Identification of dose-dependent DNA damage and repair responses from subchronic exposure to 1,4-dioxane in mice using a systems analysis approach

Georgia Charkoftaki, Jaya Prakash Golla, Alvaro Santos-Neto, David Orlicky, Rolando Garcia-Milian, Ying Chen, Nicholas Rattray, Yuping Cai, Yewei Wang, Colin Shern, Varvara Mironova, Yensheng Wang, Caroline H. Johnson, David Thompson, Vasilis Vasilou

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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 5,000 mg/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 H2AXγ-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.
Original languageEnglish
Pages (from-to)338-351
Number of pages14
JournalToxicological Sciences
Issue number2
Early online date10 Mar 2021
Publication statusPublished - 31 Oct 2021


  • bile acids
  • dioxanes
  • DNA damage
  • feces
  • genes
  • hepatocytes
  • kidney
  • liver
  • mice
  • urine
  • histopathology
  • potable water


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