MECHANISMS OF ORGANIC SOLVENT OTOTOXICITY

描述：(改编自《调查者摘要》)有机溶剂 会在人体和实验室中造成永久性听力障碍 动物。这些有机溶剂的广泛使用和特定的 已报道的听力损失的性质对公众造成了重大影响 健康风险。实验室调查似乎发现了两种截然不同的 溶剂暴露后耳蜗功能障碍和损伤的模式。一 由甲苯产生的模式涉及到外毛细胞的损伤 通常对位于中间的中频音进行编码 转身。这种耳毒性似乎源于一种偏爱的扰动 这些细胞的运动性，因此对声音的敏感性。优惠 这些细胞的变形和细胞内游离调节受损 钙水平在低浓度的甲苯中迅速出现。 预计会发生在暴露在允许水平下的人类大脑中。 因为外毛细胞本身就表现出快速的电动运动，这是一个过程 对细胞内游离钙离子浓度很敏感，它可能 特别容易受到破坏细胞内的耳毒性物质的伤害 钙调节。相比之下，三氯乙烯优先损害 内毛细胞-螺旋神经节细胞功能。这将是确定的 这是否反映了这个突触的兴奋性毒性损伤。这项建议 将表征甲苯和甲苯引起的耳蜗病的发展。 三氯乙烯重复使用对受试者内失真的评估 产物耳声发射与复合动作电位的测定 伤害目标和最低暴露浓度和持续时间 是耳毒性的。听神经综合急性耳蜗术后评估 饱和度、耳蜗微音响和耳蜗内电位测量将 指定目标单元格。将使用非耳毒性溶剂作为对照 确定耳毒性的选择性机制。甲苯优先 干扰编码中频的外毛细胞的缓慢运动 听力和通过扰乱细胞内钙升高细胞内钙 储存和/或释放机构。体外实验将确定 这种耳毒性损害的特殊的钙隔离机制 与测定外毛细胞变化之间的关系 形态计量学与外毛细胞和螺旋神经节细胞钙 动态平衡。

DESCRIPTION: (Adapted from the Investigator's Abstract) Organic solvents can produce permanent hearing impairment in people and in laboratory animals. The widespread use of these organic solvents and the specific nature of the hearing loss that has been reported pose a significant public health risk. Laboratory investigations appear to identify two distinct patterns of cochlear dysfunction and injury following solvent exposure. One pattern, produced by toluene, involves impairment of outer hair cells that normally encode middle frequency tones and which are located in the middle turns. The ototoxicity appears to stem from a preferential perturbation in motility of these cells and thereby of sensitivity to sound. Preferential dysmorphia in these cells and impaired regulation of free intracellular calcium level occurs rapidly and at the low concentrations of toluene predicted to occur in the brain of humans exposed at permissible levels. Because the outer hair cell alone shows rapid electromotility, a process that is sensitive to intracellular free calcium ion concentrations, it may be particularly vulnerable to ototoxic agents that disrupt intracellular calcium regulation. Trichloroethylene, by contrast, preferentially impairs inner hair cell-spiral ganglion cell function. It will be determined whether this reflects excitotoxic injury at this synapse. This proposal will characterize the development of cochlear impairment by toluene and trichloroethylene using repeated within subject assessment of distortion product otacoustic emission and the compound action potential to determine targets of injury and the lowest exposure concentrations and durations that are ototoxic. Comprehensive acute cochlear assessment of auditory nerve saturation, cochlear microphonic and endocochlear potential measures will specify the target cells. Non-ototoxic solvents will be used as controls to identify selective mechanisms of ototoxicity. Toluene preferentially disrupts slow motility in outer hair cells that encode middle frequency hearing and elevates intracellular calcium by disrupting intracellular storage and/or release mechanisms. In vitro experiments will identify the specific calcium sequestration mechanism that is impaired by this ototoxic solvent and determine the relationship between changes in outer hair cell morphometry and outer hair cell and spiral ganglion cell calcium homeostasis.