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MEDICAL SCIENCES
Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis
*Department of Environmental Health and the Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056; and Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA and approved January 12, 2005 (received for review August 23, 2004)
Testicular necrosis is a sensitive endpoint for cadmium (Cd2+, Cd) toxicity across all species tested. Resistance to Cd-induced testicular damage is a recessive trait assigned to the Cdm locus on mouse chromosome 3. We first narrowed the Cdm-gene-containing region to 880 kb. SNP analysis of this region from two sensitive and two resistant inbred strains demonstrated a 400-kb haplotype block consistent with the Cd-induced toxicity phenotype; in this region is the Slc39a8 gene encoding a member of the solute-carrier superfamily. Slc39a8 encodes SLC39A8 (ZIP8), whose homologs in plant and yeast are putative zinc transporters. We show here that ZRT-, IRT-like protein (ZIP)8 expression in cultured mouse fetal fibroblasts leads to a >10-fold increase in the rate of intracellular Cd influx and accumulation and 30-fold increase in sensitivity to Cd-induced cell death. The complete ZIP8 mRNA and intron-exon splice junctions have no nucleotide differences between two sensitive and two resistant strains of mice; by using situ hybridization, we found that ZIP8 mRNA is prominent in the vascular endothelial cells of the testis of the sensitive strains of mice but absent in these cells of resistant strains. Slc39a8 is therefore the Cdm gene, defining sensitivity to Cd toxicity specifically in vascular endothelial cells of the testis.
metal influx | vascular endothelial cells | solute carrier gene superfamily | in situ hybridization
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: cM, centimorgan; HA, hemagglutinin; LUC, luciferase; rv, retrovirus; SLC, solute-carrier; ZIP, ZRT-, IRT-like protein.
T.P.D. and L.H. contributed equally to this work.
To whom correspondence should be addressed. E-mail: dan.nebert{at}uc.edu.
© 2005 by The National Academy of Sciences of the USA
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