Discovery of a Mutagenically Unique Chemical (November 1999)

Although the genetic effects of chemicals are generally greater in male than in female mice, earlier mutagenesis studies at Oak Ridge had suggested that there might be a small group of compounds that are female-specific, i.e., negative in males. One of these chemicals, Bleomycin, was recently investigated more extensively, and while it turned out not to be female-specific (i.e., it did produce specific-locus mutations in males), its pattern of effect in different germ-cell stages was found to be unique, differing from those of all other chemicals heretofore studied.

In the males of all mammals, spermatogonia are the constantly dividing cells that produce those other cells which undergo specialized final divisions and differentiation ultimately resulting in sperm. Only a few of the numerous chemicals that are mutagenic in postspermatogonial stages have yielded positive results in spermatogonia, and even in these few cases, the mutation rate in the former stages has usually been higher. By contrast, Bleomycin is mutagenic primarily, and perhaps exclusively, in spermatogonia. When the nature, as well as the frequency, of mutations is considered, Bleomycin is also unique in producing deletions, while other chemicals produce much smaller (primarily intragenic) DNA lesions in spermatogonia than they do in postspermatogonial stages. The difference is particularly striking when Bleomycin is compared with ENU (ethylnitrosourea), a chemical that has an unusually high spermatogonial mutation rate but produces almost exclusively point mutations.

Thus, while BLE is not female-specific, as had been suggested, it is distinguished in several other ways. Its uniqueness lies in its germ-cell-stage specificity (positive in spermatogonia but not in postspermatogonial stages), and in the fact that the nature of the mutations (primarily deletions) is atypical for the responding germ-cell stages. (Funding: DOE-OBER; Contact: Liane Russell, 574-0860 or russelllb@ornl.gov)