THE METABOLISM OF LEAD IN BONE

铅在骨中的代谢

• 批准号: 3249469
• 负责人: JOHN F ROSEN
• 金额: $ 16.41万
• 依托单位: MONTEFIORE MEDICAL CENTER (BRONX, NY)
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-05-01 至 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3249469
• 关键词: atomic absorption spectrometry; bone metabolism; bone metabolism disorder; calcitonin; calcium metabolism; chelating agents; child (0-11); connective tissue metabolism; detoxification; diet; environmental toxicology; erythrocytes; ethylenediaminetetraacetate; gastrointestinal toxin absorption; human subject; ion transport; lead poisoning; metal metabolism; nutrition related tag; organ culture; parathyroid hormones; radiotracer; scintillation counter; scintillation spectrometry; skeletal disorder chemotherapy; toxin metabolism

Bone is the major reservoir of Pb in humans, and it is becoming increasingly evident that labile lead (Pb) compartment(s) from bone contribute to Pb concentrations in blood and soft tissues. Yet, remarkably few studies have characterized bone Pb metabolism at the cellular, organ or systemic level, as proposed herein: the specificity of parathyroid hormone's (PTH) mediation/enhancement of Pb uptake in monlayer cultures of osteoclasts (OC) will be examined by evaluating stimuli (Ca++, prostaglanding E2, A23187...) known to minic PTH. Metabolic responses of PTH and l,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-treated OC cells will be studied after marked increases in OC cell Ca uptake (far above that effected by PTH) have been produced by rising media Pb concentrations. These experiments will detemine if Pb-induced increments in OC cell Ca uptake are toxic to cell functions. If so, this pertubation may be a discrete mechanism of Pb toxicity common to other cells that depend upon Ca as a second messenger. To evaluate this Pb effect further, the studies will describe Pb effects on the homeostasis of exchangeable Ca in OC cells by desaturation techniques. In companion experiments, the steady state kinetic behavior of Pb in OC and osteoblast (OB) cells will be defined by similar techniques. These studies will determine the biological identity of kinetic Pb compartments in bone cells, describe Ca-Pb interactions and model Pb pools in OC (considerable avidity for Pb) compared to OB cells (little avidity for Pb). In bone organ culture, an integrated view of Pb metabolism in bone will be provided - a metabolic summation of bone cells, mineral and matrix. Fetal rat bones will be "leaded" in vivo or in vitro; the metabolic responses to agents that enhance or depress OC cell activity will be examined. In children who have mild to moderate increases in body Pb stores, serum concentrations of 1,25-(OH)2D, a uniquely sensitive index of soft tissue Pb, will be compared to bone Pb measurements by x-ray fluorescence (XRF). The results of CaNa2EDTA testing, the ultimate probe in assessing the body burden of Pb in humans, will be compared to measurements of bone Pb by XRF - a sensitive, accurate, safe and non-invasive technique. XRF measurements may obviate the need for CaNa2EDTA testing; and this protocol may clearly demonstrate at what point highly sensitive biochemical effects of Pb (reduction in serum 1,25-(OH)2D) are demonstrable in relation to the size of bone Pb stores measured by XRF. It is anticipated that this research may have wide applications for 780,000 American children (1-6 years of age), who have undetected low level Pb toxicity.

骨骼是人类体内铅的主要储存库，而且它正在成为 越来越明显的是，来自骨骼的不稳定铅(铅)隔室(S) 对血液和软组织中铅浓度的影响。然而，值得注意的是 很少有研究描述骨铅在细胞、器官或组织中的代谢 全身性水平：甲状旁腺的特异性 激素(PTH)介导/促进单层培养中铅的吸收 破骨细胞(OC)将通过评估刺激(Ca++， 前列腺素E2、A23187...)Minic PTH已知。新陈代谢反应 PTH和L，25-二羟基维生素D3(1，25-(OH)2D3)处理的OC细胞 在OC细胞钙摄取显著增加(远远高于 Pth的影响)是由于介质中铅浓度的增加而产生的。 这些实验将确定铅是否诱导OC细胞的生长 摄取对细胞功能是有害的。如果是这样的话，这种干扰可能是 铅毒性的离散机制与其他依赖于钙的细胞一样 作为第二个信使。为了进一步评估这种铅效应，这些研究 将描述铅对OC细胞内可交换钙稳态的影响 通过去饱和技术。在配对实验中，稳态 铅在OC和成骨细胞(OB)中的动力学行为将由 类似的技术。这些研究将确定生物身份 描述了钙铅相互作用和骨细胞中铅的动态变化 OC中的模型铅池(对铅的亲和力相当高)与OB细胞的比较 (对铅的亲和力不大)。骨器官培养中铅的整体观 将提供骨中的新陈代谢-骨细胞的代谢总和， 矿物和基质。在体内或体外，胎鼠骨骼将被“铅化”； 增强或抑制OC细胞活性的药物的代谢反应 将会被检查。对于身体有轻度到中度增长的儿童 铅储存，血清1，25-(OH)2D浓度，一个唯一敏感的指标 软组织铅的含量，将与X射线测量的骨铅进行比较 荧光(XRF)。终极探针CaNa2EDTA检测结果 在评估人体内铅的负荷时，将与 XRF法测定骨铅--灵敏、准确、安全、可靠 非侵入性技术。XRF测量可能会消除对 CaNa2EDTA测试；这项协议可以清楚地展示在什么时候 铅的高灵敏生化效应(血清1，25-(OH)2D还原) 与骨铅储存的大小有关，可通过以下方式测量 XRF。预计这项研究可能会在 780,000名美国儿童(1-6岁)，他们有未被发现的低水平 铅毒性。