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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003183-10
Application #
2153247
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1992-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Houston
Department
Ophthalmology
Type
Schools of Optometry/Ophthalmol
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77204
He, Lihua; Perkins, Guy A; Poblenz, Ann T et al. (2003) Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice. Proc Natl Acad Sci U S A 100:1022-7
Fox, D A; Poblenz, A T; He, L et al. (2003) Pharmacological strategies to block rod photoreceptor apoptosis caused by calcium overload: a mechanistic target-site approach to neuroprotection. Eur J Ophthalmol 13 Suppl 3:S44-56
Perkins, Guy A; Ellisman, Mark H; Fox, Donald A (2003) Three-dimensional analysis of mouse rod and cone mitochondrial cristae architecture: bioenergetic and functional implications. Mol Vis 9:60-73
Kueng-Hitz, N; Grimm, C; Lansel, N et al. (2000) The retina of c-fos-/- mice: electrophysiologic, morphologic and biochemical aspects. Invest Ophthalmol Vis Sci 41:909-16
He, L; Poblenz, A T; Medrano, C J et al. (2000) Lead and calcium produce rod photoreceptor cell apoptosis by opening the mitochondrial permeability transition pore. J Biol Chem 275:12175-84
Soderpalm, A K; Fox, D A; Karlsson, J O et al. (2000) Retinoic acid produces rod photoreceptor selective apoptosis in developing mammalian retina. Invest Ophthalmol Vis Sci 41:937-47
Timmers, A M; Fox, D A; He, L et al. (1999) Rod photoreceptor maturation does not vary with retinal eccentricity in mammalian retina. Curr Eye Res 18:393-402
Adamus, G; Machnicki, M; Elerding, H et al. (1998) Antibodies to recoverin induce apoptosis of photoreceptor and bipolar cells in vivo. J Autoimmun 11:523-33
He, L; Campbell, M L; Srivastava, D et al. (1998) Spatial and temporal expression of AP-1 responsive rod photoreceptor genes and bZIP transcription factors during development of the rat retina. Mol Vis 4:32
Fox, D A; He, L; Poblenz, A T et al. (1998) Lead-induced alterations in retinal cGMP phosphodiesterase trigger calcium overload, mitochondrial dysfunction and rod photoreceptor apoptosis. Toxicol Lett 102-103:359-61

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