Identification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach
Identification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach
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DOI：
10.1093/toxsci/kfab030
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发表时间：
2021-03-10
影响因子：
3.8
通讯作者：
Vasiliou, Vasilis
中科院分区：
文献类型：
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作者：
Charkoftaki, Georgia;Golla, Jaya Prakash;Vasiliou, Vasilis
1，4-二氧杂环己烷（1，4-DX）是一种在美国饮用水中发现的环境污染物。尽管它是一种疑似肝脏致癌物，但饮用水中1，4-DX没有联邦或州最高污染物水平。关于这种化学物质增强肝脏致癌性的机制知之甚少。本研究通过饮用不同浓度的1，4-DX（0、50、500和5，000 mg/L）对雌性BDF-1小鼠进行1周或4周的染毒，观察其毒性作用。进行了组织学研究和多组学方法（转录组学和代谢组学），以研究潜在的毒性机制。肝脏的免疫组织化学分析显示，暴露后H2 AX γ阳性肝细胞（DNA双链断裂的标志物）增加，前胆管细胞（反映DNA损伤和修复机制）扩张。肝脏转录组学显示，1，4-DX诱导的信号通路扰动预计会影响氧化应激反应，解毒和DNA损伤。肝脏、肾脏、粪便和尿液代谢组学分析显示，1，4-DX暴露没有影响，肝脏和粪便中的胆汁酸定量同样显示，暴露没有影响。我们推测，这些结果可能反映了DNA损伤被修复反应所抵消，最终结果是对暴露小鼠的全身生物化学的总体影响为零。我们的研究结果显示了一种新的方法，用于研究环境化学物质，这些化学物质不会引起细胞死亡，但会激活修复系统以响应1，4-DX暴露。
1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States. Although it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500, and 5,000mg/L) in their drinking water for 1 or 4 weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AX gamma-positive hepatocytes (a marker of DNA double-strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces, and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.