ToxStrategies scientist, Dr. Grace Chappell, along with co-authors from University of North Carolina, Duke University, and Texas A&M University, recently published the article “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” in Environmental Health Perspectives.
This study investigated the relationship between genotoxicity and epigenetic responses by measuring DNA adducts, messenger RNA and microRNA expression, and genome-wide chromatin accessibility in lung tissue from two genetically divergent inbred mouse strains, C57BL/6J and CAST/EiJ following inhalation exposure to very high levels of 1,3-Butadiene. This study integrated multiple –omics platforms to provide a better understanding of the role of molecular states, some of which are dynamic, in the demonstrated variation in DNA damage responses across diverse genetic backgrounds. Higher transcription and a more accessible chromatin landscape around genes involved in detoxification pathways was observed in control CAST/EiJ mice relative to C57BL/6J mice. Upon chemical exposure, chromatin was significantly remodeled in the lung of C57BL/6J mice, a strain that acquired relatively higher levels of 1,3-butadiene–induced DNA damage, around the same genes, ultimately resembling the molecular profile of CAST/EiJ.
These results emphasize the importance of considering genetic differences in model organisms that may influence metabolism and other underlying mechanisms of toxicity, as well as that of including epigenetic end points in hazard assessments of known and potential environmental carcinogens. More broadly, these results suggest that inter-individual variations in tolerance to disease susceptibility from exposures may largely depend on the “preparedness” of target tissues at a molecular level to efficiently mitigate the damaging effects of specific environmental agents.