Identification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach

被引：10

作者：

Charkoftaki, Georgia ^{[1
,8
]}

Golla, Jaya Prakash ^{[1
,8
,9
]}

Santos-Neto, Alvaro ^{[1
,2
,8
]}

Orlicky, David J. ^{[3
]}

Garcia-Milian, Rolando ^{[4
]}

Chen, Ying ^{[1
,8
]}

Rattray, Nicholas J. W. ^{[1
,5
,8
]}

Cai, Yuping ^{[1
,8
]}

Wang, Yewei ^{[1
,8
]}

Shearn, Colin T. ^{[6
]}

Mironova, Varvara ^{[1
,8
]}

Wang, Yensheng ^{[1
,8
]}

Johnson, Caroline H. ^{[1
,8
]}

Thompson, David C. ^{[7
]}

Vasiliou, Vasilis ^{[1
,8
]}

机构：

[1] Yale Univ, Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06250 USA

[2] Univ Sao Paulo, Sao Carlos Inst Chem, BR-13566590 Sao Carlos, SP, Brazil

[3] Univ Colorado, Sch Med, Dept Pathol, Anschutz Med Ctr, Aurora, CO USA

[4] Yale Sch Med, Cushing Whitney Med Lib, Bioinformat Support Program, New Haven, CT 06250 USA

[5] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow G4 0RE, Lanark, Scotland

[6] Univ Colorado, Dept Pharmaceut Sci, Skaggs Sch Pharm & Pharmaceut Sci, Anschutz Med Campus, Aurora, CO 80045 USA

[7] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Clin Pharm, Aurora, CO 80045 USA

[8] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA

[9] Vet Affairs Connecticut Healthcare Syst, West Haven, CT 06516 USA

来源：

TOXICOLOGICAL SCIENCES | 2021年 / 183卷 / 02期

基金：

巴西圣保罗研究基金会;

关键词：

1,4-dioxane; hepatotoxicity; liver transcriptome; metabolome; DNA damage; hepatocellular carcinoma; gene set enrichment analysis; PREGNANE-X-RECEPTOR; LIVER; LIPOPOLYSACCHARIDE; EXPRESSION; TOXICITY; STRESS;

D O I：

10.1093/toxsci/kfab030

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

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.

引用

页码：338 / 351

页数：14