1,3-butadiene (BD) is a volatile organic pollutant. Upon inhalation, it is metabolically activated to reactive epoxides which alkylate genomic DNA and form potentially mu-tagenic monoadducts and DNA-DNA crosslinks including N7-(1-hydroxyl-3-buten-1-yl)guanine (EB-GII) and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD). While metabolic activation resulting in mutagenicity is a well-established mode of action for 1,3-butadiene, characterization of the extent of interindividual variability in response to BD exposure is a gap in our knowledge. Previous studies showed that population-wide mouse models can be used to evaluate variability in 1,3-butadiene DNA adducts; therefore, we hypothesized that this approach can be used to also study variability in formation and loss of BD-DNA adducts across tissues and between sexes. To test this hypothesis, female and male mice from genetically diverse 5 Collaborative Cross (CC) strains were exposed to filtered air or 1,3-butadiene (600 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Some animals were kept for 2 additional weeks after exposure to study DNA adduct persistence. EB-GII and bis-N7G-BD adducts were quantified in liver, lung and kidney using established isotope dilution ESI-MS/MS methods. We observed strain- and sex-specific ef-fects on both accumulation and loss of both adducts indicating that both factors play important roles in mutagenicity of 1,3-butadiene. In addition, we quantified the intra-species variability for each adduct and found that for most tissues/adducts, variability values across strains were modest compared to default uncertainty factors.
Moran et al. (Fri,) studied this question.