CHLORAMBUCIL AND BLEOMYCIN INDUCE MUTATIONS IN THE SPECIFIC-LOCUS TEST IN FEMALE MICE

Specific-locus studies have shown chlorambucil (CHL) and bleomycin (BL E) to be mutagenic in mouse oocytes, almost doubling the number of che micals previously known to induce mutations in females. The overall CH L-induced mutation rate in oocytes is, however, one order of magnitude below that for male meiotic and postmeiotic stages, and only 1/50 tha t for early spermatids. For BLE, no specific-locus data for males are available for comparison, but the chemical had earlier been found nega tive for dominant-lethal induction in males. Both BLE and CHL were sig nificantly mutagenic only in mature and maturing oocytes. In keeping w ith an earlier report, BLE produced a high incidence of dominant letha ls in these stages. CHL failed to induce dominant lethals, indicating that for mature and maturing oocytes, in contrast with results for mal es, sensitivity to dominant-lethal mutations is not a prerequisite for induction of specific-locus mutations. Exposure of immature oocytes t o either BLE or CHL produced neither dominant lethals nor significant induction of specific-locus mutations; however, CHL gave evidence of k illing immature oocytes. By contrast, BLE, which has been considered a radiomimetic chemical, does not appear to kill immature oocytes and t hus differs markedly from radiation exposures equivalent for dominant- lethal induction. Therefore, the failure to recover specific-locus mut ations cannot be ascribed to cell selection resulting from oocyte kill ing, as has sometimes been done for radiation. Adding results on the n ature of the CHL- and BLE-induced mutations to prior information, the estimated minimum proportion of large DNA lesions induced in oocytes b y chemicals becomes 35.3%, significantly different from the correspond ing figure (similar to 70%) for radiations. For chemical treatments, t he oocyte proportion is highly significantly above the 3.6% induced in spermatogonia, but only on the borderline of statistically significan t difference from that induced in postspermatogonial stages.