LEAD NEUROTOXICITY IN THE VISUAL SYSTEM

在发育过程中接触低水平或中等水平的铅会导致 长期视杆介导的视觉缺陷或选择性视杆感受器 退化。拟议研究的总体目标是确定 这些发育缺陷背后的细胞机制。这个 有待检验的假设是铅引起的细胞离子异常 杆状感光细胞的调节与复合体密切相关。 最终导致选择性棒介导的一系列事件 改变和细胞死亡。 铅的长期影响将通过视网膜组织来检验。 从发育性铅暴露大鼠直接暴露于 Pb2+，对以下方面：(1)那些作用部位和参与的因素 介导铅中毒的线粒体功能调节 抑制线粒体能量代谢，例如：(A)呼吸作用， 氧化磷酸化、跨膜电位、NADH/NAD和ATP/ADP 以及(B)钙离子转运的动力学参数；(2)功能性质 光激活的cGMP特异性磷酸二酯酶(cGMP-PDE)和 参与其激活的细胞成分可能介导铅- 对该酶的诱导抑制，如(A)活性和动力学 CGMP-PDE的参数，(B)生物合成模式和含量 CGMP-PDE和(C)编码该基因的mRNAs的大小和浓度 CGMP-PDE亚基、转导蛋白亚基、视蛋白和48kD蛋白； Na~+，K~+-ATPaseα同工酶的功能性质 优先铅致高密度脂蛋白抑制的机制 亲和性哇巴因敏感同工酶，如(A)活性、数量 每种α同工酶的泵位置和周转率，(B)功能性 通过测量86Rb+摄取测定α同工酶的转运能力，以及(C) Pb2+对其限速作用的部分反应 检测Na+、K+、Mg2+和ATP的动力学效应； 离体杆中钙离子的浓度和时空分布 使用荧光探针和(5)亚细胞分布和含量 电子探针法测定杆状细胞水和元素钙、钠、钾、镁、磷 X射线微区分析。(6)我们还将调查杆介导的和 Well-2对铅暴露幼猴视锥细胞介导的视觉功能的影响 明确的心理物理程序。 对这些基本的和相互关联的细胞过程的研究将 显著增加我们对视网膜和中枢神经系统改变的了解 由低水平和中等水平的发育铅暴露所产生。 此外，确定铅是如何损害视觉系统处理的 灵长类动物可能会增加对铅是如何产生的理解 神经行为缺陷，如学习障碍。最后，一个 铅潜在细胞机制的确定可用于 为300-400万人建立可能的预防或治疗方法 美国儿童在那里接触到环境中的铅源 他们面临着健康不良影响的风险。

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.