Bone Toxic Effect And Its Prognosis Caused By Cadmium

Cadmium is one kind of no-essential trace elements existing in the environment as the form of greenockite and coexisting with zinc, lead and copper. Cadmium can be used broadly in industry, such as in electric plating, plastic, semiconductor and batteries fields. The waste air, water and residues discharged through mine exploitation and smelting and smoking produced by fuel burning could result in cadmium pollution. The cadmium existing in environment could enter into the body by food and water and do harm to many system and organs. Bone is one of the target organs for cadmium toxicity. It has been shown that cadmium could decrease bone mineral density, result in osteoporosis and increase the risk of bone fracture, but exact mechanism is still unknown. Most research focus on cadmium effecs on bone mass, including bone mineral density and bone mineral content, and the indirect effects caused by renal dysfuction. However, because of long biological half-life (10-30 years), it is necessary to investigate the prognosis of bone damage after reduction of cadmium exposure. We will investigate bone adverse effect and its prognosis caused by cadmium exposure from the aspects of epidemiological study, animal and cell experiments in this study.The study was based on our previous epidemiological study in 1998 in the areas polluted by a smelter which was located in southeast of China. The participants living in these three areas were selected as study object; cadmium in blood and urine collected in 1998 and 2006 were chosen as exposure markers; bone mineral density and prevalence of osteoporosis were picked out as effect markers. We analyzed the bone mineral density and prevalence of osteopososis in 2006 in different areas and different BCd, UCd group and compared the data collected in 2006 with that in 1998 to investigate cadmium damage to bone and bone prognosis after reduction of exposure and the probable related factors. Moreover, animal models for ceasetion exposure and continuous exposure was established to investigate cadmium effect on bone and the prognosis of bone damage and the probable mechanism, using parameters such as bone mass, bone microstructure, biomechanics and metabolic markers. Effect of cadmium on kidney was also observed to discuss the role of kidney in bone damage and prognosis. In vitro study, effects of cadmium on osteoblasts and osteoclasts and the prognosis after discontinuation of cadmium exposure was observed. Gene expression related to osteoblasts and osteoblasts/osteoclasts were determined to investigate the mechanism for cadmium toxicity on cell and prognosis after ceasetion of exposure.The BCd and UCd level of inhabitants living in polluted areas were still higher than those of living in control area. The BMD was declined with the increasing BCd and UCd in both sexes, especially in highest level (BCd> 5μg/L, UCd> 10μg/g crea) groups (p< 0.01). It was found that there were significantly differences in the prevalence of osteoporosis among the different BCd groups (x2= 9.30, p< 0.05) and different UCd groups (x2= 4.511, p< 0.05) in women. As for men, the prevalence of osteoporosis increased with the increasing of BCd level (x2= 4.603,p< 0.05), but not obvious correlation was found with the increasing of UCd. Correlation analysis showed significantly negative correlations exist between BMD and age and BCd in both men and women (p< 0.01). BMD also associated with weight, height and BMI. As for prognosis study, the values of the bone mineral density (BMD) change and change percentage were related with the cadmium in blood and urine at baseline. The higher BCd and UCd in 1998, the more change and percentage change in 2006, especially for female population. The prevalence of osteoporosis in 2006 was higher than that in 1998 and increased along with increasing UCd and BCd in both women and men, especially for those subjects in the group having high levels of BCd [BCd> 5μg/L OR= 3.45 (0.95-13.6); BCd> 10μg/L, OR= 4.51(1.57-13.54)] and UCd [UCd> 10μg/g crea, OR= 4.74 (1.82-12.81)] in women. It was found in correlation analysis the absolute and percentage BMD changes correlated positively with UCd and BCd and menopause status in women (p< 0.01) and with age and height and weight in men(p< 0.01), but there was no obvious correlation between the absolute or percentage BMD changes in either UCd or BCd in men.In animal study, it was suggested that cadmium could accumulate in bone and cause bone damage. Bone mass (bone mineral density and bone weight), bone biomechanical parameters (load, elastic module, crack energy, stiffness), bone mineralization ablity and some bone related gene expression (OC, I-collagen) decreased after cadmium exposure. Otherwise, bone microstructure (Tb.N, Tb.Sp) damage and bone metabolic dysfunction were also observed. Cadmium could induce MT(ⅠandⅡ), RANKL gene expression and inhibit OPG gene expression in bone tissue. Otherwise, cadmium could induce kidney dysfunction, especially for tubule, such as increasing UNAG level and mitochondria damage, but cadmium had no obvious effects on CYP27bl and CYP24al gene expression. Cadmium toxic effects on bone may not only via indirect way; the direct effects of cadmium on bone need further study. In prognosis study, bone mass, bone microstructure, biomechanical parameters, bone mineralization ability in cadmium exposure group were significantly lower than control. Uncoupling bone remodeling status occurred and renal tubule dysfunction remained. There were no obvious improvement for bone mass, bone microstructure, bone biomechanical parameters, bone mineralization ability, kidney dysfunction and gene expression in discontinual exposure group compared with continual exposure group. CYP27b1 and CYP24a1 gene expression had no obvious dfifference.It had been shown that cadmium had direct effect on bone cell and the effect concentration of cadmium on osteoclast was lower than that on osteoblast. Cadmium could inhibit proliferation, differentiation and mineralization in osteoblastic cells at relative higher level (> 0.125μmol/L). Otherwise, cadmium inhibited I-collagen, OPN, TIMP 1 and TIMP2 mRNA expression. Low concentration of cadmium (0.03μmol/L) could increase the numbers of osteoclasts (p< 0.05) and enhance pits formation. Osteoclasts may be the target cells of cadmium effects on bone. Low level of cadmium could down-regulate OPG mRNA expression and up-regulate RANKL mRNA expression. In prognosis study, proliferation, differentiation and mineralization of osteoblasts in exposure group were obvious lower than control group. But as for discontinual exposure groups, there were no obvious improvement in proliferation, differentiation and mineralization of osteoblasts compared with continual exposure groups. No obvious recovery status was found in osteoblasts after reduction of cadmium exposure for short-term time.It suggested in this study that cadmium could decrease bone mineral density, increase the prevalence of osteoporosis, in particularly for women; the adverse effects of Cd on bone remained after the main source of Cd exposure had been blocked for about 10 years. Bone status was related with the BCd and UCd level at baseline.Animal study showed that cadmium could accumulate in bone and influence bone mass, bone biomechanics, bone microstructure and bone metabolic markers which may be as a result of increasing of bone reabsorption and kidney dysfunction. At low level that no obvious renal dysfunction was observed, we have observed cadmium effects on biomechanics and bone reabsorption markers (Tracp5b). The effects of cadmium on bone persisted for a period of time, no obvious improvement for bone mass, bone microstructure and bone biomechanical parameters were found in discontinual exposure group which may be also as a result of uncoupling of bone remodeling and kidney dysfunction. In animal study, cadmium may have no obvious influence on VitD metabolic enzyme, CYP27bl and CYP24al gene expression. In vitro study, cadmium had direct effect on osteoblasts and osteoclasts and OPG/RANKL pathway may play important role. Cadmium may also inhibit matrix formation by decreasing matrix related gene expression, such as TIMP. Cadmium effects on osteoblasts still remained after marked reduction of exposure, proliferation, differentiation and mineralization had no obvious recovery. More attention should be paid on cadmium effect on health after reduction/discontinuation of exposure, expecially for postmenopausal women.