MECHANISMS OF ORGANIC SOLVENT OTOTOXICITY

有机溶剂耳毒性的机制

• 批准号: 6084873
• 负责人: LAURENCE D. FECHTER
• 金额: $ 0.53万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6084873
• 关键词: action potentials; calcium flux; calcium indicator; cell motility; cell population study; cochlear lesion; cochlear microphonic potentials; cytotoxicity; dosage; ear hair cell; electrophysiology; environmental toxicology; ganglion cell; guinea pigs; hearing disorders; neural transmission; neurotoxins; nonwater solvent; otoacoustic emission; toluene; trichloroethylene

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.

性状：（改编自研究者摘要）有机溶剂 在人体和实验室中会造成永久性听力损伤 动物 这些有机溶剂的广泛使用和特定的有机溶剂的使用， 已报告的听力损失的性质构成了一个重大的公众 健康风险。 实验室调查似乎确定了两种不同的 溶剂暴露后耳蜗功能障碍和损伤的模式。 一 模式，由甲苯产生，涉及损害外毛细胞， 通常编码中频音调 转弯 耳毒性似乎源于一个优先扰动， 这些细胞的运动性，从而对声音的敏感性。 优惠 这些细胞中的变形障碍和受损的细胞内游离 在甲苯浓度低时， 预计在允许的水平下，人类的大脑中会出现这种情况。 因为外毛细胞单独显示快速的电活动， 对细胞内游离钙离子浓度敏感， 特别容易受到破坏细胞内 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。 将确定 这是否反映了这个突触的兴奋性毒性损伤。 这项建议 将描述甲苯对耳蜗损害的发展， 三氯乙烯使用重复受试者内失真评估 产物耳声发射和复合动作电位，以确定 伤害的目标和最低接触浓度和持续时间， 是耳毒性的 听神经急性耳蜗综合评价 饱和度、耳蜗颤噪和耳蜗内电位测量将 指定目标细胞。 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 破坏编码中频的外毛细胞的缓慢运动 听力和提高细胞内钙通过破坏细胞内 存储和/或释放机构。 体外实验将确定 这种耳毒性损害了特定的钙螯合机制， 溶剂与确定外毛细胞变化之间的关系 外毛细胞和螺旋神经节细胞的形态计量学和钙 体内平衡