Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

Introduction

Inter-individual genetic variation can have profound impacts on the metabolism of pharmaceutical drugs and environmental toxicants (Ma and Lu 2011; Pierce et al. 2012). The molecular consequences of chemical exposure can therefore also vary across individuals and populations and may be attributable to variation in the expression of key metabolic genes, in the immune response, and in the DNA damage response pathway. Emerging evidence also suggests that chemical-induced effects may be transmitted transgenerationally through epigenetic means (Nadeau 2009). Yet, the underlying mechanisms for how genetics, metabolism, gene expression, and gene regulation combinatorially dictate the response to chemical exposure both within and across individuals is poorly understood.

One such genotoxic chemical with variable damaging effects in genetically diverse individuals is 1,3-butadiene. 1,3-Butadiene is an industrial chemical that is primarily used in the production of synthetic rubbers and polymers (White 2007); it is a ubiquitous environmental pollutant, is present in both automobile exhaust and cigarette smoke, and is classified as carcinogenic to humans by the World Health Organization/International Association for Research on Cancer (WHO/IARC) (Baan et al. 2009). There have been four studies on the carcinogenicity of 1,3-butadiene exposure by inhalation in mice, all conducted in the same F1 hybrid mouse strain, B6C3F1 (IARC 2008). These studies showed that 1,3-butadiene induced tumors in multiple organs in this strain at exposure concentrations ranging from 6.25 to 1,250 ppm and durations of exposure from 13 to 60 wk. Similar systematic carcinogenicity studies have not been performed in other mouse strains.

The carcinogenicity of 1,3-butadiene is mediated through the creation of highly reactive epoxide intermediates formed during 1,3-butadiene metabolism, which damage DNA through the formation of DNA adducts (Goggin et al. 2009; Swenberg et al. 2000a, 2000b). These DNA-reactive epoxide intermediates are initially processed through phase I metabolism (bioactivation) by cytochrome P450 oxidases and later conjugated and excreted through phase II metabolism (detoxification) by broad-specificity enzymes including glutathione S-transferases (Csanady et al. 1992).

In addition to DNA damage, 1,3-butadiene also causes alterations in gene expression, bulk DNA methylation, and bulk histone modifications in mouse lung and liver tissues, but not in kidney (Chappell et al. 2014; Koturbash et al. 2011b). Interestingly, these 1,3-butadiene-induced effects were found to vary across genetically divergent inbred mouse strains (Koturbash et al. 2011a). In particular, C57BL/6J (a Mus musculus domesticus subspecies and a classic laboratory strain) exhibited high levels of DNA adduct formation and changes in bulk histone modifications, whereas CAST/EiJ (a M. musculus castaneus subspecies and a wild-derived strain) exhibited relatively low levels of DNA adduct formation and bulk histone modifications. Because changes in adduct formation and bulk histone modifications do not specify which loci in the genome are affected, the mechanism behind these strain-specific differences is unknown.

Here, we sought to understand how genetic divergence influences the response to and consequences of chemical exposure. We therefore studied CAST/EiJ and C57BL/6J strain-specific differences in DNA adduct formation, messenger RNA (mRNA) expression, microRNA (miRNA) expression, and chromatin accessibility in lung tissue from mice exposed through inhalation to 1,3butadiene.

Materials and Methods

Animals and 1,3-Butadiene Exposure

Male C57BL/6J and CAST/EiJ mice (Jackson Laboratory), approximately 10 wk old at time of exposure, were housed in sterilized cages in a temperature-controlled (24[degrees]C) room with a 12/12-h light/dark cycle and were given ad libitum access to purified water and NIH-31 pelleted diet (Purina Mills). …

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