Genetic effects of exocyclic DNA adducts in vivo: heritable genetic damage in comparison with loss of heterozygosity in somatic cells

Etheno adducts are promutagenic lesions which generate point mutations, deletions, homologous recombination and gross structural DNA aberrations. High ratios of chromosome loss to forward mutations characterize vinyl bromide, vinyl chloride, ethyl carbamate, vinyl carbamate and its epoxide as effective clastogens in postmeiotic germ cells of Drosophila melanogaster. Of the mutants induced by vinyl carbamate at the vermilion gene, 68% were intra-locus or multi-locus deletions. In view of the far-reaching concordance between mutation spectra in mice and Drosophila observed in specific-locus tests with genotoxic agents, etheno bases are expected to generate mainly deletions in male mammals in the postmeiotic germ-cell stages. Twenty-two of 23 base substitutions induced in the vermilion gene after treatment of postmeiotic stages with vinyl carbamate or vinyl bromide fall into four categories of mutations expected from etheno bases: GC-->AT, AT-->GC, GC-->TA and AT-->TA base-pair changes. These types of point mutations occurred in mutated proto-oncogenes of tumours induced in rodents by vinyl chloride, ethyl carbamate or their metabolites. Of interest is the ability of vinyl carbamate to produce persistent lesions in otherwise highly repair-active premeiotic cells of Drosophila, leading to mutations of yet unknown nature. Etheno bases are also potent pro-clastogenic lesions in somatic cells in vivo. Strongly positive responses were reported for ethyl carbamate and vinyl carbamate in assays for micronucleus formation in mouse bone marrow and in the Drosophila white+/white eye mosaic test. Loss of heterozygosity in somatic cells of Drosophila was due primarily to ring-X chromosome loss, followed by homologous mitotic recombination. Particularly striking is the near failure of ethyl carbamate and vinyl carbamate to generate significant frequencies of intrachromosomal recombination. The overall genetic activity profiles of etheno adduct-forming chemicals in mice and in Drosophila support the hypothesis that vinyl carbamate is the proximate mutagen of ethyl carbamate, and vinyl carbamate epoxide is the ultimate electrophilic mutagen and carcinogen.