Relationship between osteoid formation and iron deposition induced by chronic cadmium exposure in ovariectomized rats.

Itai-itai (Japanese, "It hurts! It hurts!") disease (IID), a form of osteomalacia, can be induced in ovariectomized rats by long-term administration of cadmium (Cd). This IID rat model shows severe anemia, severe nephropathy, and osteomalacia accompanied by iron (Fe) deposition at the mineralization front. We characterized the pathogenesis of Cd-induced bone lesions by investigating the relationship between Fe deposition and osteoid tissue formation in ovariectomized rats. The rats were injected with CdCl2 (0.5 mg/kg) for 70 weeks, with or without co-injection of erythropoietin (EPO) for varying lengths of time to elucidate whether EPO prevents and/or cures anemia, and, with the restoration from anemia, lessens the osteoid tissue formation. Necropsies were performed at 25, 50, or 70 weeks. Fe deposition at the mineralization front of bone was found at 50 weeks and increased thereafter. Animals injected with EPO showed decreased Fe deposition, although there was no relation between EPO administration and osteoid formation in the femur. Because the increase in bone lesion severity was independent of the amount of Fe deposition, we suggest that Fe deposition is not involved in the etiology of Cd-induced femoral bone lesions.

The effects of a vitamin D-deficient diet on chronic cadmium exposure in rats.

Itai-itai disease (IID) of humans is one of the most severe forms of chronic cadmium (Cd) intoxication. Itai-itai disease occurs mainly in post-menopausal women and is characterized by osteoporosis with osteomalacia, renal tubular disorder, and renal anemia. Some researchers insist the major cause of IID is not Cd, but rather malnutrition, especially hypovitaminosis D. We administrated a low concentration of Cd chloride intravenously to ovariectomized female rats that were fed a vitamin D-deficient diet or a normal diet for fifty weeks. The vitamin D-deficient diet decreased serum concentration of vitamin D, but it did not affect the metabolism of the kidney or bone. Cadmium treatment alone induced a decrease in serum concentration of vitamin D, as well as renal dysfunction, renal anemia, and abnormal bone metabolism. Osteoporosis with osteomalacia, tubular nephropathy, fibrous osteodystrophy, and bone marrow hyperplasia occurred following Cd treatment. In rats treated with Cd and administered a vitamin D-deficient diet, the toxic effects of Cd on kidney, bone, and hematopoiesis were enhanced in comparison to rats treated with Cd and a normal diet. The present experiment demonstrated that hypovitaminosis D did not evoke morphologic features of IID in humans but did enhance Cd-induced toxicity in the rat model of this disease.

Chronic cadmium treatment induces islet B cell injury in ovariectomized cynomolgus monkeys.

In an attempt to establish a primate model of chronic cadmium (Cd) toxicosis, we ovariectomized cynomolgus monkeys and treated with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed an increase in blood glucose from Month 10 and a decrease in blood insulin at Month 11of the Cd-treatment. Histopathological examination of the Cd-treated animals revealed islet atrophy with reduction in islet number and vacuolation of the islet cells, whereas there was no remarkable change in the acinar cells of the exocrine pancreas. In histomorphometrical examination, insulin-positive areas in the islets were significantly decreased, accompanying a relative increase of glucagon-positive areas. Large amounts of Cd accumulated in the pancreas, and metallothionein (MT), a Cd binding protein, was localized in the islets of Cd-treated animals. The present study demonstrated that the chronic intravenous injection of Cd to cynomolgus monkeys induced the accumulation of the metal in the pancreas, degeneration of islet B cells and the diabetic clinical signs. Therefore the islet B cell is one of the major targets of the chronic Cd poisoning in monkeys.