A search for latent chromosome instabilities in mice

Abstract

Specific-locus studies have shown chlorambucil (CHL) and bleomycin (BLE) to be mutagenic in mouse oocytes, almost doubling the number of chemicals previously known to induce mutations in females. The overall CHL-induced mutation rate in oocytes is, however, one order of magnitude below that for male meiotic and postmeiotic stages, and only 150 that for early spermatids. For BLE, no specific-locus data for males are available for comparison, but the chemical had earlier been found negative for dominant-lethal induction in males. Both BLE and CHL were significantly mutagenic only in mature and maturing oocytes. In keeping with an earlier report, BLE produced a high incidence of dominant lethals in these stages. CHL failed to induce dominant lethals, indicating that for mature and maturing oocytes, in contrast with results for males, sensitivity to dominant-lethal mutations is not a prerequisite for induction of specific-locus mutations. Exposure of immature oocytes to either BLE or CHL produced neither dominant lethals nor significant induction of specific-locus mutations; however, CHL gave evidence of killing immature oocytes. By contrast, BLE, which has been considered a radiomimetic chemical, does not appear to kill immature oocytes and thus differs markedly from radiation exposures equivalent for dominant-lethal induction. Therefore, the failure to recover specific-locus mutations cannot be ascribed to cell selection resulting from oocyte killing, as has sometimes been done for radiation. Adding results on the nature of the CHL- and BLE-induced mutations to prior information, the estimated minimum proportion of large DNA lesions induced in oocytes by chemicals becomes 35.3%, significantly different from the corresponding figure (∼ 70%) for radiations. For chemical treatments, the oocyte proportion is highly significantly above the 3.6% induced in spermatogonia, but only on the borderline of statistically significant difference from that induced in postspermatogonial stages.