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

• Published in: Environmental health perspectives Vol. 125; no. 10; p. 107006
• Main Authors: Chappell, Grace A, Israel, Jennifer W, Simon, Jeremy M, Pott, Sebastian, Safi, Alexias, Eklund, Karl, Sexton, Kenneth G, Bodnar, Wanda, Lieb, Jason D, Crawford, Gregory E, Rusyn, Ivan, Furey, Terrence S
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01.10.2017; Environmental Health Perspectives
• Subjects: 1,3-Butadiene; Accessibility; Annotations; Bioinformatics; Butadiene; Cancer; Cancer genetics; Carcinogens; Chemical carcinogenesis; Chemical damage; Chromatin; Data processing; Deoxyribonucleic acid; Detoxification; DNA; DNA damage; DNA methylation; Environmental effects; Environmental toxicology; Exposure; Gene expression; Genes; Genetic diversity; Genomes; Health aspects; In vivo methods and tests; Inbreeding; Laboratories; Lungs; Measurement methods; Metabolism; Mice; MicroRNAs; miRNA; Mitochondrial DNA; Molecular chains; Ribonucleic acid; RNA; Toxicants; Toxicology; Transcription; Transcription (Genetics); Transcription factors; Tumors; United States
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/EHP1937

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. We performed an 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. 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. 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. 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.