Chronic combined exposure to cadmium and arsenic exacerbates nephrotoxicity, particularly in metallothionein-I/II null mice

Cadmium (Cd) and arsenic (As) are important inorganic toxicants in the envi ronment. Humans certainly have the potential to be exposed to the mixtures of Cd and As, but the toxicological interactions of these inorganic mixture s are poorly defined. Metallothionein (MT) is a cysteine-rich, metal-bindin g protein that plays an important role in Cd detoxication, but its role in As toxicity is less certain. To examine the role of MT in Cd- and/or As-ind uced nephrotoxicity, MT-I/II-knockout (MT-null) mice and background-matched wild-type (WT) mice were fed CdCl2 (100 ppm Cd) in the diet, NaAsO2 (22.5 ppm As) in the drinking water, or Cd plus As for 4 months. Subsequently, ne phrotoxicity was examined by morphological and biochemical techniques. Chro nic exposure to Cd produced more renal toxicity than As, and the combinatio n of Cd and As produced even more renal injury than caused by either of the chemicals given alone. In mice receiving Cd plus As, proximal tubule degen eration and atrophy, glomerular swelling and interstitial fibrosis were mor e severe than those produced by either inorganic. Furthermore, lack of MT r endered MT-null mice more sensitive than WT mice to the nephrotoxicity prod uced by chronic Cd- and/or As-exposure. MT-null mice were especially suscep tible to the toxicity produced by the combination of Cd and As, as evidence d by decreased body weight, enzymuria, glucosuria, proteinuria and nephropa thy. In conclusion, this study indicates that As may potentiate Cd nephroto xicity during the long-term, combined exposure, and that intracellular MT p lays a role in decreasing the nephropathy of combined exposure to Cd and As . (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.