Gene-teratogen interaction in insulin-induced mouse exencephaly.
Heterozygotes for the mutant genes crooked (Cd) or rib fusion (Rf), crossed to either strain A/J or SWV produce mutant F1 offspring with minor skeletal defects. If the mothers are also treated with teratogenic doses of insulin, the mutant F1 heterozygotes develop exencephaly significantly more often than nonmutants. That the heterozygous mutant gene increased the embryo's sensitivity to insulin-induced exencephaly was also demonstrated by dose-response curves. For A/J and SWV crosses, probit regression lines for the mutant crosses were fitted to common slopes that were significantly different from those of probit regression lines for the nonmutant crosses. The nonparallelism of the mutant versus the nonmutant groups of lines indicated the presence of a gene-teratogen interaction. Early exencephalic embryos showed delayed turning in one-third of treated mutant crosses and less than a quarter of treated nonmutant crosses. Another one-third of exencephalics, in treated mutant crosses only, had abnormally twisted hindbodies and appeared to be phenocopies of untreated homozygotes. Insulin treatment significantly slowed the rates of embryo turning and neural tube closure but did not affect somite number. Histologically, insulin did not appear to cause cell death, and mitotic index of mesoderm was unaffected. Only exencephalic embryos showed a significant reduction in neurectoderm mitotic index. Insulin caused a reduction in neurectoderm cell proliferation, delay in pattern of turning and delay in neural tube closure to the greatest extent in exencephalic embryos. It was postulated that extensive delays in turning could provide a mechanical basis for the failure of the neural tube to close.
D000014:Abnormalities, Drug-Induced / Q000235:genetics*; D000818:Animals; D003433:Crosses, Genetic; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D005327:Fetal Resorption / Q000209:etiology; D007328:Insulin / Q000633:toxicity*; D051379:Mice; D008817:Mice, Mutant Strains / Q000196:embryology*; D008940:Mitotic Index / Q000187:drug effects; D009154:Mutation; D009436:Neural Tube Defects / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D011247:Pregnancy; D012886:Skull / Q000002:abnormalities*; D013997:Time Factors
D007328:Insulin