The effects of methylnitrosourea (MNU) on the development of preimplantation mouse embryos were investigated in this study. ICR mice were treated intraperitoneally with single doses of 10, 20, and 30 mg MNU/kg body wt on day 0, 1, 2, or 3 of pregnancy. The uterine contents were examined on day 18 of pregnancy. The fetuses were examined for external and skeletal abnormalities. No significant differences were observed in the number of implantation sites between all the MNU-treated groups and controls. MNU treatment on day 2 or 3 of pregnancy caused dose-dependent significant increases in the incidence of abnormal fetuses over the control level, while treatment on day 0 or 1 failed to cause an increase of abnormalities. Cleft palate, exencephalus, and malformed vertebrae were the most common types of abnormalities. In the embryo transfer experiments, the frequency of fetal abnormalities induced when embryos were transferred from MNU-treated females to untreated pseudopregnant females was significantly higher than that induced when embryos were transferred from untreated females to MNU-treated or untreated pseudopregnant females. The results in the present study confirm and extend the previously proposed hypothesis that the direct effects of MNU on preimplantation embryos make a significant contribution to the induction of fetal malformations.
Ethylnitrosourea (ENU) was i.p. injected into ICR female mice at 25 or 50 mg/kg on day 10 of gestation, and male newborns treated with ENU at the embryonic stage were obtained. The treated males were aged for 10 weeks and then mated to untreated females of the same strain. The male germ cells used in the copulation correspond to primordial germ cells (PGC) at the time of ENU treatment. The F1 offspring were sampled as fetuses on day 18 of gestation and inspected for external and skeletal malformations. Evidence of F1 teratogenesis due to the mutagenized PGC was obtained when the fetuses from the males treated with 25 mg ENU/kg were inspected the frequencies of skeletally malformed fetuses in the ENU-treated series and the control being, respectively, 1.0% (14/1,360) and 0.3% (3/1,017). The fetuses from 50 mg/kg-treated males did not show a significant increase in malformations, most probably reflecting a high vulnerability of PGC to the killing effect of ENU. The findings in this study suggest that germ cell stage at PGC is at risk for the induction of congenital malformations by environmental chemicals.
The sensitive period and the dose‐response characteristics for dexametha‐sone‐induced cleft palate and palatal slit in rats were examined. Pregnant rats were injected subcutaneously with dexamethasone in a single dose of 2–6 mg/kg on one day between day 8 and 16 of the gestational period or once each day for two successive days (days 14 and 15 of gestation). All animals were euthanized on day 20 of gestation and the palatal condition of their fetuses was inspected after fixation under a dissecting microscope. The sensitive stage of palatal slit and cleft palate induction was determined and the dose‐response relationship was analyzed by the log‐probit transformation method. No maternal lethality was elicited in any of the treatment groups. High frequencies of palatal slit and cleft palate were induced when dexamethasone was administered as a single dose on any individual day from day 12 to day 14 of gestation. Omphalocele and general edema were also found to be significantly more frequent in the high‐dose group treated on days 12–14 of gestation. All groups treated showed a reduction in fetal body weight. The response data for palatal slit and cleft palate after administration of dexamethasone fitted to similar linear regression slopes, suggesting a similarity in the underlying mechanisms for palatal slit and cleft palate induction in rats. ED50 values were 3.48 mg/kg for palatal slit and 6.64 mg/kg for cleft palate. These findings indicate that dexamethasone treatment is effective in inducing palatal slit and cleft palate in rats, as well as in mice. Key words: glucocorticoid, dexamethasone, palatal slit, cleft palate, sensitive stage, doseresponse, rats
A single dose of methylnitrosourea (MNU, 25–100 mg/kg) was injected intraperitoneally into ICR strain male mice. The males were mated to untreated females of the same strain on days 1–21 and 64–80 after the treatment. On day 18 of pregnancy, the fetuses were examined for external and skeletal abnormalities. MNU treatment of paternal germ cells caused significant increases in the incidence of abnormal fetuses over the control level. The induction rate per live fetus per unit dose in mg/kg by treating spermatogonial stem cells was estimated to be 3.0 × 10−4, which is quite similar to the rate previously estimated for the same endpoint at the same germ cell stage with the fractionated doses of MNU (daily doses at 5–25 mg/kg for 5 days). Cleft palate and dwarfism were the most frequent external abnormalities in the MNU‐treated and the control series. Malformed ribs was the most frequent skeletal abnormality in the treated series. It was concluded that congenital malformations induced after treating male mice with a single dose of MNU were quantitatively and qualitatively similar to those induced after treating male mice with the fractionated doses of MNU.
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