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

Author(s):Show less -

Charkoftaki, Georgia ^{[1, 2]} ; Golla, Jaya Prakash ^{[1, 2, 3]} ; Santos-Neto, Alvaro ^{[4, 1, 2]} ; Orlicky, David J. ^[5] ; Garcia-Milian, Rolando ^[6] ; Chen, Ying ^{[1, 2]} ; Rattray, Nicholas J. W. ^{[7, 1, 2]} ; Cai, Yuping ^{[1, 2]} ; Wang, Yewei ^{[1, 2]} ; Shearn, Colin T. ^[8] ; Mironova, Varvara ^{[1, 2]} ; Wang, Yensheng ^{[1, 2]} ; Johnson, Caroline H. ^{[1, 2]} ; Thompson, David C. ^[9] ; Vasiliou, Vasilis ^{[1, 2]}

Affiliation

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

^[2] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 - USA

^[3] Vet Affairs Connecticut Healthcare Syst, West Haven, CT 06516 - USA

^[4] Univ Sao Paulo, Sao Carlos Inst Chem, BR-13566590 Sao Carlos, SP - Brazil

^[5] Univ Colorado, Sch Med, Dept Pathol, Anschutz Med Ctr, Aurora, CO - USA

^[6] Yale Sch Med, Cushing Whitney Med Lib, Bioinformat Support Program, New Haven, CT 06250 - USA

^[7] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow G4 0RE, Lanark - Scotland

^[8] Univ Colorado, Dept Pharmaceut Sci, Skaggs Sch Pharm & Pharmaceut Sci, Anschutz Med Campus, Aurora, CO 80045 - USA

^[9] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Clin Pharm, Aurora, CO 80045 - USA

• Document type: Journal article
• Source: TOXICOLOGICAL SCIENCES; v. 183, n. 2, p. 338-351, OCT 2021.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 18/01448-9 - Sample preparation and LC-MS for metabolomic and exposomic analyses: studies and application for multiple biological matrices
• Grantee: Alvaro José dos Santos Neto
• Support Opportunities: Scholarships abroad - Research