1,3-Butadiene: II. Genotoxicity profile

Abstract

1,3-Butadiene’s (BD’s) major electrophilic metabolites 1,2-epoxy-3-butene (EB), 1,2-dihydroxy-3,4-epoxybutane (EBD), and 1,2,3,4-diepoxybutane (DEB) are responsible for both its mutagenicity and carcinogenicity. EB, EBD, and DEB are DNA reactive, forming a variety of adducts. All three metabolites are genotoxic in vitro and in vivo, with relative mutagenic potencies of DEB >> EB > EBD. DEB also effectively produces gene deletions and chromosome aberrations. BD’s greater mutagenicity and carcinogenicity in mice over rats as well as its failure to induce chromosome-level mutations in vivo in rats appear to be due to greater production of DEB in mice. Concentrations of EB and DEB in vivo in humans are even lower than in rats. Although most studies of BD-exposed humans have failed to find increases in gene mutations, one group has reported positive findings. Reasons for these discordant results are examined. BD-related chromosome aberrations have never been demonstrated in humans except for the possible production of micronuclei in lymphocytes of workers exposed to extremely high levels of BD in the workplace. The relative potencies of the BD metabolites, their relative abundance in the different species, and the kinds of mutations they can induce are major considerations in BD’s overall genotoxicity profile.

Induction of DNA Damage and G2 Cell Cycle Arrest by Diepoxybutane through the Activation of the Chk1-Dependent Pathway in Mouse Germ Cells

“…34,35 These results indicated that male reproductive genotoxicity of BD may still depend on the production of potent metabolites. 10,11 Our studies showed that DEB-induced long tails in the comet assay and the increase of MN frequencies in the CBMN assay, and the upregulation of γ-H2AX expression in Western blot in GC-2 cells further confirmed such damage. Previous studies in germ cells on the effects of DEB have been restricted to DNA damage.…”

“…10 In addition to being carcinogenic in laboratory rodents and exposed workers, exposures to BD are associated with reproductive toxicity, 8 and there was evidence indicating that male reproductive genotoxicity of BD may still depend on the production of potent metabolites, corresponding to the results from carcinogenicity studies. 10,11 Previously in this study, we demonstrated the increased frequencies of MNi and nucleoplasmic bridges (NPBs) in BD-exposed workers. 12 In line with the epidemiological study, experimental studies have shown DEB to be a potent inducer of chromosome aberrations and MNi in germinal cells in vivo and in vitro.…”

“…9 There is also accumulating evidence that all three metabolites are genotoxic in vivo and in vitro, with the relative mutagenic potencies of DEB ≫ EB > EBD. 10 Experiments indicated that DEB induces not only gene mutations in different assay systems but also chromosome-level changes including aberrations, aneuploidy, and micronuclei (MNi). 10 In addition to being carcinogenic in laboratory rodents and exposed workers, exposures to BD are associated with reproductive toxicity, 8 and there was evidence indicating that male reproductive genotoxicity of BD may still depend on the production of potent metabolites, corresponding to the results from carcinogenicity studies.…”

“…10 Experiments indicated that DEB induces not only gene mutations in different assay systems but also chromosome-level changes including aberrations, aneuploidy, and micronuclei (MNi). 10 In addition to being carcinogenic in laboratory rodents and exposed workers, exposures to BD are associated with reproductive toxicity, 8 and there was evidence indicating that male reproductive genotoxicity of BD may still depend on the production of potent metabolites, corresponding to the results from carcinogenicity studies. 10,11 Previously in this study, we demonstrated the increased frequencies of MNi and nucleoplasmic bridges (NPBs) in BD-exposed workers.…”

“…12 In line with the epidemiological study, experimental studies have shown DEB to be a potent inducer of chromosome aberrations and MNi in germinal cells in vivo and in vitro. 10 Thus, it is likely that the mutagenic effect of DEB is mediated, to a large extent, by causing clastogenic damage of DNA. Generally, DNA damage activates a complex damage response pathway, namely, DNA damage response (DDR).…”