Metallothionein-I/II null mice are more sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of chronic oval or injected inorganic arsenicals

Metallothionein (MT) is a low-molecular-weight, sulfhydryl-rich, metal-bind ing protein that can protect against the toxicity of cadmium, mercury, and copper. However, the role of MT in arsenic (As)-induced toxicity is less ce rtain. To better define the ability of MT to modify As toxicity, MT-I/II kn ockout (MT-null) mice and the corresponding wild-type mice (WT) were expose d to arsenite [As(III)] or arsenate [As(V)] either through the drinking wat er for 48 weeks, or through repeated sc injections (5 days/week) for 15 wee ks. Chronic As exposure increased tissue MT concentrations (2-5-fold) in th e WT but not in MT-null mice. Arsenic by both routes produced damage to the liver (fatty infiltration, inflammation, and focal necrosis) and kidney (t ubular cell vacuolization, inflammatory cell infiltration, and interstitial fibrosis) in both MT-null and WT mice. However, in MT-null mice, the patho logical lesions were more frequent and severe when compared to WT mice. Thi s was confirmed biochemically, in that, at the higher oral doses of As, blo od urea nitrogen (BUN) levels were increased more in MT-null mice (60%) tha n in WT mice (30%). Chronic As exposures produced 2-10 fold elevation of se rum interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha leve ls, with greater increases seen by repeated injections than by oral exposur e, 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-nu ll 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 M T-null mice, indicative of apoptotic cell death. In summary, chronic inorga nic As exposure produced injuries to multiple organs, and MT-null mice are generally more susceptible than WT mice to As-induced toxicity regardless o f route of exposure, suggesting that MT could be a cellular factor in prote cting against chronic As toxicity.