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 i ntraperitoneally on day 9.0 of gestation, 4 mg/kg cadmium chloride produces forelimb defects (predominantly ectrodactyly) in over 80% of fetuses of th e C57BL/6 mouse strain, while no limb defects are observed in the identical ly treated SWV strain, Like other examples of strain-specific teratogenic a ctivity, the underlying nature of the differential susceptibility remains u nknown. The present study investigates the segregation of sensitivity to Cd -induced forelimb defects in crosses between C57BL/6 and SWV mice and provi des evidence for the involvement of both maternal and fetal factors in the determination of defect expression. In addition, quantitative trait loci (Q TL) analysis of the fetal genetic component was performed among 198 backcro ss progeny, utilizing a genomic linkage map of 149 informative microsatelli te 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. (C) 2000 Academic Press.