钱海雷 氟, 镉对骨的效应
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氟(fluorine，F)是非金属元素，在地球上分布广泛，人体通过多种途径摄入氟，它是人体必需的14种微量元素之一，与钙磷代谢有着密切的关系。近几十年来，氟化物广泛用于预防和控制龋齿。然而，氟也是一种有毒物质，过量摄入氟可引起氟中毒，骨骼是氟的主要靶器官，可导致氟骨症。镉(cadmium，Cd)是金属元素，是受WHO、IARC、美国ATSDR关注的重金属污染物，对多种器官皆具有毒害作用。骨骼是镉的主要靶器官之一，人群流行病学调查和动物实验显示，镉能导致骨软化及骨质疏松。 骨质疏松是氟骨症的主要症状之一，目前我国仍以X线摄片作为氟骨症的主要诊断标准。但X线摄片所需仪器体积庞大，难以在流行病学的现场调查中应用。而镉对骨骼的影响既有影响肾脏合成活性维生素D3的间接作用，也有通过血液进入骨组织对骨骼细胞产生直接作用。为进一步明确氟、镉与其所致骨效应的剂量—反应关系，本研究使用便于移动的单光子骨密度仪，对江苏省北部饮水型氟中毒人群及我国温州地区环境镉接触人群进行流行病学调查。对氟中毒人群主要测量了骨密度并进行接触评定(问卷调查、尿氟、血氟测定)和效应评定(血清BGP、血清AKP、血清BAKP、尿HYP)，分离人外周血淋巴细胞测定CBFA1基因mRNA的表达水平。计算了Z评分(Z评分＜-2.5时判为骨质疏松)等指标的尿氟基准剂量值。对镉接触人群测定了人群接触指标(尿镉、血镉、总镉摄入量)与反映肾功能和骨质疏松的指标(UMT、UNAG、UNAGB、UB2M、URBP、UALB、骨密度)，计算了T、Z评分(T评分＜-2.5时判为骨质疏松)及各指标的尿镉和血镉BMDL值。 研究发现：氟接触组人群的骨密度与对照组比显著降低，氟接触组人群的BGP、HYP也显著高于对照组，但AKP、BAKP虽有升高趋势，但不显著。以对照组各指标第90百分位数作为上限值，得到人群各指标的异常率。按Z评分＜-2作为判断骨质疏松的标准，同时将Z评分的绝对值＞2作为骨代谢异常的判断标准，记作Z2。氟接触组男性只有BGP的异常率与对照有显著差异，而接触组女性的Z评分、Z2及BGP的异常率均显著高于对照组。将人群按尿氟水平分组后，BGP在尿氟水平＞2mg／gCr组即显著升高，而HYP、骨密度分别在＞4mg／gCr及＞8mg／gCr组时与对照组比有显著差异。AKP与BAKP的变化程度不明显。氟接触组人群外周血淋巴细胞CBFA1的mRNA表达水平显著低于对照组，按尿氟分组后，有随尿氟水平升高而下降的显著趋势，尤以女性明显。CBFA1表达的异常率也随尿氟水平升高而显著升高。经过计算各效应指标的尿氟BMDL值后发现不同性别间各指标的尿氟BMDL值按由小到大排序后顺序不一致，BOP的尿氟BMDL值无论男女均为最小，但女性BGP的方程拟合不佳；CBFA1则可排在第二位。反映骨代谢的Z评分与Z2的顺序则与性别有关。在镉接触人群中，人群骨密度与血镉、URBP、UB2M、UNAG、UNAGB均有显著的相关性。在尿镉＞10μg／gCr及血镉＞20μg／L时人群的骨密度显著下降。随着尿镉、血镉水平的升高，骨质疏松的患病率也随着升高，有显著性趋势。反映肾功能的指标也随尿镉、血镉的升高而升高，其异常率也都有显著升高的趋势。UMT可作为镉的接触与效应指标，在UMT升高或异常时，肾功能效应指标皆随之升高或有异常率的显著上升，但骨密度的变化不够明显。计算人群各指标的尿镉、血镉BMDL值后发现，无论尿镉、血镉，UNAGB与UNAG具有最低的BMDL值，UB2M排第三，UMT与URBP很接近，T评分、UALB、Z评分排位靠后。 同时，本研究分离培养了SD乳鼠头颅骨成骨细胞，观察不同浓度氟化钠、氯化镉染毒对成骨细胞增殖活性及碱性磷酸酶活性的影响，并测定了染毒前后成骨细胞VDR、OPG、ODF、TGF-β、IGF-ImRNA的表达水平。 体外实验证实，0.01～1.0mmol／L剂量的氟能促进大鼠成骨细胞增殖活性和碱性磷酸酶的活性，剂量＞2.0mmol／L时表现为抑制作用。而镉在剂量＞0.5μmol／L后，能引起大鼠成骨细胞增殖活性和碱性磷酸酶活性的下降，与对照组比有统计学意义。氟能上调ODF的表达水平，与剂量的增加一致。本实验中镉在各个水平均未能诱导ODFmRNA的表达。0.5、1.0mmol／L的氟能上调OPG的表达，在剂量为4.0mmol／L时则下调OPG的表达。镉则在0.01、0.05μmol／L时显著上调OPGmRNA的表达水平，1.0、5.0μmol／L时则下调其表达水平。氟对VDR、TGF-β、IGF-Ⅰ的表达起抑制作用并在高剂量组时与对照组比有显著差异。而0.05μmol／L的镉能上调VDRmRNA的表达水平，＞0.5μmol／L时则抑制其表达。对TGF-β与IGF-Ⅰ而言，镉能抑制其mRNA的表达，但分别在＞0.5μmol／L和＞1.0μmol／L的剂量时与对照组比才有显著性差异。 以上结果表明，人群接触氟可导致骨密度下降，引起骨质疏松。原因在于接触氟导致骨形成与骨吸收的程度加强，使氟接触人群骨转换加速，矿物质未能及时沉积，造成骨量减少。通过各指标尿氟BMDL值的比较，可以认为BGP和外周血淋巴细胞的CBFA1mRNA表达是比较敏感的能早期反映氟中毒骨损伤的指标，而Z评分是相对特异且敏感的效应指标。AKP、HYP缺乏特异性，BAKP则缺乏敏感性。低剂量的氟对成骨细胞有直接刺激作用，能促进部分成骨细胞细胞因子mRNA的表达水平，但高剂量时，氟能直接抑制多种促进成骨细胞功能的细胞因子mRNA的表达水平，表现出直接的毒害作用。 人群接触镉也能导致骨质疏松，但要在较高接触水平时才与对照组有明显差异，与反映镉致肾功能障碍的指标相比，T评分与Z评分皆不够敏感。UMT反映镉致骨损伤的敏感度不高。比较各指标的血镉、尿镉BMDL值后可以看出，镉致骨质疏松的时间要晚于镉致肾功能障碍的时间。体外实验表明，低剂量的镉对成骨细胞OPG、VDRmRNA的表达有上调作用，可能是由于镉具有的雌激素样作用。但高剂量的镉对成骨细胞的直接损伤比较明显，同时能下调多个细胞因子的mRNA表达水平。这也从一方面解释了镉要在高剂量下才能使人群出现明显的骨质疏松症状，时间上晚于镉致肾损伤的出现。
Abstract: fluoride (fluorine, F) is a nonmetallic element widely distributed in the earth, the human intake of fluoride through a variety of ways, it is an essential one of 14 kinds of trace elements, and is closely related to calcium and phosphorus metabolism. In recent decades, fluoride is widely used in the prevention and control of dental caries. However, fluoride is a toxic substance, excessive intake of fluoride can cause fluorosis, bone is the main target organ of fluoride can lead to skeletal fluorosis. Cd (cadmium, Cd) is a metallic element that is subject to WHO, IARC, U.S. ATSDR heavy metal pollutants of concern for a number of organs are having toxic effects. Bone is a major target organ of cadmium, epidemiological investigations and animal experiments show that cadmium can cause osteomalacia and osteoporosis. Osteoporosis is a skeletal fluorosis is one of the main symptoms present, China is still X-ray skeletal fluorosis as the primary diagnostic criteria. However, X-ray equipment required bulky, difficult to live in the epidemiological investigation of the application. The effect of cadmium on bone affect the kidneys synthesize both the indirect effects of active vitamin D3, but also through the blood into the bone tissue direct effect on bone cells. To further clarify the fluorine, cadmium and their effects caused by bone dose - response relationship, this study uses easy to move single photon absorptiometry, in northern Jiangsu Province fluorosis drinking crowd and the environment of cadmium exposure in Wenzhou epidemiological populations investigation. Fluorosis crowd on the main measurement of bone mineral density and conduct exposure assessments (questionnaires, urinary fluoride, fluorine determination of blood) and effects assessment (serum BGP, serum AKP, serum BAKP, urinary HYP), isolated from human peripheral blood lymphocytes was measured CBFA1 gene mRNA expression. Calculate the Z score (Z score <-2.5 judged as osteoporosis) and other indicators of urinary fluoride benchmark dose values. Population exposed to cadmium determination of human exposure indicator (cadmium in urine, blood cadmium, total cadmium intake) and of renal function and osteoporosis indicators (UMT, UNAG, UNAGB, UB2M, URBP, UALB, bone density), calculated the T, Z score (T score <-2.5 judged as osteoporosis) and various indicators of cadmium in urine and blood cadmium BMDL values. Study found that: BMD fluoride exposed population group and the control group was significantly lower than the fluorine exposure group crowd BGP, HYP also significantly higher, but the AKP, BAKP although an increasing trend, but not significantly. Indicators in the control group as the 90th percentile upper limit, get the crowd abnormal rate of each index. By Z-score <-2 as judged by the criteria of osteoporosis, while the absolute value of the Z-score> 2 as a criterion of abnormal bone metabolism, denoted by Z2. Fluoride exposure group males have only abnormal rate of BGP significant difference with the control, while the exposed group of women Z score, Z2, and BGP were significantly higher in the abnormal. The crowd grouped by urinary fluoride levels, BGP in urinary fluoride levels> 2mg/gCr group that is significantly increased, while HYP, bone mineral density, respectively> 4mg/gCr and> 8mg/gCr group compared with the control group were significantly different. BAKP AKP and the degree of change is not obvious. Fluoride exposure group populations of peripheral blood lymphocytes CBFA1 mRNA expression was significantly lower than the control group, grouped by urinary fluoride have elevated levels of urinary fluoride with a significant decline trend, especially in women significantly. CBFA1 abnormal expression rate of urinary fluoride levels with significantly increased. After calculating the effect indicators urine fluoride BMDL values found between genders each index value of urinary fluoride BMDL sorted by ascending order of inconsistency, BOP of both male and female urinary fluoride BMDL values are minimal, but women BGP equation proposed fit poorly; CBFA1 can came in second place. Z score reflects bone metabolism and Z2 order is gender-related. Cadmium exposure in the crowd, the crowd bone mineral density and blood cadmium, URBP, UB2M, UNAG, UNAGB showed a significant correlation. In the urinary cadmium> 10μg/gCr and blood cadmium> 20μg / L when the crowd BMD decreased significantly. With urinary cadmium, blood cadmium levels increased prevalence of osteoporosis with elevated significant trend. Indicators of renal function with the urine cadmium, blood cadmium increased, following the abnormal rate has significantly increased trend. UMT can be used as indicators of cadmium exposure and effects in the UMT elevated or abnormal renal function or effect indicators are abnormal with an increasing rate increased significantly, but the changes in bone mineral density is not obvious. Each index calculation crowd urinary cadmium, blood cadmium BMDL values found, regardless of urinary cadmium, blood cadmium, UNAGB BMDL with UNAG has the lowest value, UB2M ranked third, UMT and URBP very close, T score, UALB, Z score row place on the list. Meanwhile, the study of isolated and cultured neonatal rat skull SD osteoblasts, the effects of different concentrations of sodium chloride, cadmium exposure on osteoblast proliferation and alkaline phosphatase activity, and measured before and after exposure to bone cells VDR, OPG, ODF, TGF-β, IGF-ImRNA expression. In vitro experiments confirmed, 0.01 ~ 1.0mmol / L doses of fluoride can promote the proliferation of osteoblasts and alkaline phosphatase activity, dose> 2.0mmol / L when the performance of inhibition. And cadmium at doses> 0.5μmol / L, can cause proliferation of osteoblasts and alkaline phosphatase activity decreased, compared with control group was statistically significant. Fluorine can increase the expression of ODF, consistent with increasing doses. In this study, the average cadmium in various water failed to induce the expression of ODFmRNA. 0.5,1.0 mmol / L of fluoride can increase the expression of OPG, at a dose of 4.0mmol / L then decreased when the expression of OPG. Cadmium in 0.01,0.05 μmol / L was significantly increased expression levels OPGmRNA, 1.0,5.0 μmol / L when the expression level decreased. Fluoride on VDR, TGF-β, IGF-Ⅰ inhibit expression from the high dose group and the control group were significantly different. The 0.05μmol / L cadmium can increase the expression level VDRmRNA,> 0.5μmol / L inhibited the expression time. The TGF-β and IGF-Ⅰ, the cadmium can inhibit the expression of mRNA, but the difference in> 0.5μmol / L and> 1.0μmol / L dose group compared with the control only significant difference. These results show that human exposure fluoride can cause decreased bone mineral density, causing osteoporosis. The reason is that fluoride exposure leading to bone formation and bone resorption degree strengthened to accelerate bone fluoride exposed population, failed to timely deposit of minerals, resulting in reduced bone mass. BMDL urinary fluoride through each index value comparison can be considered and peripheral blood lymphocytes CBFA1mRNA BGP expression is more sensitive to early reflect fluorosis bone injury indicators, and Z score is relatively specific and sensitive indicator of effects. AKP, HYP lack of specificity, BAKP the lack of sensitivity. Low doses of fluoride on osteoblasts have a direct stimulating effect, can promote some osteoblast cytokine mRNA expression levels, but high doses, fluoride can directly inhibit osteoblast function to promote a variety of cytokine mRNA expression levels, demonstrated direct toxic effects. Population exposure to cadmium can lead to osteoporosis, but only at high exposure levels there are significant differences with the control group, and reflect the cadmium-induced renal dysfunction compared indicators, T score and Z-score are not sensitive enough. UMT reflects the sensitivity of cadmium-induced bone damage is not high. Compare each index blood cadmium, urinary cadmium BMDL values can be seen, the time of cadmium-induced osteoporosis later than cadmium-induced renal dysfunction time. In vitro experiments showed that low doses of cadmium on osteoblasts OPG, VDRmRNA upregulate the expression may be due to cadmium have estrogen-like effects. However, high doses of cadmium on osteoblasts direct damage is more obvious, and can cut multiple cytokine mRNA expression. This also explains the cadmium from one hand to be at high doses can make people appear obvious symptoms of osteoporosis, the time is later than the appearance of cadmium-induced renal injury.
Mottled teeth just like "fluorosis"...
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