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Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis
Timothy P Dalton1, Lei He, Bin Wang
1Department of Environmental Health and the Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Abstract:
Testicular necrosis is a sensitive endpoint for cadmium (Cd(2+), 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.
Insights
Cadmium (Cd) toxicity causes testicular necrosis, a sensitivity linked to the Slc39a8 gene. This gene, encoding the ZIP8 transporter, dictates Cd sensitivity in testicular vascular endothelial cells, explaining strain differences in toxicity.
Area of Science:
- Toxicology
- Genetics
- Molecular Biology
Background:
- Testicular necrosis is a key indicator of cadmium toxicity.
- Genetic resistance to cadmium-induced testicular damage is a recessive trait linked to the Cdm locus on mouse chromosome 3.
Purpose of the Study:
- To identify the specific gene responsible for cadmium resistance/sensitivity in mouse testes.
- To elucidate the mechanism by which cadmium induces testicular toxicity.
Main Methods:
- Fine mapping of the Cdm locus and haplotype analysis.
- Gene expression analysis using in situ hybridization.
- Functional studies of Slc39a8 (ZIP8) in cultured cells.
Main Results:
- The Slc39a8 gene, encoding the ZIP8 transporter, was identified within the Cdm locus.
- ZIP8 expression significantly increased intracellular cadmium influx, accumulation, and sensitivity to cadmium-induced cell death.
- ZIP8 mRNA was found in testicular vascular endothelial cells of cadmium-sensitive mice but not in resistant strains.
Conclusions:
- Slc39a8 is the Cdm gene, determining sensitivity to cadmium toxicity.
- Cadmium sensitivity is specifically mediated by ZIP8 expression in testicular vascular endothelial cells.
