Cadmium (Cd) is an environmental pollutant with high toxic potential. Over half of the body burden of Cd is concentrated in liver and kidney and bound to metallothionein (MT). MT is a low molecular weight, cysteine-rich metal-binding protein. The long-term goal of the research is to explore the mechanism of Cd toxicity and the role of MT in the toxicity of Cd. The target organ of toxicity for acute Cd exposure is liver, while kidney is the target organ of chronic exposure. The current theory holds that Cd-induced nephrotoxicity is mediated through the Cd-metallothionein (CdMT) complex which """"""""leaks"""""""" out of the liver and is taken up by the kidney to produce renal toxicity. However, a single CdMT injection model does not mimic, in many aspects, the nephrotoxicity produced by human chronic exposure to the metal. Therefore, the first aim (1) is to test the hypothesis that Cd-induced nephrotoxicity is not necessarily mediated through CdMT, and a single injection of CdMT is not an appropriate model to study chronic Cd nephropathy.
This aim i s essential so that efforts will not be directed at the mechanism of acute CdMT -induced nephrotoxicity, if it has no relevance to human exposure. In the second (2) aim, the hypothesis that MT protects against chronic Cd-induced renal injury as well as other toxic effects will be tested. Using MT-null mice, which are identical to control mice but cannot synthesize MT, the role of MT in chronic Cd toxicity will be determined with certainty. In the third (3) aim, the link between chronic Cd exposure, oxidative stress, and renal injury will be explored via (a) urine analysis (urinary lipid metabolites vs proteinuria, glucosuria and enzymuria), (b) blood analysis (serum tumor necrosis factor-alpha, interleukin-1 and interleukin-6 vs blood urea nitrogen), (c) histology (localization of 4-hydroxynonenal- and malondialdehyde-adducts vs histopathology), (d) tissue analysis (antioxidant components vs tissue Cd content), and (e) electron paramagnetic resonance (ESR)-spin trapping to detect free radical metabolites generated in vivo during chronic Cd exposure. These studies with MT-null mice will determine the role of MT in chronic Cd nephrotoxicity and other toxicities and will be helpful in developing strategies for treating Cd poisoning as well as setting criteria for the protection of human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES001142-23
Application #
6055886
Study Section
Special Emphasis Panel (ZRG4-ALTX-4 (05))
Project Start
1975-06-23
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
23
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Klaassen, Curtis D; Reisman, Scott A (2010) Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver. Toxicol Appl Pharmacol 244:57-65
Liu, Jie; Kadiiska, Maria B; Corton, J Christopher et al. (2002) Acute cadmium exposure induces stress-related gene expression in wild-type and metallothionein-I/II-null mice. Free Radic Biol Med 32:525-35
Harstad, Eric B; Klaassen, Curtis D (2002) Analysis of strain difference in sensitivity to cadmium-induced hepatotoxicity in Fischer 344 and Sprague-Dawley rats. Toxicol Sci 67:329-40
Park, Jung D; Cherrington, Nathan J; Klaassen, Curtis D (2002) Intestinal absorption of cadmium is associated with divalent metal transporter 1 in rats. Toxicol Sci 68:288-94
Park, Jung D; Habeebu, Sultan S M; Klaassen, Curtis D (2002) Testicular toxicity of di-(2-ethylhexyl)phthalate in young Sprague-Dawley rats. Toxicology 171:105-15
Harstad, Eric B; Klaassen, Curtis D (2002) Gadolinium chloride pretreatment prevents cadmium chloride-induced liver damage in both wild-type and MT-null mice. Toxicol Appl Pharmacol 180:178-85
Leazer, Tyra M; Liu, Yaping; Klaassen, Curtis D (2002) Cadmium absorption and its relationship to divalent metal transporter-1 in the pregnant rat. Toxicol Appl Pharmacol 185:18-24
Harstad, Eric B; Klaassen, Curtis D (2002) iNOS-null mice are not resistant to cadmium chloride-induced hepatotoxicity. Toxicology 175:83-90
Harstad, Eric B; Klaassen, Curtis D (2002) Tumor necrosis factor-alpha-null mice are not resistant to cadmium chloride-induced hepatotoxicity. Toxicol Appl Pharmacol 179:155-62
Liu, Y; Liu, J; Klaassen, C D (2001) Metallothionein-null and wild-type mice show similar cadmium absorption and tissue distribution following oral cadmium administration. Toxicol Appl Pharmacol 175:253-9

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