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.
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