Frequency of congenital defects and dominant lethals in the offspring of male mice treated with methylnitrosourea.
ICR strain male mice were injected intraperitoneally with daily doses of MNU (5-25 mg/kg) for 5 days and mated to untreated virgin females of the same strain on days 1-7, 8-14, 15-21 and 64-80 after the last dose. Copulations during these periods involve, respectively, spermatozoa, late spermatids, early spermatids, and spermatogonial stem cells at the time of the last treatment. The uterine contents were examined on day 18 of pregnancy for post-implantation losses (dominant lethality). Fetuses were examined for external and skeletal abnormalities. In contrast to the results reported for specific-locus mutations, MNU treatment of either postmeiotic cells or spermatogonial stem cells caused dose-dependent significant increases in the incidence of congenital defects and of dominant lethals over the control levels. The relative sensitivity of germ cells sampled on days 1-7, 8-21 and 64-80 to MNU-induced congenital defects was 1:1.6:2. For the induction of dominant lethals, the sensitivity ratio was 1:1.8:0.5. It is proposed that congenital defects in the offspring of mice following paternal treatment with MNU may represent mostly chromosomal rather than genic changes. Cleft palate was the most frequent of the external abnormalities, which were significantly induced in every treatment series; fused ribs were the most frequent of the skeletal abnormalities, which were significantly induced in the treatment series for spermatogonial stem cells.