The long-term goal of this project is to identify and characterize the gene(s) responsible for interindividual differences in response to cadmium (Cd). Environmental Cd is absorbed by the small intestine and lung, is bound to metallothionein and glutathione in hepatocytes, and is deposited in the kidney. The kidney is the major target organ for human and lab animal Cd exposure. During the current funding period, we identified the Slc39a8 gene as the Cdm locus responsible for Cd-induced testicular necrosis. Slc39a8 encodes the ZIPS transporter protein, which we show is a high-affinity apically-oriented rogue Cd/HCO3- cotransporter. ZIPS expression in culture increases Cd influx and sensitizes (>30-fold) the cells to Cd. ZIPS is expressed in a cell-type-specific manner and is highest in alveolar and tubular epithelial cells in the lung and kidney, respect- tively. A BAC-transgenic (BTZIP8) mouse line containing 2 + 1 additional copies of the Slc39a8 gene shows a gene-dose-dependent increase in ZIPS mRNA in all tissues tested, and is acutely sensitive to Cd-induced kidney dysfunction. Slc39a8 is one of 14 members of a solute-carrier (SLC) family of metal transporters;Slc39a14 shares the most recent ancestry with Slc39a8;ZIP14 exists as two peptides, ZIP14A and ZIP14B, as a consequence of alternate exon splicing. The ZIP14s are expressed highest in small intestine and liver and have transport and toxicologic properties similar to ZIPS. Our hypothesis is that the ZIPS and ZIP14 transporters are the principal mediators of Cd-induced renal dysfunction. For the next funding period, we propose to: [1] characterize the transport and physiological properties of ZIPS, ZIP14A and ZIP14B in vitro;[2] study the physiological role of ZIPS in Cd-induced renal dysfunction using our BTZIP8 overexpresser and Slc39a8(-/-) knockout mouse models;and [3] develop and characterize similar mouse models for Slc39a14 These studies will improve our understanding of heavy-metal toxicity and may lead to uncovering new targets that might be useful for preventive strategies as well as therapeutic intervention in heavy-metal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010416-09
Application #
7649472
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Mcallister, Kimberly A
Project Start
2000-05-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
9
Fiscal Year
2009
Total Cost
$328,538
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Chen, Jing; Gálvez-Peralta, Marina; Zhang, Xiang et al. (2018) In utero gene expression in the Slc39a8(neo/neo) knockdown mouse. Sci Rep 8:10703
McDermott, Joseph R; Geng, Xiangrong; Jiang, Lan et al. (2016) Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake. Oncotarget 7:35327-40
Boycott, Kym M; Beaulieu, Chandree L; Kernohan, Kristin D et al. (2015) Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8. Am J Hum Genet 97:886-93
Jorge-Nebert, Lucia F; Gálvez-Peralta, Marina; Landero Figueroa, Julio et al. (2015) Comparing gene expression during cadmium uptake and distribution: untreated versus oral Cd-treated wild-type and ZIP14 knockout mice. Toxicol Sci 143:26-35
Park, Julien H; Hogrebe, Max; Grüneberg, Marianne et al. (2015) SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation. Am J Hum Genet 97:894-903
Schneider, Scott N; Liu, Zhiwei; Wang, Bin et al. (2014) Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: comparison of uptake, distribution, metal content, and toxicity. Int J Toxicol 33:14-20
Gálvez-Peralta, Marina; Wang, Zhifang; Bao, Shengying et al. (2014) Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals. Int J Toxicol 33:246-258
Liu, Ming-Jie; Bao, Shengying; Gálvez-Peralta, Marina et al. (2013) ZIP8 regulates host defense through zinc-mediated inhibition of NF-?B. Cell Rep 3:386-400
Nebert, Daniel W; Gálvez-Peralta, Marina; Hay, E Ben et al. (2012) ZIP14 and ZIP8 zinc/bicarbonate symporters in Xenopus oocytes: characterization of metal uptake and inhibition. Metallomics 4:1218-25
Gálvez-Peralta, Marina; He, Lei; Jorge-Nebert, Lucia F et al. (2012) ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. PLoS One 7:e36055

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