Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line.
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, we isolated a 168.7-kb bacterial artificial chromosome (BAC), carrying only the Slc39a8 gene, from a Cd-sensitive 129/SvJ BAC library and generated BAC-transgenic mice. The BTZIP8-3 line, having three copies of the 129/SvJ Slc39a8 gene inserted into the Cd-resistant C57BL/6J genome (having its normal two copies of the Slc39a8 gene), showed tissue-specific ZIP8 mRNA expression similar to wild-type mice, mainly in lung, testis, and kidney. The approximately 2.5-fold greater expression paralleled the fact that the BTZIP8-3 line has five copies, whereas wild-type mice have two copies, of the Slc39a8 gene. The ZIP8 mRNA and protein localized especially to endothelial cells of the testis vasculature in BTZIP8-3 mice. Cd treatment reversed Cd resistance (seen in nontransgenic littermates) to Cd sensitivity in BTZIP8-3 mice; reversal of the testicular necrosis phenotype confirms that Slc39a8 is unequivocally the Cdm locus. ZIP8 also localized specifically to the apical surface of proximal tubule cells in the BTZIP8-3 kidney. Cd treatment caused acute renal failure and signs of proximal tubular damage in the BTZIP8-3 but not nontransgenic littermates. BTZIP8-3 mice should be a useful model for studying Cd-induced disease in kidney.
Wang
Bin
B
Department of Environmental Health, and the Center for Environmental Genetics (CEG), University Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Schneider
Scott N
SN
Dragin
Nadine
N
Girijashanker
Kuppuswami
K
Dalton
Timothy P
TP
He
Lei
L
Miller
Marian L
ML
Stringer
Keith F
KF
Soleimani
Manoocher
M
Richardson
Douglas D
DD
Nebert
Daniel W
DW
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009336:Necrosis; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D013737:Testis / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology
D027682:Cation Transport Proteins; D012333:RNA, Messenger; C499256:Slc39a8 protein, mouse; D002104:Cadmium