Loss of bone mineral after ovariectomy was studied in mice exposed to dietary cadmium at 0.25, 5, or 50 ppm. Results show that dietary cadmium at 50 ppm increased bone mineral loss to a significantly greater extent in ovariectomized mice than in sham-operated controls. These results were obtained from two studies, one in which skeletal calcium content was determined 6 months after ovariectomy and a second in which 45Ca release from 'Ca-prelabeled bones was measured immediately after the start of dietary cadmium exposure. Furthermore, experiments with 4sCa-prelabeled fetal rat limb bones in culture demonstrated that Cd at 10 nM in the medium, a concentration estimated to be in the plasma of mice exposed to 50 ppm dietary Cd, strikingly increased bone resorption, from 27 ± 2% (mean ± SEM) "Ca release in cultures with no added cadmium to 68 ± 6% release in cultures containing cadmium (n -4). These in vitro results indicate that cadmium may enhance bone mineral loss by a direct action on bone. Results of the in vivo studies are consistent with a significant role of cadmium in the etiology of Itai-Itai disease among postmenopausal women in Japan and may in part explain the increased risk of postmenopausal osteoporosis among women who smoke.Osteoporosis affects [15][16][17][18][19][20] million people in the United States and is a major cause ofbone fractures in older persons, particularly postmenopausal women (1). One striking form of postmenopausal bone disease has occurred among women in Toyama prefecture, Japan, in the form of Itai-Itai (OuchOuch) disease, which is characterized by severe osteoporosis/osteomalacia and renal tubular dysfunction (2-5). Elevated levels of cadmium were present in both the diet and drinking water of women with Itai-Itai disease. The Japanese Ministry of Health in May 1968 declared cadmium to be one of the causative factors in the etiology of this bone disease on the basis of epidemiologic data relating disease incidence to cadmium exposure and the finding of high cadmium levels in tissues taken at autopsy from women with the disease (4, 6).The studies reported here were designed on the basis of the unusual finding that 95% of the cases of Itai-Itai disease occurred in postmenopausal women, not in younger women, men, or children (4). Although many studies of cadmiuminduced bone loss had been conducted in male animals or in females with intact ovaries, none had addressed the question of whether the combination of cadmium exposure and ovariectomy (to simulate conditions of postmenopausal hormone depletion) might accelerate the loss of bone calcium that normally occurs after removal of the ovaries. Such results might explain why Itai-Itai disease did not appear until after menopause.Results of our studies show that loss of bone mineral after ovariectomy in female mice was strikingly increased by dietary cadmium exposure. In addition, when cadmium was added at low concentrations (10 nM) to bone cultures, bone resorption was stimulated to an extent similar to that observed after treat...
The transfer of 109Cd from dam to offspring during gestation and lactation was studied in uniparous mice. From 70 to 210 d of age and during the subsequent reproductive period, young adult female mice received drinking water containing tracer amounts of 109Cd (8 ppb total Cd) and nutrient-sufficient or -deficient solid diet containing stable Cd (5 ppm Cd). The nutrient quality of the deficient diet was patterned after that consumed by Japanese women who contracted itai-itai disease. To evaluate established maternal stores as a potential source of cadmium transfer to pups, some dams were switched to water with no 109Cd and diet with an environmental or control level of cadmium (0.25 ppm Cd) during the reproductive period. The resulting pups were analyzed for 109Cd at birth and at 7-d intervals throughout the lactation period. Pup 109Cd content at birth, representative of the amount transferred via the placenta during gestation, accounted for less than 1% of the total 109Cd transferred during the full reproductive period. During lactation, 109Cd levels in pups from dams with current 109Cd exposure approximately tripled with each 7-d interval; no significant differences occurred due to nutrient quality of the dams' diet. For 21-d-old pups, 98% of the 109Cd burden came from the diet of the dam, while only 2% came from her tissue stores, primarily the hepatic one. Such fractions represented a transfer per pup of about 0.01% of the oral 109Cd dose ingested by the dam during the reproductive period and about 0.05% of the 109Cd in her tissue stores. Overall, transfer per litter amounted to about 7% of the dietary 109Cd dose absorbed and retained by the dam during that interval and about 0.2% of the 109Cd from tissue stores. On lactation d 21, 90% of the total 109Cd in pups was sequestered in the gastrointestinal tract. Cadmium transfer was additionally examined in multiparous mice that began a repetitive breeding program at 70 d of age at the time of introduction to the same diet/water regimens already described. Overall, females consuming nutrient-sufficient diet experienced 5 consecutive 42-d rounds of gestation/lactation, while their deficient diet counterparts experienced 3 nonconsecutive rounds during an equivalent period. Transfer was examined during their last gestation/lactation experience. Throughout the lactation interval, 109Cd transfer to pups was about 30% increased for multiparous versus uniparous females; however, transfer again was not significantly affected by nutrient quality of the dams' diet.(ABSTRACT TRUNCATED AT 400 WORDS)
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