CADMIUM TOXICITY AND DISTRIBUTION IN METALLOTHIONEIN-I AND -II DEFICIENT TRANSGENIC MICE

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Abstract
To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the pre sent study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metalloth-ionein-l and -II deficient (MT−/−) mice and the parental strain carrying intact metalloth ionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT−/− mice expressed lower levels of cadmium-binding proteins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc pretreated MT−/− mice. The cadmium LD50 was similar for MT−/−, MT+/+, and zinc-pretreated MT−/− mice (15-17To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the pre sent study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metalloth-ionein-l and -II deficient (MT−/−) mice and the parental strain carrying intact metalloth ionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT−/− mice expressed lower levels of cadmium-binding proteins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc pretreated MT−/− mice. The cadmium LD50 was similar for MT−/−, MT+/+, and zinc-pretreated MT−/− mice (15-17 μmol CdCl2/kg body weight delivered ip). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 μmol CdCIJkg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+ and MT−/− mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cad mium. However, after zinc pretreatment, MT+/+ mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT−/− mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+ mice relative to MT−/− mice. This difference was accentuated after zinc pretreatment. Together these results indi cate that basal levels of metallothionein do not protect from the acute toxicity of a single ip cadmium challenge. Furthermore, it does not appear that the cytosolic compartmental-ization of cadmium is correlated with reduced toxicity.