Sex-specific differences in genotoxic and epigenetic effects of 1,3-butadiene among mouse tissues

Lauren Lewis, Grace A. Chappell, Tetyana Kobets, Bridget E. O’Brian, Dewakar Sangaraju, Oksana Kosyk, Wanda Bodnar, Natalia Y. Tretyakova, Igor P. Pogribny, Ivan Rusyn

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9 Scopus citations


Exposure to environmental chemicals has been shown to have an impact on the epigenome. One example is a known human carcinogen 1,3-butadiene which acts primarily by a genotoxic mechanism, but also disrupts the chromatin structure by altering patterns of cytosine DNA methylation and histone modifications. Sex-specific differences in 1,3-butadiene-induced genotoxicity and carcinogenicity are well established; however, it remains unknown whether 1,3-butadiene-associated epigenetic alterations are also sex dependent. Therefore, we tested the hypothesis that inhalational exposure to 1,3-butadiene will result in sex-specific epigenetic alterations. DNA damage and epigenetic effects of 1,3-butadiene were evaluated in liver, lung, and kidney tissues of male and female mice of two inbred strains (C57BL/6J and CAST/EiJ). Mice were exposed to 0 or 425 ppm of 1,3-butadiene by inhalation (6 h/day, 5 days/week) for 2 weeks. Strain- and tissue-specific differences in 1,3-butadiene-induced DNA adducts and crosslinks were detected in the liver, lung and kidney; however, significant sex-specific differences in DNA damage were observed in the lung of C57BL/6J mice only. In addition, we assessed expression of the DNA repair genes and observed a marked upregulation of Mgmt in the kidney in female C57BL/6J mice. Sex-specific epigenetic effects of 1,3-butadiene exposure were evident in alterations of cytosine DNA methylation and histone modifications in the liver and lung in both strains. Specifically, we observed a loss of cytosine DNA methylation in the liver and lung of male and female 1,3-butadiene-exposed C57BL/6J mice, whereas hypermethylation was found in the liver and lung in 1,3-butadiene-exposed female CAST/EiJ mice. Our findings suggest that strain- and sex-specific effects of 1,3-butadiene on the epigenome may contribute to the known differences in cancer susceptibility.

Original languageEnglish (US)
Pages (from-to)791-800
Number of pages10
JournalArchives of Toxicology
Issue number3
StatePublished - Mar 6 2019

Bibliographical note

Funding Information:
Acknowledgements This work was supported, in part, by grants from National Institutes of Health (R01 ES023195, R01 CA095039 and P30 ES025128). The views expressed in this article are those of the authors and do not necessarily reflect the views of NIH.

Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.


  • Butadiene
  • Epigenetic
  • Kidney
  • Liver
  • Lung
  • Mouse


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