Metallothionein-null mice are highly susceptible to the hematotoxic and immunotoxic effects of chronic CdCl2 exposure

Cadmium (Cd) is an environmental pollutant. Chronic exposure of humans to Cd results in various maladies, including anemia and altered immune function. Metallothionein (MT) has been proposed to play an important role in Cd detoxication. Thus, we hypothesized that intracellular MT protects against Cd-induced hematotoxicity and immunotoxicity. Control and MT-I/II knockout (MT-null) mice were given s.c. injections of CdCl2 over a wide range of doses, 6 times/week for up to 10 weeks. Cd-induced anemia was evident after 5 weeks of exposure and progressed with time. MT-null mice were about 10 times more susceptible to Cd-induced anemia, as evidenced by decreased erythrocytes (25%), hemoglobin concentration (30%), and hematocrit (35%) after 10 weeks of Cd injections. Cd produced dose- and time-dependent increases in neutrophils (7x), along with a marked elevation of serum IL-1 beta (6x) and TNF-alpha (20x) levels. MT-null mice were more susceptible than controls to Cd-induced alterations in peripheral leukocytes and cytokine levels. Chronic exposure to Cd also produced dose- and time-dependent splenomegaly (5x), with loss of lymphoid structure, inflammation, hyperplasia, appearance of giant cells, and fibrosis. Thymus weights were decreased by Cd in a dose-dependent manner (60%). MT-null mice were also approximately 10 times more susceptible than controls to these lesions. In conclusion, the present study demonstrates that repeated injections of Cd produces hematotoxicity and immunotoxic effects, and intracellular MT protects against these chronic Cd-induced effects. (C) 1999 Academic Press.