Identification of Mouse SLC39A8 as the Transporter Responsible for Cadmium-Induced Toxicity in the Testis

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 re...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-03, Vol.102 (9), p.3401-3406
Main Authors: Dalton, Timothy P., He, Lei, Wang, Bin, Miller, Marian L., Jin, Li, Stringer, Keith F., Chang, Xiaoqing, Baxter, C. Stuart, Nebert, Daniel W., Palmiter, Richard D.
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Antibodies
Base Sequence
Biological Sciences
Blotting, Northern
Blotting, Western
Cadmium - toxicity
Cation Transport Proteins - genetics
Cation Transport Proteins - metabolism
Cell lines
Cloning, Molecular
DNA Primers
DNA, Complementary
Endothelial cells
Exons
Genes
Immunohistochemistry
In Situ Hybridization
Inbred strains
Male
Medical research
Messenger RNA
Metals
Mice
Proteins
Rodents
Sertoli cells
Testes
Testis - drug effects
Testis - metabolism
Toxicity
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0406085102