Identification of a Murine Locus Conveying Susceptibility to Cadmium-induced Forelimb Malformations

The heavy metal cadmium (Cd), an environmentally ubiquitous contaminant, is a potent teratogen in mice. When administered parenterally, it induces an array of malformations that vary in scope and severity with the route, dose, time of administration, and the strain of the animal. When administered intraperitoneally on day 9.0 of gestation, 4 mg/kg cadmium chloride produces forelimb defects (predominantly ectrodactyly) in over 80% of fetuses of the C57BL/6 mouse strain, while no limb defects are observed in the identically treated SWV strain. Like other examples of strain-specific teratogenic activity, the underlying nature of the differential susceptibility remains unknown. The present study investigates the segregation of sensitivity to Cd-induced forelimb defects in crosses between C57BL/6 and SWV mice and provides evidence for the involvement of both maternal and fetal factors in the determination of defect expression. In addition, quantitative trait loci (QTL) analysis of the fetal genetic component was performed among 198 backcross progeny, utilizing a genomic linkage map of 149 informative microsatellite markers. One QTL demonstrating significant linkage to expression of the defect, designated Cadfar (cadmium-induced forelimb autopod reduction), was mapped to the distal end of chromosome 6 with a lod score of 3.1.