长期环境镉暴露人群骨骼健康效应及骨代谢机制研究

发布时间：2018-03-20 02:38

本文选题：镉　切入点：基准剂量　出处：《南方医科大学》2017年博士论文　论文类型：学位论文

【摘要】：镉的健康效应一直是公共卫生的研究热点,迄今已有研究主要集中在职业暴露或国外非暴露区人群,对镉致骨代谢损伤机制研究不多,与肾损伤关系仍存在不同结论。本研究通过对某环境高镉区流行病学调查,了解当地居民镉暴露及骨质疏松情况,采用基准剂量法研究骨质疏松的尿镉阈值,采用多元回归、logistic回归分析骨质疏松与肾损伤的关系,研究调查人群骨转换的变化及影响因素,在人群水平探讨镉致骨质疏松的机制。还通过CdCl2慢性经口染毒大鼠模型,探讨镉对骨髓间充质干细胞(MSCs)的影响,同时观察肾脏的改变,初步构建镉毒性有害结局路径(AOP)框架。本研究纳入的1116名40-79岁调查对象尿镉中位数为3.97 μg/g Cr.(0.21-87.31 μg/g Cr.)。引起5%和10%人群骨质疏松的尿镉阈值BMD5和BMD10分别为 1.14μg/gCr.和 2.73 μg/gCr.;BMD 的 95%下限 BMDL5和 BMDLio分别为 0.61μg/gCr.和1.83μg/gCr.。女性的BMD值低于男性。通过多元回归分析,扣除混杂因素后,尿镉每增加1μg/gCr.,骨密度T值下降0.03。校正不同肾损伤标志物对结果不造成明显影响。低、中、高三个暴露组骨质疏松的OR(95%CI)分别为 3.07(1.77,5.33)、4.63(2.68,7.98)和 9.15(5.26,15.94)。联合作用统计分析未见肾损伤的修饰效应。为排除肾功能的潜在影响,在肾小球滤过率正常的调查人群中进行敏感性分析,镉仍增加骨质疏松风险。上述结果表明镉的骨骼毒性可能不是继发于肾损伤,而是与之同时发生的独立效应。人群骨代谢研究表明,尿镉是五个骨代谢指标(β-CTX,PINP,BALP,RANKL和OPG)的独立相关因素,其中β-CTX是反映镉引发骨质疏松良好的生物标志物。CdC12经口染毒大鼠38周的实验结果表明,剂量组肾镉、尿镉高于对照组,机体镉负荷升高。终期体重、脏器重、脏体比与对照组比较,差异无统计学意义。实验结束时动物未见骨质疏松,但MSCs表达RANKL升高,OPG下降,成骨诱导过程中关键基因 Colla2、Osterix、Osteopontin、Runx2、Osteocalcin、ALP 的表达均有不同程度的降低。肾损伤标志物和尿钙未见升高,肾脏未见受试物相关的病理改变,但HO-1,LC3B,p62,Beclin-1蛋白表达增加。结论:1.调查人群BMDL5和BMDL10分别为0.61 μg/g Cr.和1.83μg/g Cr.,与引发肾损伤的临界值相近。女性的BMD值低于男性。中国人群对镉毒性的耐受程度不比外国人群高。2.镉增加骨质疏松的风险,其骨骼毒性效应可能不是继发于肾损伤,而是与之同时发生。骨骼可能与肾脏一样,均为镉早期损伤的靶器官。3.人群和动物研究表明,镉的骨骼毒性机制涉及RANKL/RANK/OPG通路。4.β-CTX是镉致骨质疏松良好的生物标志物。5.镉还可直接影响MSCs成骨诱导过程,可能是镉致骨质疏松的另一机制。6.与课题组前期研究相结合初步提出镉毒性的AOP框架。
[Abstract]:Health effects of cadmium has been a hot research in public health, has been mainly focus on the occupation exposure and non exposed areas of foreign population, not many studies on Mechanism of cadmium induced damage to bone metabolism, there are different conclusions of renal injury and relationship. This study through the epidemiological investigation of high cadmium region of a environment, understand the local residents exposed to cadmium and osteoporosis, urinary cadmium threshold of osteoporosis using benchmark dose method, using multiple regression, logistic regression analysis of the relationship between osteoporosis and kidney injury, and effect of investigation on the changes of bone conversion population factors, to explore the mechanism of cadmium induced osteoporosis at the population level. The CdCl2 of chronic oral exposure in rats the model, discuss the influence of cadmium on bone marrow mesenchymal stem cells (MSCs) of renal changes observed at the same time, initial construction of cadmium toxicity harmful outcome path (AOP) framework. This study included 1116 40-7 The 9 year old survey of urinary cadmium for a median of 3.97 g/g Cr. (0.21-87.31 g/g Cr.). By 5% and 10% of the population of osteoporosis urinary cadmium thresholds of BMD5 and BMD10 were 1.14 g/gCr. and 2.73 g/gCr.; 95% BMD lower BMDL5 and BMDLio were 0.61 g/gCr. and 1.83 g/gCr.. Women with low BMD value in the male. Through multiple regression analysis, excluding the confounding factors, each increase of urinary cadmium 1 g/gCr., T value of BMD decreased 0.03. correction of different renal injury markers do not cause significant impact on the results. The low, high exposure group of osteoporosis OR (95%CI) were 3.07 (1.77,5.33), 4.63 (2.68,7.98) and 9.15 (5.26,15.94). The combined effect of statistical analysis of the modified effect no renal injury. To exclude potential effects of renal function, sensitivity analysis of prevalence in normal glomerular filtration, cadmium still increased the risk of osteoporosis. The results showed that cadmium Skeletal toxicity may not secondary to renal injury, but also with independent effect. The study of bone metabolism population showed that urinary cadmium is the five indexes of bone metabolism (beta -CTX, PINP, BALP, RANKL and OPG) of the independent factors, which is a reflection of Cd induced beta -CTX biomarkers.CdC12 osteoporosis is good the exposure of rats for 38 weeks. The experimental results show that the dose of kidney cadmium, cadmium in urine was higher than the control group, increased body cadmium load. The final body weight, organ weight, organ body ratio compared with the control group, the difference was not statistically significant. At the end of the experiment, no animal osteoporosis, but decreased the expression of MSCs RANKL increased. OPG, a key gene Colla2, bone induction process Osterix, Osteopontin, Runx2, Osteocalcin, decreased the expression of ALP in varying degrees. The renal injury markers and urinary calcium did not increase, no change of renal pathology, test substance related but HO-1, LC3B, p62, Beclin-1 Protein expression was increased. Conclusion: BMDL5 and BMDL10 1. population were 0.61 g/g Cr. and 1.83 g/g Cr., similar to the critical value lead to kidney damage. Women's BMD value is lower than the male. Chinese population risk of osteoporosis increased tolerance to cadmium than foreigners group high.2. CD, the bones the toxic effect is not secondary to renal damage, but also with bone and kidney. May, for cadmium early injury of target organ of.3. population and animal studies suggest that skeletal toxicity mechanism of cadmium to RANKL/RANK/OPG pathway.4. beta -CTX is cadmium induced osteoporosis biomarkers of good.5. cadmium can also directly affect the MSCs osteogenic induction process, may be cadmium induced osteoporosis another mechanism of.6. and the previous research combining put forward AOP framework of cadmium toxicity.

【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R580

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