摘要
镉是一种人体非必需的微量元素,多以硫镉矿形式存在,并常与锌、铅、铜等矿并存。镉在电镀、塑料、半导体、电池等工业中应用广泛,尤其是有色金属矿产开发和冶炼排出的废气、废水和废渣,以及石油等燃料燃烧排出的烟气,都会对环境造成不同程度镉污染。环境镉污染进而可污染农作物和水源,人体因摄入受镉污染的食物和水而造成多系统、多器官的损害。骨骼是镉的主要效应器官之一,镉暴露可导致骨密度下降、骨质疏松发生率增加,并能增加骨折的风险,但是其确切机理不甚清楚,且以往研究多以骨量作为效应指标,关注点也多集中在继发于肾损伤后的骨效应。此外,由于镉在人体的生物半衰期可长达10-30年,而环境镉暴露减少／停止后镉致骨毒效应的预后急待研究。本论文从人群流行病学、动物和细胞三个层面探讨镉致骨毒效应及其相关机理,以及镉暴露减少／停止后的预后改变。
本研究以1998年中国东南部某镉污染地区流行病学现况调查建立的人群队列资料为基础,在2006年对该队列的部分人群进行了追踪随访：以血镉、尿镉作为镉接触剂量指标,以骨密度及骨质疏松发生率作为效应指标,追踪观察镉暴露中止10年后该地区不同镉接触水平人群的骨密度、骨质疏松发生率改变,并与1998年的研究结果进行比较,探讨环境镉暴露对人群骨代谢不良效应及停止接触后骨效应的预后和可能影响因素。同时,采用镉染毒后中止和镉连续染毒二种大鼠动物模型,应用骨量、骨结构、骨生物力学、骨代谢指标等,进一步探讨镉致骨损伤效应、预后及可能机制,结合对镉致肾损伤效应及其相关性分析,进一步探讨肾损伤程度对骨效应和预后的影响作用。此外,应用间断性和连续性镉染毒对成骨细胞、破骨细胞生物学效应和功能基因表达的影响,尤其是从成骨细胞相关基因及成骨／破骨偶联基因表达的改变,探讨镉致骨不良效应及预后的分子生物学机制。
人群流行病学研究结果表明：居民在停止食用含镉大米10年后,镉污染区居民血镉、尿镉水平仍明显高于对照组,人群骨密度则呈明显下降趋势,下降幅度与血镉和尿镉水平相关。尤其是血镉水平大于5μg/L的人群和尿镉水平大于10μg/g肌酐的女性人群,骨密度下降趋势更明显,且女性人群骨质疏松的发生率随着血镉和尿镉水平明显增高(x2值分别为9.30和4.51,p<0.05),男性人群骨质疏松的发生率也随着血镉升高而明显增加(χ2值为4.603,p<0.05),但与尿镉含量的相关性并不明显。进一步的相关分析结果表明,在可能影响骨密度的因素中,血镉和年龄对骨密度有明显影响作用(p<0.01)。此外,身高和体重也是影响骨密度的重要因素之一。进一步的对照研究发现,对于女性,骨密度下降幅度与镉暴露中止时人群的基础血镉和尿镉水平有关,即暴露中止时血镉和尿镉水平越高,此后的骨量丢失速率和骨质疏松发生率越高：血镉在5-10μg/L、>10μg/L和尿镉>10μg/g肌酐组女性骨质疏松发生的OR值分别为4.51(1.57-13.54),3.45(0.95-13.6)和4.74(1.82-13.5)。相关分析结果也表明,女性人群骨密度的变化与血镉、尿镉和绝经情况相关(p<0.05),但男性人群中骨密度变化与血镉和尿镉的相关性并不明显。
动物实验研究结果证实,镉在骨骼中高度蓄积并对骨造成损害,表现为骨量降低(骨密度下降,股骨和腰椎干灰重降低),骨代谢失衡(血清Tracp5b水平升高、OC水平下降),骨骼微结构损伤(骨小梁数量减少、分离度增加),骨骼生物力学性能下降(载荷、应力、断裂能量、抗压强度等下降),骨矿化能力抑制。同时,镉暴露能诱导骨组织金属硫蛋白(MT1和MT2)及RANKL基因的高表达,并对OPG基因表达等产生抑制作用。此外,镉对肾脏尤其是肾小管有明显损害作用,电镜可见肾小管上皮细胞线粒体水肿、嵴缺失、空泡化等改变,高剂量染毒组大鼠可见肾小管上皮细胞的坏死,肾小管功能指标UNAG及尿总蛋白也明显升高,并且与骨密度降低明显相关。但镉对肾脏CYP27b1和CYP24a1基因表达未见明显影响,推测镉对骨骼的毒性效应至少不是完全继发于肾损伤,提示镉对骨骼的直接作用有待进一步关注。预后研究结果表明,间断性镉染毒大鼠即使在中止镉暴露1个月后,骨量、骨结构、骨生物力学性能仍明显低于对照组,骨形成和骨吸收功能同时亢进,以肾小管为主的肾损伤也持续存在。并且,与持续染毒大鼠相比,骨代谢和骨矿盐结构的损伤未见明显恢复,肾功能损伤无明显改善,但肾脏CYP27b1和CYP24a1基因表达未见明显差异。
进一步的体外实验研究结果表明,镉对成骨细胞和破骨细胞均有直接作用,但镉对破骨细胞的效应剂量明显小于其对成骨细胞的效应剂量：对于成骨细胞,大于0.125μmol/L染毒剂量的镉可明显抑制成骨细胞的增殖、分化、矿化等生物功能,并能降低Ⅰ型胶原、骨桥蛋白、基质金属蛋白酶抑制剂l和基质金属蛋白酶抑制剂2的表达。而对于破骨细胞,0.03μmol/L的染毒剂量即可明显增加TRAP(+)破骨细胞数量并促进骨吸收陷窝形成能力,推测镉对骨的直接作用是以破骨细胞为主要作用靶点。对成骨／破骨偶联基因表达的影响研究表明,镉能明显抑制成骨细胞OPG基因表达,上调RANKL基因表达,即OPG/RANKL通路可能是镉对骨直接作用的重要通路之一。细胞预后效应的研究结果也进一步证明,采用0.5μmol/L镉对成骨细胞染毒48hr后中止暴露24h,镉染毒仍可导致成骨细胞增殖和分化功能的明显抑制；同样,中止暴露3d、5d及7d后,染毒组矿化结节数量和面积仍明显低于对照组,即成骨细胞的矿化能力也不能有效恢复。且与持续镉染毒组比较,间断性镉染毒对成骨细胞增殖、分化和矿化能力的影响作用没有明显差异(p>0.05),即镉暴露中止并不能使镉对成骨细胞生物学功能的损伤作用有效恢复。
本论文研究表明,环境镉暴露能引起人群骨密度降低,并增加骨质疏松发生率,对女性尤其是绝经后人群的作用更加明显。即使在镉暴露中止10年后,镉对骨骼的影响作用仍然持续存在,表现为降低骨密度、增加骨质疏松发生率,且镉致骨损伤效应的进展情况与暴露中止时的基础血镉和尿镉水平有关。动物研究结果进一步证明,镉能在骨骼中沉积,除了对骨量产生明显影响外,还能改变骨生物力学性能和骨微观结构的完整性,可能与骨吸收功能亢进的高转换状态有关。而即使在极低剂量镉暴露水平,虽然未见明显的肾损伤和骨密度下降,染毒大鼠的骨生物力学性能和骨吸收功能指标Tracp5b就已经有明显改变。此外,间断性染毒大鼠在中止镉暴露后,镉对骨损伤效应仍明显存在,骨量、骨微结构、骨生物力学性能等均没有明显改善,并表现为骨吸收和骨形成功能的亢进即高骨转换状态。但镉染毒动物实验中未发现继发于肾损伤的VitD代谢相关酶即肾1α羟化酶和24α羟化酶基因表达的明显改变。体外研究表明,镉对成骨细胞生物学功能呈抑制作用,而对破骨细胞数和骨吸收活性均有一定促进作用,OPG/RANKL通路可能是镉致骨直接损伤作用的重要通道之一；镉还可能对骨基质相关基因表达,尤其是基质金属蛋白酶抑制剂有一定抑制作用。中止染毒后,镉对成骨细胞的作用仍然持续存在：抑制OB增殖、矿化及分化。应关注镉接触减少或中止后对骨骼的持续影响效应,尤其是对绝经后女性等敏感人群。
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.
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