复杂网络用于取代苯类内分泌干扰物的毒性通路

Identifying toxicity pathways of substituted benzenes endocrine disrupting chemicals by complex networks

内分泌干扰物可干扰机体的信号途径,影响动物和人体正常的激素平衡,其信号转导途径非常复杂,涉及多条信号通路的激活.本文通过复杂网络技术构建了乙草胺、地散磷等20个取代苯类内分泌干扰物与71个有效靶标的相互作用网络,分析其网络的拓扑系数后获得6个基因作为网络的中心节点基因并带入KEGG信号通路数据库.通过复杂网络预测取代苯类化合物可通过与靶标基因ESR2和MMP9的作用影响雌激素信号通路;通过与靶标基因HIST3H3和MMP9的作用影响前列腺癌及多发性骨髓癌的误转录调节通路,其中,多发性骨髓癌误转录通路可能是取代苯类内分泌干扰物毒性作用的一条新的信号通路."复杂网络"技术的应用有助于从基因/基因的角度出发,将化合物和机体信号通路相互联系,探讨取代苯类内分泌干扰物对机体的毒性机制,基于整体评价内分泌干扰物对机体的毒性作用,为环境污染物的研究提供了一种新的手段.

Endocrine disrupting chemicals can affect the signaling pathways of organism and disturb the balance of hormones in animals,including mammals. In the present study we built a complex network formed by a ligand-target interaction database, consisting of 20 substituted benzene endocrine disrupting chemicals and 71 valid targets. Six genes were identified as the hub genes by topological analysis and then put into the KEGG（Kyoto encyclopedia of genes and genomes）signaling pathway database. Based on complex network prediction substituted benzene compounds can interact with target genes ESR2 and MMP9 and disrupt estrogen signal pathway. Meanwhile,target genes HIST3H3 and MMP9 appear to play a very important role in transcriptional misregulation in cancer,including prostate cancer and multiple myeloma. Among them,multiple myeloma may be a new pathway in endocrine disrupting toxicity for the substituted benzenes. The results,though preliminary,provide some novel insights into the mechanisms the toxicity of the substituted benzene endocrine disrupting chemicals. The complex network has been demonstrated as new and effective means for the study on the toxicity pathways of environmental pollutants.