LEAD AND RED CELL MEMBRANE

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This proposal investigates the multifactorial interaction of lead and the red cell membrane. It derives from the investigators' evidence that increases in blood lead to the currently acceptable maximum for children (30 ug/dl) evoke hemolysis manifest by target cells with decreases in membrane fluidity, osmotic fragility, cell survival and pyrimidine-5 feet-nucleotidase activity, and the accumulation of cytosolic pyrimidine nucleotides and their diesters, CDP choline (CDP-C) and CDP ethanolamine (CDP-E). The specific aims are: 1) Test the hypothesis that lead induced pyrimidine-5 feet-nucleotidase deficiency (PND) evokes hemolysis via accumulation in the red cell cytosol of CDP choline and CDP ethanolamine, key intermediates in the synthesis of membrane phosphoglycerides. The effect of lead, with and without secondary accumulation of CDP-C and CDP-E, will be determined on the de novo synthesis of membrane phospholipids by the reticulocyte and the kinetics of membrane phospholipid turnover and repair by mature red cells. 2) Test the hypothesis that the effects of lead on red cell metabolism are distinct from those of PND and lead-induced PND by 31P NMR studies of MgATP, glycolytic intermediates and intracellular pH. 3) Investigate the effect of lead and lead-induced PND on lecithin acyltransferase and the phospholipid:cholesterol ratio of the red cell membrane and test the hypothesis that these are the result, not the cause, of the altered surface area/volume ratio of the red cells on lead exposure. The studies will be conducted on human red cells from normal subjects, lead workers and children with undue lead exposure. Mechanistic studies will utilize the rabbit model. The functional and biochemical changes of the red cell membrane will be correlated with 4 corroborative indices of lead exposure: blood lead, red cell lead, fluorescent erythrocyte protoporphyrins and pyrimidine-5 feet-nucleotidase of the red cell cytosol.