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Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice.

Publication ,  Journal Article
Chappell, GA; Israel, JW; Simon, JM; Pott, S; Safi, A; Eklund, K; Sexton, KG; Bodnar, W; Lieb, JD; Crawford, GE; Rusyn, I; Furey, TS
Published in: Environ Health Perspect
October 16, 2017

BACKGROUND: The damaging effects of exposure to environmental toxicants differentially affect genetically distinct individuals, but the mechanisms contributing to these differences are poorly understood. Genetic variation affects the establishment of the gene regulatory landscape and thus gene expression, and we hypothesized that this contributes to the observed heterogeneity in individual responses to exogenous cellular insults. OBJECTIVES: We performed an in vivo study of how genetic variation and chromatin organization may dictate susceptibility to DNA damage, and influence the cellular response to such damage, caused by an environmental toxicant. MATERIALS AND METHODS: We measured DNA damage, messenger RNA (mRNA) and microRNA (miRNA) expression, and genome-wide chromatin accessibility in lung tissue from two genetically divergent inbred mouse strains, C57BL/6J and CAST/EiJ, both in unexposed mice and in mice exposed to a model DNA-damaging chemical, 1,3-butadiene. RESULTS: Our results showed that unexposed CAST/EiJ and C57BL/6J mice have very different chromatin organization and transcription profiles in the lung. Importantly, in unexposed CAST/EiJ mice, which acquired relatively less 1,3-butadiene-induced DNA damage, we observed increased transcription and a more accessible chromatin landscape around genes involved in detoxification pathways. Upon chemical exposure, chromatin was significantly remodeled in the lung of C57BL/6J mice, a strain that acquired higher levels of 1,3-butadiene-induced DNA damage, around the same genes, ultimately resembling the molecular profile of CAST/EiJ. CONCLUSIONS: These results suggest that strain-specific changes in chromatin and transcription in response to chemical exposure lead to a "compensation" for underlying genetic-driven interindividual differences in the baseline chromatin and transcriptional state. This work represents an example of how chemical and environmental exposures can be evaluated to better understand gene-by-environment interactions, and it demonstrates the important role of chromatin response in transcriptomic changes and, potentially, in deleterious effects of exposure. https://doi.org/10.1289/EHP1937.

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Published In

Environ Health Perspect

DOI

EISSN

1552-9924

Publication Date

October 16, 2017

Volume

125

Issue

10

Start / End Page

107006

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Toxicology
  • Mice, Inbred Strains
  • Mice, Inbred C57BL
  • Mice
  • DNA Damage
  • Chromatin
  • Butadienes
  • Animals
  • Air Pollutants
 

Citation

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Chicago
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Chappell, G. A., Israel, J. W., Simon, J. M., Pott, S., Safi, A., Eklund, K., … Furey, T. S. (2017). Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice. Environ Health Perspect, 125(10), 107006. https://doi.org/10.1289/EHP1937
Chappell, Grace A., Jennifer W. Israel, Jeremy M. Simon, Sebastian Pott, Alexias Safi, Karl Eklund, Kenneth G. Sexton, et al. “Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice.Environ Health Perspect 125, no. 10 (October 16, 2017): 107006. https://doi.org/10.1289/EHP1937.
Chappell GA, Israel JW, Simon JM, Pott S, Safi A, Eklund K, Sexton KG, Bodnar W, Lieb JD, Crawford GE, Rusyn I, Furey TS. Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice. Environ Health Perspect. 2017 Oct 16;125(10):107006.

Published In

Environ Health Perspect

DOI

EISSN

1552-9924

Publication Date

October 16, 2017

Volume

125

Issue

10

Start / End Page

107006

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Toxicology
  • Mice, Inbred Strains
  • Mice, Inbred C57BL
  • Mice
  • DNA Damage
  • Chromatin
  • Butadienes
  • Animals
  • Air Pollutants