Metallothionein-I/II null mice are sensitive to chronic oval cadmium-induced nephrotoxicity

Chronic exposure to cadmium (Cd) via food and drinking water is a major hum an health concern. We have previously shown that metallothionein (MT), a me tal-binding protein, plays an important role in protecting against Cd toxic ity produced by repeated sc injections. However, it is unclear whether MT p rotects against Cd-induced nephrotoxicity following chronic oral exposure, a route with obvious human relevance. To clarify this issue, MT-I/II knocko ut (MT-null) and background-matched wild-type (WT) mice were allowed free a ccess to drinking water containing CdCl2 (30, 100, and 300 ppm Cd), or feed containing CdCl2 (100 ppm Cd) for 6 months, and the resultant nephrotoxici ty was examined. Chronic oral Cd exposure produced a dose-dependent accumul ation of Cd in liver and kidney of WT mice, reaching levels up to 50 mug Cd /g tissue. Immunohistological localization of renal MT indicated that chron ic oral Cd exposure in WT mice greatly increased MT in the proximal tubules and the medulla, with cellular localization in both the cytoplasm and nucl ei. As expected, no MT was detected in kidneys of MT-null mice. After 6 mon ths of Cd exposure, tissue Cd concentrations in MT-null mice were only abou t one-fifth of that in WT mice. Even though the renal Cd concentrations wer e 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 gamma -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 la ck of MT renders MT-null mice vulnerable to Cd-induced nephrotoxicity after chronic oral exposure, the primary route of human Cd exposure.