本文選題：鎘　切入點(diǎn)：基準(zhǔn)劑量　出處：《南方醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：鎘的健康效應(yīng)一直是公共衛(wèi)生的研究熱點(diǎn),迄今已有研究主要集中在職業(yè)暴露或國(guó)外非暴露區(qū)人群,對(duì)鎘致骨代謝損傷機(jī)制研究不多,與腎損傷關(guān)系仍存在不同結(jié)論。本研究通過(guò)對(duì)某環(huán)境高鎘區(qū)流行病學(xué)調(diào)查,了解當(dāng)?shù)鼐用矜k暴露及骨質(zhì)疏松情況,采用基準(zhǔn)劑量法研究骨質(zhì)疏松的尿鎘閾值,采用多元回歸、logistic回歸分析骨質(zhì)疏松與腎損傷的關(guān)系,研究調(diào)查人群骨轉(zhuǎn)換的變化及影響因素,在人群水平探討鎘致骨質(zhì)疏松的機(jī)制。還通過(guò)CdCl2慢性經(jīng)口染毒大鼠模型,探討鎘對(duì)骨髓間充質(zhì)干細(xì)胞(MSCs)的影響,同時(shí)觀察腎臟的改變,初步構(gòu)建鎘毒性有害結(jié)局路徑(AOP)框架。本研究納入的1116名40-79歲調(diào)查對(duì)象尿鎘中位數(shù)為3.97 μg/g Cr.(0.21-87.31 μg/g Cr.)。引起5%和10%人群骨質(zhì)疏松的尿鎘閾值BMD5和BMD10分別為 1.14μg/gCr.和 2.73 μg/gCr.;BMD 的 95%下限 BMDL5和 BMDLio分別為 0.61μg/gCr.和1.83μg/gCr.。女性的BMD值低于男性。通過(guò)多元回歸分析,扣除混雜因素后,尿鎘每增加1μg/gCr.,骨密度T值下降0.03。校正不同腎損傷標(biāo)志物對(duì)結(jié)果不造成明顯影響。低、中、高三個(gè)暴露組骨質(zhì)疏松的OR(95%CI)分別為 3.07(1.77,5.33)、4.63(2.68,7.98)和 9.15(5.26,15.94)。聯(lián)合作用統(tǒng)計(jì)分析未見腎損傷的修飾效應(yīng)。為排除腎功能的潛在影響,在腎小球?yàn)V過(guò)率正常的調(diào)查人群中進(jìn)行敏感性分析,鎘仍增加骨質(zhì)疏松風(fēng)險(xiǎn)。上述結(jié)果表明鎘的骨骼毒性可能不是繼發(fā)于腎損傷,而是與之同時(shí)發(fā)生的獨(dú)立效應(yīng)。人群骨代謝研究表明,尿鎘是五個(gè)骨代謝指標(biāo)(β-CTX,PINP,BALP,RANKL和OPG)的獨(dú)立相關(guān)因素,其中β-CTX是反映鎘引發(fā)骨質(zhì)疏松良好的生物標(biāo)志物。CdC12經(jīng)口染毒大鼠38周的實(shí)驗(yàn)結(jié)果表明,劑量組腎鎘、尿鎘高于對(duì)照組,機(jī)體鎘負(fù)荷升高。終期體重、臟器重、臟體比與對(duì)照組比較,差異無(wú)統(tǒng)計(jì)學(xué)意義。實(shí)驗(yàn)結(jié)束時(shí)動(dòng)物未見骨質(zhì)疏松,但MSCs表達(dá)RANKL升高,OPG下降,成骨誘導(dǎo)過(guò)程中關(guān)鍵基因 Colla2、Osterix、Osteopontin、Runx2、Osteocalcin、ALP 的表達(dá)均有不同程度的降低。腎損傷標(biāo)志物和尿鈣未見升高,腎臟未見受試物相關(guān)的病理改變,但HO-1,LC3B,p62,Beclin-1蛋白表達(dá)增加。結(jié)論:1.調(diào)查人群BMDL5和BMDL10分別為0.61 μg/g Cr.和1.83μg/g Cr.,與引發(fā)腎損傷的臨界值相近。女性的BMD值低于男性。中國(guó)人群對(duì)鎘毒性的耐受程度不比外國(guó)人群高。2.鎘增加骨質(zhì)疏松的風(fēng)險(xiǎn),其骨骼毒性效應(yīng)可能不是繼發(fā)于腎損傷,而是與之同時(shí)發(fā)生。骨骼可能與腎臟一樣,均為鎘早期損傷的靶器官。3.人群和動(dòng)物研究表明,鎘的骨骼毒性機(jī)制涉及RANKL/RANK/OPG通路。4.β-CTX是鎘致骨質(zhì)疏松良好的生物標(biāo)志物。5.鎘還可直接影響MSCs成骨誘導(dǎo)過(guò)程,可能是鎘致骨質(zhì)疏松的另一機(jī)制。6.與課題組前期研究相結(jié)合初步提出鎘毒性的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.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R580

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