LEAD NEUROTOXICITY IN THE VISUAL SYSTEM

在发育过程中暴露于低水平或中等水平的铅会导致 长期视杆细胞介导的视觉缺陷或选择性视杆细胞感光器 退化 本研究的总体目标是确定 这些发育缺陷背后的细胞机制。 的 有待检验假设是，铅诱导的细胞离子异常 视杆细胞光感受器的调节与复合物密切相关 最终导致选择性杆介导的 改变和细胞死亡。 铅的长期影响将通过视网膜组织进行检查 从发育期铅暴露大鼠或直接暴露于 Pb ~（2+）对以下几个方面的影响：（1）与Pb ~（2+）有关的作用位点和因子 线粒体功能调节介导铅诱导的 抑制线粒体能量代谢，例如，（a）呼吸， 氧化磷酸化、跨膜电位、NADH/NAD和ATP/ADP （B）Ca ~（2+）转运动力学参数：（2）功能特性 光激活cGMP特异性磷酸二酯酶（cGMP-PDE）， 参与其激活的细胞成分可能介导铅， 这种酶的诱导抑制，如（a）活性和动力学 （B）cGMP-PDE的生物合成模式和含量， cGMP-PDE和（c）编码CGMP-PDE的mRNA的大小和浓度。 cGMP-PDE亚基、转导素亚基、视蛋白和48 kD蛋白; Na+，K+-ATP酶α同工酶的功能特性，以确定 优先铅诱导的高抑制的机制 亲和哇巴因敏感同工酶，例如，（a）活性，数量， 每种α同工酶的泵位点和周转率，（B）功能性 通过测量86 Rb+摄取来测定α同工酶的转运能力，和（c） 部分反应，其中Pb 2+的限速作用是由 研究Na+、K+、Mg ~（2+）和ATP的动力学效应 离体视杆细胞内Ca ~（2+）浓度及其时空分布 （5）细胞内的亚细胞分布和含量， 使用电子探针测量细胞水和杆中的元素Ca、Na、K、Mg和P X射线微区分析 (6)我们还将研究杆介导的， 铅暴露幼猴视锥细胞介导的视觉功能 明确的心理生理程序 对这些基本的和相互关联的细胞过程的研究将 显著增加了我们对视网膜和中枢神经系统改变的认识 由低水平和中等水平的铅暴露产生。 此外，确定铅如何损害视觉系统的处理， 灵长类动物的研究可能会增加对铅如何产生 神经行为缺陷，如学习障碍。 最后 铅的潜在细胞机制的确定可用于 为300万至400万人建立可能的预防或治疗方法， 美国儿童暴露于铅的环境来源， 他们面临着对健康产生不利影响的风险。

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.