Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line.

  title={Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line.},
  author={Bin Wang and Scott N. Schneider and Nadine Dragin and Kuppuswami Girijashanker and Timothy P. Dalton and Lei He and Marian L Miller and Keith F. Stringer and Manoocher Soleimani and Douglas D. Richardson and Daniel W. Nebert},
  journal={American journal of physiology. Cell physiology},
  volume={292 4},
Resistance to cadmium (Cd)-induced testicular necrosis is an autosomal recessive trait defined as the Cdm locus. Using positional cloning, we previously identified the Slc39a8 (encoding an apical-surface ZIP8 transporter protein) as the gene most likely responsible for the phenotype. In situ hybridization revealed that endothelial cells of the testis vasculature express high ZIP8 levels in two sensitive inbred mouse strains and negligible amounts in two resistant strains. In the present study… 

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Discovery of ZIP transporters that participate in cadmium damage to testis and kidney.

Generation of a Slc39a8 hypomorph mouse: markedly decreased ZIP8 Zn²⁺/(HCO₃⁻)₂ transporter expression.

FK506, a calcineurin inhibitor, prevents cadmium-induced testicular toxicity in mice.

The protection afforded by FK506, found by the current study, indicated that CN is likely to be important in the mechanism of cadmium toxicity in the testis and possibly other organs.

Oral Cadmium in Mice Carrying 5 Versus 2 Copies of the Slc39a8 Gene

At the daily oral Cd exposures chosen for this study, 5 versus 2 Slc39a8 gene copies result in no differences in Cd toxicity but do cause differences in tissue-specific content of Cd, zinc, manganese, calcium, iron, and copper.

Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats

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Comparing gene expression during cadmium uptake and distribution: untreated versus oral Cd-treated wild-type and ZIP14 knockout mice.

Over 10 days of oral Cd, a bimodal response was seen for Cd content in PSI and for various mRNAs; initially, acute effects caused by the toxic metal; subsequently, the up- or down-regulation of important genes presumably to combat the sustained adversity.

A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity

Results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure.

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

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The role of ZIP8 down‐regulation in cadmium‐resistant metallothionein‐null cells

The data suggest that ZIP8 plays an important role in cellular uptake of cadmium, and may be conferred primarily by the down‐regulation of ZIP8 in A7 and B5 cells.



Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis.

  • T. DaltonLei He D. Nebert
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
It is shown 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.

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

Identification and characterization of the mouse Cdm gene should enhance the understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavyMetal toxicity.

Genetic Analysis of Resistance to Cadmium-Induced Testicular Damage in Mice

  • B. TaylorH. HeinigerH. Meier
  • Biology
    Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine
  • 1973
Resistance to cadmium-induced testicular necrosis is determined by a single autosomal recessive gene (cdm) in inbred mice, which is not closely linked with several gene loci.

ZIP8, Member of the Solute-Carrier-39 (SLC39) Metal-Transporter Family: Characterization of Transporter Properties

The present study showed that cadmium uptake operated maximally at pH 7.5 and a temperature of 37°C and was inhibited by cyanide, and that Cadmium is a rogue hitchhiker displacing manganese to cause cadMium-associated disease.

Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery.

It is postulate that CYP1A1 and CYp1A2 might have overlapping substrate specificity for metabolism of the EL, such that basal CYP 1A2 in the liver can compensate for the loss of CYP2A1.

Expression of the iron transporter DMT1 in kidney from normal and anemic mk mice.

DMT1 may act as a re-uptake system for divalent cations at the brush border of kidney proximal tubules and a pathological mutation at DMT1 affects targeting/expression of the protein in the kidney is suggested.

Distribution of cadmium 109 and zinc 65 in mice of inbred strains.

Mice of CBA/J and DBA/1J strains, which are known to be susceptible to cadmium-induced testicular necrobiosis, exhibited a greater uptake of 109Cd by the testes than cadMium-resistant strains C57BL/6J and BALB/cJ.

Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex.

Data indicate that Cd-induced renal injury is not necessarily mediated through the CdMT complex and that MT is an important intracellular protein in protecting against chronic Cd nephrotoxicity.

Light-microscopic and immunopathologic observations on cadmium chloride-induced injury in mature rat testis.

Evidence supports the enzymeinhibition concept, but the conclusion that spermiogenic epithelium is the primary target is open to question since it has been shown by autoradiography that the concentration of cadmium is lower in seminiferous tubules than in the interstitium of the testis, which indicates that the relation between concentration and damage is unclear.