Mouse teratogenesis, like many biomedical sciences, has numerous instances where strain differences are well documented. Previously, in a majority of cases, these genotype-based differences were reported without a systemic approach for determining the factors causing the variability in response. This proposal suggests a genetic approach to characterizing the difference between the C57BL/6N and the SWV strains to cadmium-induced postaxial forelimb ectrodactyly (missing digits). The C57BL/6 mouse is highly sensitive to this defect while the SWV mouse at the same dose is totally resistant. It is suggested that the use of polymorphic micro satellite markers to perform a whole genome scan or quantitative trait locus analysis will identify chromosomal loci representative of specific genes responsible for this teratogenic strain difference. Two subsequent genome scans will be performed for teratogenic outcomes with a similar strain response. One with the same teratogen (cadmium) at a different gestational time and one in which a different agent (all-trans-retinoic acid) induces the same malformation. The goal of these latter genome scans is to determine to what extent the genes responsible for the common strain difference are the same. Experiments will be performed to determine if cadmium gets to the embryo or placenta to a greater extent in the sensitive strain, and whether the strains differ in terms of metallothionein, a cadmium-binding protein. Congenic mice will be produced and then bred to make polycongenics to examine the interaction of genes in strain susceptibility. Two different genes that are thought to be important in cadmium-sensitivity to teratogenesis, cdm and a chromosome 6 locus labeled Cadfar, will be mapped to specific locations in the genome as a prelude to cloning these genes. An additive oligogenic model involving nine genes for the induction of the forelimb defect has been proposed.
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