Discovery of Gene Responsible for Cadmium Transport in Mice.

Dalton TP, He L, Wang B, Miller ML, Jin L, Stringer KF, Chang X, Baxter CS, Nebert DW. 2005. Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc Natl Acad Sci USA 102:3401-3406.

Cadmium is a toxic and carcinogenic nonessential metal released from mining, smelting, battery manufacturing, and coal burning. Among other routes, humans are exposed to cadmium by smoking cigarettes and eating contaminated seafood or plants grown in contaminated soil. Environmental levels of cadmium have risen along with advances in industrialization, and the role of cadmium in human disease is therefore of increasing concern. Now NIEHS grantee Daniel W. Nebert and colleagues have discovered a gene responsible for the transport of cadmium in mice, which hints at a target that could be employed to prevent the toxic effects of cadmium in humans.

Cadmium is readily absorbed through the lungs, intestines, and skin, and accumulates in the kidneys. The toxic mechanisms of cadmium are not well understood, but it is known to act intracellularly, causing damage particularly to the lungs, kidneys, bone, central nervous system, and reproductive tissues. Cadmium is also known to cause abnormalities in the developing embryo. The testis is a sensitive marker of cadmium exposure; cadmium-induced testicular necrosis is common across all studied animal species having testes. Exposure to this metal is a significant problem in many developing countries, where undernourishment and iron deficiency are associated with increased cadmium toxicity.

Nebert and colleagues administered low doses of cadmium to mice and demonstrated that the SLC39A8 (ZIP8) protein, coded by the Slc39a8 gene, transported cadmium to the testis, causing vascular endothelial cell injury and subsequent testicular tissue death. Using in vitro models, the research team found that vascular endothelial cells from cadmium-insensitive mice did not accumulate ZIP8 mRNA, whereas cells from cadmium-sensitive mice did. The team suggests, therefore, that loss of vascular endothelial ZIP8 mRNA expression in the insensitive strains protected the mice's testes against cadmium toxicity.

Nebert and colleagues suspect that ZIP8 is normally responsible for the transport of other metals such as manganese and zinc, and that cadmium "participates as an opportunistic hitchhiker." Because humans carry the analogous SLC39A8 gene, these findings have identified a potential target for exploration in preventing the toxic effects of cadmium in exposed people.