Induction of chromosome-specific aneuploidy and micronuclei in human lymphocytes by metabolites of 1,3-butadiene

1,3-Butadiene is a carcinogen in rodents, but its potential carcinogenicityto humans remains controversial. Numerous studies have shown that butadieneand its metabolites cause sister chromatid exchanges in vitro and in vivo.To test for other types of genotoxicity, the micronucleus assay andfluorescence in situ hybridization (FISH) have been used to detectchromosome damage in human lymphocytes caused by two reactive metabolitesof butadiene, diepoxybutane (DEB) and monoepoxybutene (MEB). DEB (0.5-5.0microM) significantly increased micronucleus formation 4- to 6-fold (P<0.01) and MEB (1-500 microM) by 2- to 4-fold (P <0.01) over controllevels. The ability of DEB and MEB to induce aneuploidy of chromosomes 7,8, 12, and X was examined using dual-color FISH in both interphase andmetaphase cells. These chromosomes were chosen because of their involvementin leukemogenesis. Both DEB and MEB caused dose-dependent increases inhyperdiploidy of chromosomes 12 and X, but had no discernible effect onchromosomes 7 and 8. These results suggest that DEB and MEB causechromosome-specific aneuploidy in human cells. If formed in sufficientamounts, DEB and MEB may produce chromosome damage of the type found inleukemia following exposure to butadiene.