Toxicological Sciences 55, 460-467 (2000)
Copyright © 2000 by the Society of Toxicology
Metallothionein-I/II Null Mice Are More Sensitive than Wild-Type Mice to the Hepatotoxic and Nephrotoxic Effects of Chronic Oral or Injected Inorganic Arsenicals
* Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F0-09, Research Triangle Park, North Carolina 27709;
University of Kansas Medical Center, Kansas City, Kansas; and
Office of the Director, NIEHS, Research Triangle Park, North Carolina
Metallothionein (MT) is a low-molecular-weight, sulfhydryl-rich, metal-binding protein that can protect against the toxicity of cadmium, mercury, and copper. However, the role of MT in arsenic (As)-induced toxicity is less certain. To better define the ability of MT to modify As toxicity, MT-I/II knockout (MT-null) mice and the corresponding wild-type mice (WT) were exposed to arsenite [As(III)] or arsenate [As(V)] either through the drinking water for 48 weeks, or through repeated sc injections (5 days/week) for 15 weeks. Chronic As exposure increased tissue MT concentrations (2–5-fold) in the WT but not in MT-null mice. Arsenic by both routes produced damage to the liver (fatty infiltration, inflammation, and focal necrosis) and kidney (tubular cell vacuolization, inflammatory cell infiltration, and interstitial fibrosis) in both MT-null and WT mice. However, in MT-null mice, the pathological lesions were more frequent and severe when compared to WT mice. This was confirmed biochemically, in that, at the higher oral doses of As, blood urea nitrogen (BUN) levels were increased more in MT-null mice (60%) than in WT mice (30%). Chronic As exposures produced 2–10 fold elevation of serum interleukin-1ß, interleukin-6, and tumor necrosis factor-
levels, with greater increases seen by repeated injections than by oral exposure, and again, MT-null mice had higher serum cytokines than WT mice after As exposure. Repeated As injections also decreased hepatic glutathione (GSH) by 35%, but GSH-peroxidase and GSH-reductase were minimally affected. MT-null mice were more sensitive than WT mice to the effect of GSH depletion by As(V). Hepatic caspase-3 activity was increased (2–3-fold) in both WT and MT-null mice, indicative of apoptotic cell death. In summary, chronic inorganic As exposure produced injuries to multiple organs, and MT-null mice are generally more susceptible than WT mice to As-induced toxicity regardless of route of exposure, suggesting that MT could be a cellular factor in protecting against chronic As toxicity.
Key Words: arsenite; arsenate; chronic exposures; metallothionein-I/II null mice; nephrotoxicity; serum cytokines; hepatotoxicity; glutathione.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Wu, J. Liu, M. P. Waalkes, M.-L. Cheng, L. Li, C.-X. Li, and Q. Yang High Dietary Fat Exacerbates Arsenic-Induced Liver Fibrosis in Mice Experimental Biology and Medicine, March 1, 2008; 233(3): 377 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Andrew, V. Bernardo, L. A. Warnke, J. C. Davey, T. Hampton, R. A. Mason, J. E. Thorpe, M. A. Ihnat, and J. W. Hamilton Exposure to Arsenic at Levels Found in U.S. Drinking Water Modifies Expression in the Mouse Lung Toxicol. Sci., November 1, 2007; 100(1): 75 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kimura, Y. Ishida, T. Hayashi, T. Wada, H. Yokoyama, T. Sugaya, N. Mukaida, and T. Kondo Interferon-{gamma} Plays Protective Roles in Sodium Arsenite-Induced Renal Injury by Up-Regulating Intrarenal Multidrug Resistance-Associated Protein 1 Expression Am. J. Pathol., October 1, 2006; 169(4): 1118 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, S. Li, J. Liu, B. A. Diwan, J. C. Barrett, and M. P. Waalkes Chronic inorganic arsenic exposure induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis Carcinogenesis, September 1, 2004; 25(9): 1779 - 1786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N. Pires Das Neves, F. Carvalho, M. Carvalho, E. Fernandes, E. Soares, M. D. L. Bastos, and M. D. L. Pereira Protective Activity of Hesperidin and Lipoic Acid Against Sodium Arsenite Acute Toxicity in Mice Toxicol Pathol, August 1, 2004; 32(5): 527 - 535. [Abstract] [PDF]
|
|
|
|
|
|
J. Shen, H. Wanibuchi, E. I. Salim, M. Wei, A. Kinoshita, K. Yoshida, G. Endo, and S. Fukushima Liver tumorigenicity of trimethylarsine oxide in male Fischer 344 rats--association with oxidative DNA damage and enhanced cell proliferation Carcinogenesis, November 1, 2003; 24(11): 1827 - 1835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schuliga, S. Chouchane, and E. T. Snow Upregulation of Glutathione-Related Genes and Enzyme Activities in Cultured Human Cells by Sublethal Concentrations of Inorganic Arsenic Toxicol. Sci., December 1, 2002; 70(2): 183 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-S. Bae, C. Gennings, W. H. Carter Jr., R. S. H. Yang, and J. A. Campain Toxicological Interactions among Arsenic, Cadmium, Chromium, and Lead in Human Keratinocytes Toxicol. Sci., September 1, 2001; 63(1): 132 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liu, H. Chen, D. S. Miller, J. E. Saavedra, L. K. Keefer, D. R. Johnson, C. D. Klaassen, and M. P. Waalkes Overexpression of Glutathione S-Transferase II and Multidrug Resistance Transport Proteins Is Associated with Acquired Tolerance to Inorganic Arsenic Mol. Pharmacol., August 1, 2001; 60(2): 302 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, M. B. Kadiiska, Y. Liu, T. Lu, W. Qu, and M. P. Waalkes Stress-Related Gene Expression in Mice Treated with Inorganic Arsenicals Toxicol. Sci., June 1, 2001; 61(2): 314 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Lu, J. Liu, E. L. LeCluyse, Y.-S. Zhou, M.-L. Cheng, and M. P. Waalkes Application of cDNA Microarray to the Study of Arsenic-Induced Liver Diseases in the Population of Guizhou, China Toxicol. Sci., January 1, 2001; 59(1): 185 - 192. [Abstract] [Full Text] [PDF]
|
|