LEAD NEUROTOXICITY IN THE VISUAL SYSTEM

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Exposure to low or moderate levels of lead during development leads to long-term rod-mediated visual deficits or selective rod photoreceptor degeneration. The overall goal of the proposed research is to determine the cellular mechanisms underlying these developmental defects. The hypothesis to be tested is that lead-induced abnormalities in cellular ion regulation in rod photoreceptors are intimately involved in the complex sequence of events that ultimately result in selective rod-mediated alterations and cell death. The long-term effects of lead will be examined using retinal tissue obtained from developmentally lead-exposed rats of directly exposed to Pb2+, on the following: (1) Those sites of action and factors involved in the regulation of mitochondrial function that mediate the lead-induced inhibition of mitochondrial energy metabolism such as, (a) respiration, oxidative phosphorylation, transmembrane potential, NADH/NAD and ATP/ADP and (b) kinetic parameters of Ca2+ transport; (2) The functional properties of the light-activated cGMP-specific phosphodiesterase (cGMP-PDE) and cellular components involved in its activation which may mediate the lead- induced inhibition of this enzyme such as, the (a) activity and kinetic parameters of cGMP-PDE, (b) pattern of biosynthesis and content of the cGMP-PDE and (c) size and concentration of the mRNAs that code for the cGMP-PDE subunits, transducin subunits, opsin and 48 kD protein; (3) The functional properties of the Na+,K+-ATPase alpha isozymes to determine the mechanism underlying the preferential lead-induced inhibition of the high affinity ouabain sensitive isozyme such as, the (a) activity, number of pump sites and turnover rates of each alpha isozyme, (b) functional transport capacity of the alpha isozymes by measuring 86Rb+ uptake, and (c) partial reactions on which the rate-limiting effect of Pb2+ is exerted by examining the kinetic effects of Na+, K+, Mg2+ and ATP; (4) The concentrations and spatial-temporal distributions of Ca2+ in isolated rods using fluorescent probes and (5)The subcellular distribution and content of cell water and elemental Ca, Na, K, Mg and P in rods using electron probe X-ray microanalysis. (6) We will also investigate the rod-mediated and cone-mediated visual functions in lead-exposed juvenile monkeys using well- defined psychophysical procedures. Studies on these fundamental and interrelated cellular processes will significantly increase our knowledge of the retinal and CNS alterations produced by low and moderate level developmental lead exposure. Furthermore, determining how lead impairs visual system processing in primates may lead to an increased understanding of how lead produces neurobehavioral deficits such as learning disabilities. Finally, a determination of the underlying cellular mechanisms of lead may be used to establish possible prophylactic or therapeutic treatment to the 3-4 million children in the U.S. exposed to environmental sources of lead that place them at risk of adverse health effects.