Male‐Mediated Developmental Toxicity: Enhanced Susceptibility to Induced Teratogenesis in the Offspring of Male Mice Treated with Ethylnitrosourea

Abstract

Male ICR strain mice were injected intraperitoneally with ENU at 50 mg/kg daily for 5 days and mated to untreated virgin females of the same strain on days 64-80 after the last dose. Copulations during this period involved spermatogonial stem cells at the time of the last treatment. Subsequently, copulated females were injected intraperitoneally with ENU at 25-100 mg/kg on day 8 of gestation, at 50-200 mg/kg on day 12 of gestation or injected subcutaneously with triamcinolone acetonide at 1.25-10 m g k g on day 12 of gestation. The uterine contents were examined on day 18 of gestation. Fetuses of dams treated on day 8 of gestation were inspected for external and skeletal abnormalities, and those of dams treated on day 12 were inspected for external abnormalities including cleft palate. Frequencies of microphthalmia and cleft palate in the group in which females mated with ENU-treated males were treated with ENU at 50 mg/kg on day 8 of gestation or with ENU at 50 mg/kg on day 12 of gestation, respectively, were significantly higher than those in the group in which females mated with phosphate buffer-treated males were treated with ENU at 50 mgkg on day 8 or at 50 mg/kg on day 12. No significant increases in the frequency of cleft palate were observed in the groups in which females mated with ENUtreated males were treated with triamcinolone acetonide on day I : ! of gestation as compared with groups in which females mated with phosphate buffer-treated males were treated with triamcinolone acetonide on day 12 of gestation. These results suggested the increased susceptibility to induced teratogenesis (congenital malformations induced by exposure of embryo/fetus during gestation) in the offspring derived from paternal germ cells treated with the potent mutagen ENU, but not the non-mutagen triamcinolone acetonide.