Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis

Cadmium (Cd++) is a widespread environmental pollutant and classified as an IARC 'Category I' human carcinogen, Cd++ can also cause severe renal toxic ity and may be involved clinically in cardiovascular disease and osteoporos is. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data ex ist, Resistance to cadmium-induced testicular damage was reported in 1973 t o be associated with a single major recessive gene, named Cdm, which has no w been localized to mouse chromosome (Chr) 3, Using polymorphic microsatell ite markers and semiquantitative histological parameters, we have corrobora ted the original 1973 data concerning mendelian inheritance and have furthe r refined the region containing the Cdm gene from more than 24 cM to 0.64 c M (estimated 40-80 genes), We phenotyped 26 recombinant inbred lines genera ted from C57BL/6] (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, a nd determined that the Cdm gene maps between microsatellite markers D3Mit11 0 and D3Mit255, Although toxicity to numerous heavy metals is well known, v irtually no molecular mechanisms have yet been uncovered either in humans o r laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifyin g and characterizing, for the first time, a major mammalian gene responsibl e for susceptibility to diseases caused by heavy metal toxicity. Pharmacoge netics 10:141-151 (C) 2000 Lippincott Williams & Wilkins.