的作用，我们通过miRNA芯片技术，探讨了Aroclor1254和TCDD联合作用对ApoE-/-小鼠肝组织miRNA表达的诱导情况。通过IPA等软件分析，我们发现Aroclor1254和TCDD联合暴露可以显著下调调控动脉粥样硬化关键 miRNA：miRNA-26a-5p、miRNA-30c-5p、miRNA-193a-3p、miRNA-130a-3p和miRNA-376a-3p的表达。       为了进一步验证体内试验的结果，我们以人血管内皮细胞EA.hy926和人单核细胞THP-1为体外实验模型，模拟动脉粥样硬化的起始过程，并且探讨联合暴露对内皮细胞RIG-I信号通路的诱导激活情况。实验结果表明，Aroclor1254和TCDD联合暴露显著的增加了单核细胞向内皮细胞的黏附率，促进了动脉粥样硬化的形成；并且显著诱导炎症反应信号通路RIG-I及其下游基因的表达。       基于上述研究结果，我们首次证实了Aroclor1254和TCDD联合暴露能显著的加剧动脉粥样硬化的形成，并且发现联合作用机制同RIG-I炎症反应信号通路和Nrf2氧化应激信号通路激活密切相关。
英文摘要	Persistent organic pollutants (POPs) are a class of compounds that have the characteristics of long-term residual resistance, bioaccumulation, semi-volatile and highly toxic, can migrate long distances in the atmosphere, could be deposited back to earth and have potential significant impacts on human health and the environment. A growing number of epidemiological studies showed that POPs and the occurrence of atherosclerosis present a significant correlation. However, the potential mechanisms of atherosclerosis induced by POPs were still unclear. Therefore, in our present study, we have chosen of two kinds of surface structure of PCBs (PCB77, PCB126), two kinds of non-coplanar structure of PCBs (PCB153, PCB104), TCDD, PBDEs (BDE47, BDE209) and Aroclor1254 (a mixture of PCBs) to investigate the possible POPs which can enhanced the atherosclerosis in ApoE-/- mice. By using of the ApoE-/ - mice as an experimental model, our results showed that atherosclerotic disease was exacerbated in mice that co-exposed to TCDD and Aroclor1254. In addition, the inflammatory cytokines MCP-1 and RIG-I were significantly induced by co-exposure. Our data suggested that co-exposure to TCDD and Aroclor1254 enhanced atherogenesis in ApoE-/- mice may through the inflammatory response. Non-alcoholic fatty liver is one of the causes of cardiovascular disease. Our results demonstrated that co-exposed to Aroclor1254 and TCDD can developed serious liver steatosis, necrosis, and inflammatory stimuli. Interestingly, all treatment can induced hepatic cytochrome P450 1A1 (CYP1A1) expression, but the maximal level of CYP1A1 was not observed in the co-exposure group. Microarray analysis by Ingenuity Pathway Analysis software showed that the Nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response pathway was significantly activated following co-exposure to TCDD and Aroclor1254. Increasing evidences have shown that miRNAs were found to play an important role in regulating diseases. We sought to determine which miRNAs expression would be changed by TCDD and Aroclor1254 co-expoure in the livers of ApoE-/- mice with Microarray analysis. By using of the Ingenuity Pathway Analysis software and database pathway analysis, we evaluated that the expression of miRNA-26a-5p, miRNA-193a-3p, miRNA-30c-5p, miRNA-130a-3p and miRNA-376a-3p were changed significant in cardiovascular disease (CVD) processes after co-exposured by TCDD and Aroclor1254. In order to verify the results in in vitro, human vascular endothelial cells EA. hy926 and human monocytes cells THP-1 were used to simulate the starting process of atherosclerosis. Oue results have shown that Aroclor1254 and TCDD co-exposure significantly increased the adhesion rate of mononuclear cells to endothelial cell and promoted the formation of atherosclerosis. Significantly, TCDD and Aroclor1254 co-exposure induced the expression of inflammation factor RIG-I and its downstream genes. In summary, we first confirmed that Aroclor1254 and TCDD co-exposure markedly enhanced atherosclerosis than the individual exposure. The potential mechanisms might involve in RIG-I immunity reswponse and Nrf2 oxidative stress signaling pathway activation.
公开日期	2015-06-12
内容类型	学位论文
源URL	[http://ir.rcees.ac.cn/handle/311016/13447]
专题	生态环境研究中心_中国科学院环境生物技术重点实验室
推荐引用方式 GB/T 7714	单秋丽. POPs暴露对动脉粥样硬化的影响及其相关分子机制的研究[D]. 北京. 中国科学院研究生院. 2014.

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