中文摘要：

本研究通过microRNA-mRNA相互作用考察PCBs的基因毒性,探讨PCBs致动脉粥样硬化可能的分子机制.研究使用8周龄ApoE-/-小鼠,腹腔注射PCBs混合物Aroclor1254（55 mg·kg^-1体重）,暴露6周后获取其肝脏,提取总RNA,获取cDNA或对RNA去磷酸化及特征标记.采用Affymetrix GeneChipMouse Genome430 2.0基因芯片和Agilent Mouse microRNA array芯片,分析Aroclor1254暴露前后mRNAs和miRNAs的差异表达情况.随后,结合Affymetrix mRNA芯片平台,使用IPA软件分析差异表达的miRNAs和mRNAs,揭示Aroclor1254暴露对基因调控网络和信号通路的影响.研究结果显示,Aroclor1254暴露后有18个差异表达的miRNAs能够靶向调控110个差异表达的mRNAs,二者可共同影响糖代谢、脂代谢、细胞死亡、分子运输等生物学功能.进一步考察与动脉粥样硬化发生发展密切相关的糖代谢、脂代谢网络调控,发现miRNA-22、let-7family、miRNA-15a/b,以及靶基因PPARα、PPARγ辅助激活因子1α和Foxo1,在PCBs暴露致动脉粥样硬化发生发展的糖脂代谢异常中发挥了重要作用.

英文摘要：

microRNAs（ miRNAs） are powerful negative regulators of mRNA expression, and therefore,are responsible for the modulation of important mRNA networks. Polychlorinated biphenyls（ PCBs）,among the important family numbers of persistent organic pollutants（ POPs）,are known to induce the development of atherosclerosis,probably through the alteration of gene expression. The present study was aimed to investigate the changes of miRNA-mRNA networks and their associations with the genotoxocity of PCBs,the potential molecular mechanisms involved in the atherosclerosis.Male ApoE^-/-mice of 8 weeks were exposed to Aroclor1254（ a representative mixture of PCBs,55 mg·kg^-1 body weight） by intraperitoneal injection four times over six weeks of duration. The total RNA was isolated from the liver of ApoE^-/-mice with or without exposure to Aroclor1254. cDNA and the RNA with specific staining after dephosphorylation were used in gene arrays with Affymetrix GeneChip Mouse Genome 430 2. 0 gene chip and Agilent Mouse microRNA array,respectively.Then IPA software,combined with the platform of Affymetrix mRNA gene array was used to analyze the alterations of mRNAs and miRNAs. The results were furthermore used to evaluate the effects of Aroclor1254 on the gene regulation network and the related cell signaling pathways. Our results showed that 18 miRNAs regulated 110 mRNAs after Aroclor1254 exposure,both of them could modulate the common biological functions,such as glucose metabolism,lipid metabolism,cell deathand survival and cell transport. Further investigation showed that miRNA-22,let-7 family,miRNA-15 a /b and the target genes of PPARα,PPARγ-coactivator1α and Foxo1 play important roles on the metabolism of glucose and lipid,which are closely related with the development of atherosclerosis.