BONE PB TOXICITY AND REMOBILIZATION IN RATS

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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.