Cadmium (Cd) and arsenic (As) are important inorganic toxicants in the environment.
Humans certainly have the potential to be exposed to the mixtures of Cd and As, but
the toxicological interactions of these inorganic mixtures are poorly defined. Metallothionein
(MT) is a cysteine-rich, metal-binding 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-induced nephrotoxicity, MT-I/II-knockout (MT-null) mice and background-matched
wild-type (WT) mice were fed CdCl(2) (100 ppm Cd) in the diet, NaAsO(2) (22.5 ppm
As) in the drinking water, or Cd plus As for 4 months. Subsequently, nephrotoxicity
was examined by morphological and biochemical techniques. Chronic exposure to Cd produced
more renal toxicity than As, and the combination 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 degeneration and atrophy, glomerular swelling and interstitial
fibrosis were more severe than those produced by either inorganic. Furthermore, lack
of MT rendered MT-null mice more sensitive than WT mice to the nephrotoxicity produced
by chronic Cd- and/or As-exposure. MT-null mice were especially susceptible to the
toxicity produced by the combination of Cd and As, as evidenced by decreased body
weight, enzymuria, glucosuria, proteinuria and nephropathy. In conclusion, this study
indicates that As may potentiate Cd nephrotoxicity during the long-term, combined
exposure, and that intracellular MT plays a role in decreasing the nephropathy of
combined exposure to Cd and As.