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

Abstract

The mutagenic potential and mutational spectra of butadiene (BD), 1,2-epoxybutene (EB), and diepoxybutane (DEB) were determined in splenic T cells from exposed B6C3F1 mice. Mice exposed by inhalation to 625 p.p.m. BD for 2 weeks displayed an average hprt- mutation frequency of 6.2 x 10(-6) compared to 1.2 x 10(-6) in controls. Mice were also given three daily i.p. doses of 60, 80 and 100 mg EB/kg or 7, 14 and 21 mg DEB/kg. Average hprt- frequencies of 5.4 x 10(-6), 4.1 x 10(-6) and 8.6 x 10(-6) were seen in the EB groups, respectively, while average frequencies of 4.6 x 10(-6), 9.4 x 10(-6) and 13 x 10(-6) were seen in the DEB groups. DNA sequencing revealed that approximately half of the mutations induced in vivo by BD, EB and DEB were frameshift mutations. A +1 frameshift 'hotspot' in six consecutive guanine bases in exon 3 was observed with all three compounds. The remaining mutations produced by BD, EB and DEB were transition and transversion mutations at both AT and GC base pairs. Base pair substitutions induced by BD were biased in favor of mutation at AT base pairs. The mutational spectra produced by BD, EB and DEB were very similar to that observed previously with ethylene oxide, suggesting that these epoxide agents may be working through a similar mutagenic mechanism.

Assessment of 1,3-Butadiene Exposure in Polymer Production Workers Using HPRT Mutations in Lymphocytes as a Biomarker

“…A 2-fold, but nonsignificant, increase in the proportion of base substitution mutations at A-T base pairs was observed, and a higher proportion of frameshift mutations was seen in the exposed group (p < 0.05) (35). These observations are consistent with the types of mutations induced by BD and DEB in cell culture (16,37) and in animals (11,12,17,38). The observation of this pattern of mutation supports the idea that at least some of the mutations observed in these workers are attributable to the mutagenic activity of butadiene.…”

“…At BD doses as low as 50 ppm for 5 days, micronuclei were induced in both bone marrow and peripheral blood erythrocytes (10). Exposure of mice to BD doses as low as 20 ppm for 4 weeks induced gene mutations at the HPRT locus in spleen lymphocytes (11,12) and in thymic lymphocytes (12). In transgenic mice, exposures to 62.5 ppm of BD for 4 weeks resulted in increased frequencies of mutations at the lacI locus in bone marrow cells (13).…”

Structure of the 1,4-Bis(2‘-deoxyadenosin-N6-yl)-2S,3S-butanediol Intrastrand DNA Cross-Link Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence

“…These experiments revealed transitions and transversions at both G•C and A•T sites, suggesting the presence of both dG and dA adducts arising from BDO 2 . They also revealed the presence of significant levels of deletion mutants, consistent with the presence of DNA cross-links (37,102,103).…”

Characterization of 1,2,3,4-Diepoxybutane−2‘-Deoxyguanosine Cross-Linking Products Formed at Physiological and Nonphysiological Conditions

“…DEB is also ∼50-fold more effective than EB at inducing sister chromatid exchanges in human lymphocytes (24). Whereas both EB and DEB induce DNA base substitutions at GC and AT base pairs and frameshift mutations, only DEB causes large numbers of partial deletions (23,25,26). …”