Mutagenicity of butadiene and its epoxide metabolites: II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice

The mutagenic potential and mutational spectra of butadiene(BD), 1,2-epoxybutene (EB), and diepoxybutane (DEB) were determinedin splenic T cells from exposed B6C3F1 mice. Mice exposed byinhalation to 625 p.p.m. BD for 2 weeks displayed an averagehprt^– mutation frequency of 6.2 x10^–6 compared to1.2x10^–6 in controls. Mice were also given three dailyi.p. doses of 60, 80 and 100 mg EB/kg or 7, 14 and 21 mg DEB/kg.Average hprt^– frequencies of 5.4x10^–6, 4.lx10^–6and 8.6x10^–6 were seen in the EB groups, respectively,while average frequencies of 4.6x10^–6, 9.4x10^–6and 13x10^–6 were seen in the DEB groups. DNA sequencingrevealed that approximately half of the mutations induced invivo by BD, EB and DEB were frameshift mutations. A +1 frameshift‘hotspot’ in six consecutive guanine bases in exon3 was observed with all three compounds. The remaining mutationsproduced by BD, EB and DEB were transition and transversionmutations at both AT and GC base pairs. Base pair substitutionsinduced by BD were biased in favor of mutation at AT base pairs.The mutational spectra produced by BD, EB and DEB were verysimilar to that observed previously with ethylene oxide, suggestingthat these epoxide agents may be working through a similar mutagenicmechanism.