Cadmium (Cd) is an environmental pollutant which is toxic to a number of tissues. The metal is highly cumulative with a biological half-life of 10-40 years in humans. Over half of the total body burden is concentrated in liver and kidney bound to metallothionein (MT), a low molecular weight protein (6800 daltons) containing 30% cysteine and having a pronounced affinity for metals. The overall objective of this research is to determine the role of MT in the toxicity of Cd. Basal levels of MT appear to be extremely important in determining the susceptibility to the toxic effects of Cd. Our recent studies suggest that the degradation of MT is very important in regulating the basal levels of MT. Therefore, the hepatic degradation of MT will be examined in detail. Nephrotoxicity is the major injury that results from chronic environmental exposure to Cd. This renal toxicity is suspected to be due to CdMT that is synthesized in the liver, released, and taken up by the kidney where the Cd is released to produce the toxicity. However, this hypothesis is not universally accepted. More work is needed to support or refute this hypothesis, which we propose to do, and if the hypothesis appears to be true to exploit this mechanism and determine if one could alter the degradation of Cd in the kidney and prevent its nephrotoxicity. Information will also be obtained on differences in Cd toxicity to hepatic parenchymal and endothelial cells from sensitive and resistant strains of mice to determine if the strain difference in toxicity is due to differences in susceptibility of parenchymal or endothelial cells to Cd. Endothelial cell in testes will be examined using in situ hybridization with mRNA probes for MT-I to determine if metals such as Cd and Zn increase mRNA for MT and this might be the mechanism for tolerance to testicular injury for Cd. Studies will also be performed with ethanol, the most highly used drug and which we recently demonstrated to induce MT, to determine its effects on the toxicity of Cd. Experiments will also be performed to determine if endotoxin increases MT concentration through interleukin-I. Overall, critical information will be obtained in these studies that are relevant not only for Cd but other metals as well. From the experiments proposed, data on MT will be obtained that will not only enable us to understand its interactions with toxic metals but help us to determine its normal physiological role. Before making rational decisions on treatment of Cd poisoning and setting rational criteria for the protection of mankind, the above questions must be answered.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES001142-14
Application #
3249500
Study Section
Toxicology Study Section (TOX)
Project Start
1975-06-23
Project End
1993-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Kansas
Department
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
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, 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
Park, J D; Liu, Y; Klaassen, C D (2001) Protective effect of metallothionein against the toxicity of cadmium and other metals(1). Toxicology 163:93-100

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