Bleomycin, unlike other male-mouse mutagens, is most effective in spermatogonia, inducing primarily deletions.
Dominant-lethal tests [P.D. Sudman, J.C. Rutledge, J.B. Bishop, W.M. Generoso, Bleomycin: female-specific dominant lethal effects in mice, Mutat. Res. 296 (1992) 205-217] had suggested that Bleomycin sulfate (Blenoxane), BLM, might be a female-specific mutagen. While confirming that BLM is indeed a powerful inducer of dominant-lethal mutations in females that fails to induce such mutations in postspermatogonial stages of males, we have shown in a specific-locus test that BLM is, in fact, mutagenic in males. This mutagenicity, however, is restricted to spermatogonia (stem-cell and differentiating stages), for which the specific-locus mutation rate differed significantly (P<0.008) from the historical control rate. In treated groups, dominant mutations, also, originated only in spermatogonia. With regard to mutation frequencies, this germ-cell-stage pattern is different from that for radiation and for any other chemical studied to date, except ethylnitrosourea (ENU). However, the nature of the spermatogonial specific-locus mutations differentiates BLM from ENU as well, because BLM induced primarily (or, perhaps, exclusively) multilocus deletions. Heretofore, no chemical that induced specific-locus mutations in spermatogonia did not also induce specific-locus as well as dominant-lethal mutations in postspermatogonial stages, making the dominant lethal test, up till now, predictive of male mutagenicity in general. The BLM results now demonstrate that there are chemicals that can induce specific-locus mutations in spermatogonia without testing positive in postspermatogonial stages. Thus, BLM, while not female-specific, is unique, (a) in its germ-cell-stage specificity in males, and (b) in inducing a type of mutation (deletions) that is atypical for the responding germ-cell stages (spermatogonia).
Russell
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Life Sciences Division, Oak Ridge National Laboratory, Building 9210, P.O. Box 2009, MS 8077, 37831-8077, Oak Ridge, TN, USA. russelllb@orn1.gov
Hunsicker
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PR
Kerley
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MK
Johnson
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DK
Shelby
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MD
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D005804:Genes, Lethal; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012727:Sex Characteristics; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*
D009153:Mutagens; D001761:Bleomycin; D004247:DNA