Toxicological Sciences 57, 167-176 (2000)
Copyright © 2000 by the Society of Toxicology
Systems Toxicology |
Metallothionein-I/II Null Mice Are Sensitive to Chronic Oral Cadmium-Induced Nephrotoxicity
* Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; and
Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Research Triangle Park, North Carolina
Chronic exposure to cadmium (Cd) via food and drinking water is a major human health concern. We have previously shown that metallothionein (MT), a metal-binding protein, plays an important role in protecting against Cd toxicity produced by repeated sc injections. However, it is unclear whether MT protects against Cd-induced nephrotoxicity following chronic oral exposure, a route with obvious human relevance. To clarify this issue, MT-I/II knockout (MT-null) and background-matched wild-type (WT) mice were allowed free access to drinking water containing CdCl2 (30, 100, and 300 ppm Cd), or feed containing CdCl2 (100 ppm Cd) for 6 months, and the resultant nephrotoxicity was examined. Chronic oral Cd exposure produced a dose-dependent accumulation of Cd in liver and kidney of WT mice, reaching levels up to 50 µg Cd/g tissue. Immunohistological localization of renal MT indicated that chronic oral Cd exposure in WT mice greatly increased MT in the proximal tubules and the medulla, with cellular localization in both the cytoplasm and nuclei. As expected, no MT was detected in kidneys of MT-null mice. After 6 months of Cd exposure, tissue Cd concentrations in MT-null mice were only about one-fifth of that in WT mice. Even though the renal Cd concentrations were much lower in the MT-null mice, they were more sensitive than WT mice to Cd-induced renal injury, as evidenced by more severe nephropathic lesions, increased urinary excretion of 
-glutamyl-transferase and glucose, and elevated blood urea nitrogen. Six months of Cd exposure to MT-null animals resulted in greater increases in renal caspase-3 activity, an indicator of apoptosis, than to WT mice. In conclusion, this study demonstrates that lack of MT renders MT-null mice vulnerable to Cd-induced nephrotoxicity after chronic oral exposure, the primary route of human Cd exposure.
Key Words: cadmium; chronic oral exposure; nephrotoxicity, metallothionein-I/II null mice; histopathology; apoptosis; immunohistochemistry.
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