BONE PB TOXICITY AND REMOBILIZATION IN RATS

这一拟议项目的广泛长期目标是确定 导致铅暴露增加的行为者，这些行为特定于 绝经后女性，并研究铅对老年人的影响 骨骼作为毒性的靶器官。这项研究将调查 骨骼作为铅暴露的内源性来源的作用 作为毒性的靶器官，铅对骨骼的影响，使用 一种灵敏的稳定铅同位素示踪技术和 去卵巢大鼠人激素耗竭骨量减少模型的建立 和骨铅中毒。本研究的具体目的是：(L) 确定从骨骼重新动员回体内的铅的量 实验性骨量减少对大鼠血液循环的影响 骨铅水平低和升高：(2)检查骨骼的影响 铅水平。和雌激素的治疗。甲状旁腺激素和 双磷酸盐(利塞膦酸盐)对骨中铅的动员作用。和 关于骨生理学：和(3)确定骨骼铅是否 重新分配到其他靶器官。尤其是大脑和肾脏。 从而导致骨量减少。低铅和高铅大鼠 水平将被卵巢切除或假卵巢切除，然后接受 赋形剂、雌激素、甲状旁腺素和利塞膦酸酯的治疗干预 (双磷酸盐)以评估卵巢切除的效果和这些 治疗骨铅和矿物质流失。在建议的条件下 在这里，骨骼将被标记有骨骼特异性示踪剂~3H- 四环素和铅204Pb同位素示踪剂有明显不同 在治疗开始时从软组织中取出。这个 这项研究的主要结果指标是：(I)空气中~(204)Pb水平 骨骼和软组织，以及作为骨铅示踪剂的尿液，(Ii) 骨骼软组织中总铅浓度的变化 铅动员或预防：(3)~3H-四环素水平 在骨骼、血清和尿液中作为骨矿物质状态的示踪剂，(Iv) 骨和尿钙含量，以及(V)骨钙素，碱性 血清和尿液中磷酸酶和吡啶酚交联物水平 骨生理学的标志物。这项研究的理论基础是基于 需要阐明铅升高的程度和可能的风险(S) 绝经后妇女暴露于可再活化性骨骼铅的情况也一样 骨铅水平升高是否会改变骨的成骨反应 对荷尔蒙刺激和治疗的疗效降低 骨量减少的发展。

The broad long-tenn objectives of this proposed project are to identify actors contributing to increased lead exposures that are specific to postmenopausal females, and to examine effects of lead on the aged skeleton as a target organ of toxicity. This study will investigate the role of the skeleton as an endogenous source of lead exposure, as well as effects of lead on the skeleton as a target organ of toxicity, using a sensitive stable lead isotope (204Pb) tracer technique and the ovariectomized rat model of human hormone depletion-induced osteopenia and bone lead toxicity. The specific aims of this study are: (l) Determine the magnitude of lead remobilized from the skeleton back into the circulation as a result of experimentally induced osteopenia in rats with low and elevated bone lead levels: (2) Examine the effects of bone lead levels. and treatments with estrogen. parathyroid hormone and bisphosphonate (risedronate) on the mobilization of lead from bone. and on bone physiology: and (3) Determine whether skeletal lead is redistributed to other target organs. specifically the brain and kidney. as a result o induced osteopenia. Rats with low and elevated bone lead levels will be ovariectomized or sham-ovariectomized, and then undergo therapeutic interventions with vehicle, estrogen, PTH, and risedronate (bisphosphonate) to evaluate the effects of ovariectomy and these treatments on bone lead and mineral loss. Under the conditions proposed here, the skeleton will be labeled with the bone-specific tracer 3H- tetracycline and a lead 204Pb isotopic tracer distinguishably different from the soft tissues at the beginning of the therapeutic treatments. The primary outcome measures of this study are (i) the levels of 204Pb in skeletal and soft tissues, and urine as a tracer of bone lead, (ii) changes in total lead concentrations in soft tissues resulting from bone lead mobilization or its prevention, (iii) the levels of 3H-tetracycline in bone, serum, and urine as a tracer of bone mineral status, (iv) the calcium content of bone and urine, and (v) osteocalcin, alkaline phosphatase, and pyridinoline crosslinks levels in serum and urine as markers of bone physiology. The rationale for this study is based on the need to elucidate the magnitude and possible risk(s) of elevated lead exposure from remobilized skeletal lead in postmenopausal women, as well whether elevated bone lead levels alter the osteogenic response of bone to hormonal stimuli and the efficacy of therapeutic treatments to reduce the development of osteopenia.