经口六价铬暴露毒作用模式中关键毒性通路的生物信息学分析
Bioinformatics analysis of key toxicity pathways in the mode of action of oral exposure to hexavalent chromium
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摘要:
背景 经口六价铬Cr(Ⅵ)暴露可导致小鼠消化道肿瘤发生，而目前机制尚未明确。通过网络数据挖掘和计算毒理学的分析预测化学物的暴露风险已成为毒理学研究的重要研究手段，可助于阐述毒作用模式（MOA）和识别关键毒性通路。
目的 识别并评价经口Cr(Ⅵ)暴露MOA中的关键事件。
方法 通过比较毒理基因组数据库（CTD）和基因表达综合数据库（GEO），分别构建基因集，并导入Ingenuity® Pathway Analysis（IPA）软件进行通路富集分析及生物学功能分析，识别经口Cr(Ⅵ)暴露靶器官毒效应的潜在关键毒性通路。基于改良Bradford Hill原则，对Cr(Ⅵ)经口暴露MOA的潜在关键毒性通路进行证据权重（WOE）评价。
结果 CTD中筛选出与经口Cr(Ⅵ)暴露相关文献共54篇，其中肝脏及肠道相关文献分别有18篇和9篇，对应125个和272个相关基因。通路富集及生物学功能分析显示，肝脏及肠道扰动通路主要与细胞应激和损伤、细胞周期调控和凋亡相关。核因子E2相关因子2（Nrf2）通路及芳香烃受体（AHR）通路或为关键毒性通路，参与Cr(Ⅵ)细胞毒性介导的MOA。Nrf2通路激活与小鼠隐窝细胞增殖的染毒剂量（≥170 mg·L−1 重铬酸钠）及出现时间点（90 d）相似，提示Nrf2通路激活或为细胞毒性介导的MOA关键事件。WOE评价结果显示这一假设的证据效力为中等，其中生物学合理性及剂量-反应关系的证据效力较高。
结论 Nrf2通路激活或为Cr(Ⅵ)经口暴露引起小肠肿瘤发生细胞毒性介导的MOA中启动或维持隐窝细胞增殖的关键事件。
Abstract:Background Oral exposure to hexavalent chromium Cr(VI) can lead to gastrointestinal tumorigenesis in mice, and the mechanism is not yet clear. To predict health risk due to chemical exposure, data mining and computational toxicology analysis has become an important tool in toxicology research, which can help to elucidate mode of action (MOA) and identify key toxicity pathways.
Objective This study aims to identify and evaluate key events in the MOA of oral Cr(VI) exposure.
Methods Gene sets established from Comparative Toxicogenomics Database (CTD) and Gene Expression Omnibus (GEO) respectively were imported into Ingenuity® Pathway Analysis (IPA) software for pathway enrichment analysis and biological function analysis to identify potential key toxicity pathways of target organs/tissues toxicity of oral exposure to Cr(Ⅵ). Next, the weight of evidence (WOE) of the identified key toxicity pathways in the MOA of oral exposure to Cr(VI) was evaluated based on the modified Bradford Hill principle.
Results A total of 54 pieces of literature related to oral Cr(VI) exposure were screened in CTD, among which 18 and 9 were related to liver and intestine with 125 and 272 corresponding genes, respectively. The pathway enrichment and biological function analysis results showed that liver and intestinal perturbation pathways were mainly related to cell stress and injury, cell cycle regulation, and apoptosis, indicating that Nrf2 pathway and AHR pathway might be the key toxicity pathways involved in the cytotoxic-mediated MOA. Meanwhile, the dose (≥170 mg·L−1 sodium dichromate) and the time point (90 d) of the activation of Nrf2 pathway was similar to the emergence of crypt cell proliferation. It was proposed that Nrf2 pathway activation might be a key event for cytotoxic-mediated MOA of small intestinal tumors. The WOE results showed moderate validity of evidence in this hypothesis, with high validity of evidence for biological plausibility and dose-response manner.
Conclusion Nrf2 pathway activation might be the key event in the cytotoxic-mediated MOA of small intestinal tumors induced by oral exposure to Cr(VI) via initiating or maintaining crypt cell proliferation.
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