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

Arch Toxicol. 2019 Mar;93(3):791-800. doi: 10.1007/s00204-018-2374-x. Epub 2018 Dec 14.

Abstract

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.

Keywords: Butadiene; Epigenetic; Kidney; Liver; Lung; Mouse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Butadienes / metabolism
  • Butadienes / toxicity*
  • DNA
  • DNA Adducts / metabolism
  • DNA Damage
  • DNA Methylation
  • Epigenesis, Genetic*
  • Female
  • Inhalation Exposure
  • Kidney
  • Liver
  • Lung
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutagens / metabolism
  • Mutagens / toxicity*
  • Sex Characteristics
  • Toxicity Tests

Substances

  • Butadienes
  • DNA Adducts
  • Mutagens
  • DNA
  • 1,3-butadiene