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Review
, 238 (3), 250-7

Discovery of ZIP Transporters That Participate in Cadmium Damage to Testis and Kidney

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Review

Discovery of ZIP Transporters That Participate in Cadmium Damage to Testis and Kidney

Lei He et al. Toxicol Appl Pharmacol.

Abstract

It has been known for decades that cadmium (Cd) must enter the cell to cause damage, but there was no mechanism to explain genetic differences in response to Cd toxicity until 2005. Starting with the mouse Cdm locus associated with differences in Cd-induced testicular necrosis between inbred strains, a 24.6-centiMorgan region on chromosome 3 was reduced ultimately to 880 kb; in this segment is the Slc39a8 gene encoding the ZIP8 Zn(2+)/HCO(3)(-) symporter. In endothelial cells of the testis vasculature, Cd-sensitive mice exhibit high ZIP8 expression, Cd-resistant mice exhibit very low expression. A 168.7-kb bacterial artificial chromosome (BAC) from a 129S6 (Cd-sensitive) BAC library containing the Slc39a8 gene was inserted into the Cd-resistant C57BL/6J genome: Cd treatment produced testicular necrosis in BAC-transgenic BTZIP8-3 mice but not in non-transgenic littermates, thereby proving that the Slc39a8 gene is indeed the Cdm locus. Cd-induced renal failure also occurred in these BTZIP8-3 mice. Immunohistochemistry showed highly expressed ZIP8 protein in the renal proximal tubular epithelial apical surface, suggesting that ZIP8 participates in Cd-induced renal failure. Slc39a14, most closely evolutionarily related to Slc39a8, encodes differentially-spliced products ZIP14A and ZIP14B that display properties similar to ZIP8. ZIP8 in alveolar cells brings environmental Cd into the organism and ZIP14 in intestinal enterocytes carries Cd into the organism and into the hepatocyte. We believe these two transporters function endogenously as Zn(2+)/HCO(3)(-) symporters important in combating inflammation and carrying out other physiological functions; Cd is able to displace the endogenous cation, enter the cell, and produce tissue damage and disease.

Figures

Fig. 1
Fig. 1
Haplotype blocks (denoted by the “h” numbers) identified across the region of the Chr 3 Slc39a8 gene among 15 inbred mouse strains (Frazer et al., 2007). The large bold arrow signifies the genomic location (and 5′ to 3′ orientation) of our Slc39a8-containing BAC; the BAC begins at 135,396 k (just 5 kb 3′-ward of the start of haplotype block h12757). The orientations of the Nfkb1 gene (left) and small portion of the Bank1 gene (right) indicate that these two genes are located on the negative strand. ENSMUSG00000045520, LOC100039350, and LOC383923 represent putative protein-coding genes not yet identified. The bottom colored rectangles represent the specific haplotype blocks of the Cd-resistant B6 and A/J strains and Cd-sensitive D2 and 129S6 strains—across the BAC-spanning region. Segments B–E show that the same haplotype exists in all four strains. Segment A–B shows that B6 and A/J carry the same haplotype block (yellow), while a second haplotype block occurs in the D2 (green) and a third haplotype block occurs in the 129S6 strain (blue). Subtle haplotype–block differences might exist (Threadgill et al., 1997) between the 129S6/SvEvTac sub-line from which the BAC was isolated (Wang et al., 2007) and the 129S1/SvImJ sub-line resequenced by Perlegen (Frazer et al., 2007).
Fig. 2
Fig. 2
Diagram of bicarbonate reabsorption in the renal proximal tubular epithelial cell. The glomerular filtrate moves vertically down the left side of the diagram, next to the apical surface of the epithelial cell. Solute moving back into the blood across the basolateral surface is shown at right. NHE3, sodium/hydrogen exchanger-3 (encoded by SLC9A3). NBC1, sodium/bicarbonate cotransporter-4 (encoded by SLC4A4). CA II, carbonic anhydrase-2 (encoded by CA2 gene). Na,K-ATPase is shown at upper right on basolateral side. CYP27B1, mitochondrial 25-hydroxy-D3 1α-hydroxylase.
Fig. 3
Fig. 3
Nearest-neighbor joining (NNJ)-generated phylogenetic tree of the 14 mouse ZIP domains of the Slc39 gene-encoded proteins. In terms of evolution, the mouse Slc39a14 and Slc39a8 genes can be seen to be most closely related. ZIP8 and ZIP14 diverged from one another some time after the land animal–sea animal split ~425 million years ago, because the puffer fish (Takefugu rubripes) genome contains one gene having almost equal identity to both mouse genes (Girijashanker et al., 2008). The human SLC39A14 and SLC39A8 genes (not shown) are homologous to the mouse orthologs (Girijashanker et al., 2008).
Fig. 4
Fig. 4
Diagram of the anatomy of various organs important in Cd uptake. ZIP14 participates principally in the small intestine and hepatocyte; ZIP8 participates predominantly in the lung, kidney and testis; both ZIP14 and ZIP8 participate in the central nervous system. Cd is carried as GS–Cd–SG and MT–Cd–MT complexes in the blood. Cd passes from the small intestine to the liver, then to the right heart and through the lung to the arterial side of the body; in addition, inhaled Cd passes from the lung to the heart and then to the arterial side of the body. Cd ultimately becomes stored to some degree in the liver and to a much greater degree in the kidney.

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