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Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse

Lauren Lewis1, Barbara Borowa-Mazgaj2, Aline de Conti2

  • 1Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences , Texas A&M University , College Station , Texas 77843 , United States.

Chemical Research in Toxicology
|April 17, 2019
PubMed

Insights

1,3-butadiene exposure causes DNA damage, but cancer risk varies by tissue and individual. This study used diverse mice to reveal genetic and epigenetic factors influencing this variability, aiding cancer risk assessment.

Area of Science:

  • Environmental Toxicology
  • Carcinogenesis
  • Epigenetics

Background:

  • 1,3-butadiene is a human carcinogen forming reactive epoxides.
  • While DNA adducts are widespread, carcinogenicity is tissue-specific (liver, lung, lymphoid).
  • Strain- and tissue-specific epigenetic effects may explain susceptibility to 1,3-butadiene-induced damage.

Purpose of the Study:

  • Investigate interindividual variability in 1,3-butadiene effects using a population-based mouse model.
  • Identify mechanisms driving tissue-specific carcinogenicity and quantify population variability.
  • Develop a chemical-specific human variability factor for improved cancer risk assessment.

Main Methods:

  • Exposed male mice from 20 Collaborative Cross strains to 1,3-butadiene (635 ppm) for 2 weeks.
  • Assessed DNA damage via N-7-(2,3,4-trihydroxybut-1-yl)-guanine (THB-Gua) adducts.
  • Evaluated global histone modifications (H3/H4 trimethylation/acetylation) and DNA methylation (LINE-1, SINE B1).

Main Results:

  • Quantified interstrain variation in DNA damage and epigenetic alterations across tissues (lung, liver, kidney).
  • Identified four candidate genes involved in chromatin remodeling linked to interstrain susceptibility.
  • Derived a chemical-specific human variability factor from observed population variability.

Conclusions:

  • The Collaborative Cross mouse population effectively models interindividual variability in chemical carcinogenesis.
  • Genetic and epigenetic factors significantly contribute to tissue-specific susceptibility to 1,3-butadiene.
  • This approach provides a framework for quantifying population variability in carcinogenic risk assessment.

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