metallothionein and Anemia

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 knock-out (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 hematotoxic and immunotoxic effects, and intracellular MT protects against these chronic Cd-induced effects.

Topics: Anemia; Animals; Apoptosis; Blood; Blood Cell Count; Cadmium Chloride; Dose-Response Relationship, Drug; Immune System; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Species Specificity; Splenomegaly; Thymus Gland; Time Factors

Cadmium (Cd) chloride was intravenously injected at doses of 0.05 and 0.5 mg/kg/day in ovariectomized rats for 50 weeks, and the chronic Cd exposure-induced nephrotoxicity and anemia were investigated. The rats treated with 0.05 mg/kg Cd showed no apparent hematological, urinary, and histopathological abnormalities. In the 0.5-mg/kg group, renal tubular disorders became marked at 16 weeks, and cortical fibrosis with glomerular dysfunction appeared at 50 weeks. Anemia occurred at 12 weeks in the 0.5-mg/kg group and became increasingly marked with time. The mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were decreased at 12 and 25 weeks; however, the decreases of MCV and MCH disappeared at 50 weeks. A slight decrease in mean corpuscular hemoglobin concentration was noted at 50 weeks. The blood chemistry from the same group revealed a decrease in plasma iron levels and an increase in total iron binding capacity throughout the administration period. The erythropoietin (EPO) level was increased as the hemoglobin level decreased at 12 weeks, whereas the EPO level was not elevated even when the hemoglobin level was decreased at 50 weeks. These findings showed that renal anemia also occurred in addition to the iron deficiency anemia at 50 weeks.

Topics: Anemia; Animals; Body Weight; Cadmium; Cadmium Poisoning; Drinking; Erythropoietin; Female; Ferritins; Hemoglobins; Injections, Intravenous; Kidney; Kidney Diseases; Liver; Metallothionein; Ovariectomy; Rats; Rats, Sprague-Dawley; Urine

The effects of erythropoiesis on cadmium-metallothionein (Cd-MT)2 levels in spleen, a major erythropoietic tissue, was examined following sc injection of 109CdCl2 into mice. As the concentration of Cd in plasma decreased following injection of 109CdCl2 into control mice, the levels in spleen and liver increased rapidly. After 48 hr, when the concentration of Cd in the erythrocyte (RBC) was at maximum, the level of Cd in the spleen, but not liver, had decreased. These variations of Cd concentration in spleen and RBC were more notable in mice made anemic by phenylhydrazine (PH). Zinc (Zn)-MT was detected in the PH-induced hemopoietic spleen. A subsequent injection of CdCl2 further induced Cd-MT in the spleen. The protein in spleen contained Cd and Zn but not Cu as in RBCs. Maximum levels of Cd-MT in spleen and RBCs of the PH-treated mice were about four times higher than those of control mice. The concentration of Cd-MT in the spleen of polyemia mice, induced by RBC transfusion, was 50% lower than that of control mice. When erythropoietin was injected into the polyemia mice prior to CdCl2, the concentration of Cd-MT in spleen increased about sixfold. These changes in Cd-MT levels in spleen were not observed in either liver or kidney. The effects of erythropoiesis on the concentration of Cd-MT in the spleen corresponded with effects seen in RBC. These results suggest that splenic Cd-MT can be the source of Cd-MT in mature RBC.

Topics: Anemia; Animals; Cadmium; Erythrocytes; Erythropoiesis; Male; Metallothionein; Mice; Spleen

Twenty-one male rabbits were divided into three groups: rabbits of two groups were given pelleted food containing cadmium chloride at a dose level of 300 micrograms Cd/g over periods of 44 or 19 weeks. Rabbits of the last group were given ordinary commercial pelleted food and served as controls. Cadmium increased urinary protein and amino acid by week 19 and increased it to a remarkably high level by week 44. After cessation of cadmium exposure, rabbits of the first group (44 weeks exposure group) showed only little recovery from cadmium health effects: proteinuria and aminoaciduria were slightly improved. Depressed hepatic functions were also slightly improved, but did not return to the control level in 24 weeks. Fat and bone metabolism also remained depressed below the control level. Anemia did not also readily recover. On the other hand, rabbits of the second group (19 weeks exposure) recovered from the effects of cadmium: proteinuria and aminoaciduria in most animals disappeared soon after the end of cadmium exposure, plasma GPT fell after 1 week, and hemoglobin and hematocrit returned to normal in 6-11 weeks. The above results show that after cessation of cadmium exposure, mild cadmium-induced health effects were reversible in a short period, while more severe effects were not readily reversible. High performance liquid chromatographic (HPLC) profiles of renal and hepatic cadmium-thionein (Cd-MT) during and after exposure to cadmium showed no correlation to the degree of cadmium health effects, and therefore, did not help to elucidate mechanisms of the recovery from cadmium-induced health effects, probably because cadmium not bound with metallothionein (non-MT-Cd) is responsible for inducing renal effects.

Topics: Amino Acids; Anemia; Animals; Blood; Body Weight; Cadmium; Chromatography, High Pressure Liquid; Copper; Glycosuria; Kidney; Liver; Male; Metallothionein; Molecular Weight; Proteinuria; Rabbits