DEPENDENCE OF ACETAZOLAMIDE TERATOGENESIS ON FETAL AND NOT MATERNAL GENOTYPES

This study assesses the relative contributions of dam and conceptus to sensitivity to acetazolamide teratogenesis in an in vivo mouse model. Reciprocal F1 outcrosses were made between mice resistant to the teratogenic effects of acetazolamide (SWV) and the susceptible C57BL/6JBk line. Female F1 progeny were back-crossed either to C57BL or to SWV males. The F1 outcross resulted in identical fetuses developing in genetically different uterine environments. In the backcrosses, genetically identical hybrid dams were gestating genetically different populations of segregating fetuses. In both F1 outcrosses and backcrosses, as well as in pure-line controls, dams were treated on day 9 of gestation by subcutaneous injection of acetazolamide (ACZM) at a dose level of 1500 mg/kg, or identical volume of the vehicle. The principal abnormality seen was right front limb ectrodactyly. Among pure-line matings, SWV produced no ectrodactyly, but 68% of C57BL showed this defect. Only two cases were seen in outcross of C57BL females to SWV males, and one litter produced three ectrodactylous fetuses in the reciprocal cross. A highly significant increase in ectrodactyly was seen in treated backcrosses to C57BL relative to backcrosses to SWV. Thus, a litter in which most of the genes segregating are from a susceptible line will show major increases in susceptibility, despite being in a heterotic and somewhat resistant uterine environment, whereas the susceptible C57BL uterine environment does not result in significant abnormality in heterozygous resistant fetuses. These results unequivocally demonstrate that it is the genotype of the conceptus, and not the genotype of the dam, nor heterosis, that determines sensitivity to acetazolamide teratogenesis. They further suggest that this genetic approach may be useful in determining the relative contribution of dam and conceptus for other teratogens.