OTOTOXICITY OF CHEMICAL ASPHYXIANTS AND NOISE

这项研究将确定基本机制， 毒物产生耳蜗功能障碍和损伤。 这将改善 耳毒性化学品的预测和环境 污染物加重了噪音对听力的损害作用。 两 核心假设推动了这项研究。 第一个假设指出， 听觉系统中由内毛细胞形成的最初突触 (IHC)而1型螺旋神经节细胞（SGC1）对谷氨酸敏感 兴奋性毒性 这一假设将通过测量 听神经单位的自发和声诱发放电率 三甲基锡（TMT）后，并通过评估谷氨酸受体是否 拮抗剂可防止突触功能障碍和突触后 损伤 子假设，即过量释放谷氨酸从 IHC依赖于增加的细胞外Ca++摄取，并且SGC1 由Ca++升高引起的功能障碍将通过测定 使用Ca++敏感的荧光染料测定细胞溶质Ca++水平， Ca++升高的来源，以及是否有Ca++通道拮抗剂 可以防止TMT功能障碍。 第二个假设指出， 外毛细胞（OHC）内Ca++水平升高是导致 TMT后观察到的功能障碍和损伤。 这一假设将是 通过建立TMT在OHC的影响是独立的， 它的兴奋性毒性作用，然后通过与细胞质中的升高 Ca++，随后破坏OHC形状。 Ca++敏感染料将 用于评估胞质Ca++水平。 TMT将作为一种模式 化合物来测试这些假设，因为来自中枢神经系统的数据 系统涉及兴奋性毒性和增强胞质Ca++水平， 神经毒性 虽然其他几种环境化学品也 重要的兴奋性毒性候选者，TMT具有公认的毒性作用 在耳蜗中的两个不同的目标。 进一步的TMT激发了一个非常 在剂量水平接近全剂量时， 低于用于检测CNS功能障碍的数量级， 病理

This research will identify fundamental mechanisms by which environmental toxicants produce cochlear dysfunction and injury. This will improve prediction of ototoxic chemicals and instances where environmental contaminants potentiate the damaging effect of noise on hearing. Two central hypotheses drive this research. The first hypothesis states that the initial synapse in the auditory system formed by the inner hair cell (IHC) and Type 1 spiral ganglion cell (SGC1) is vulnerable to glutamate excitotoxicity. This hypothesis will be tested by measuring changes in spontaneous and sound-elicited firing rates of auditory nerve units following trimethyltin (TMT) and by assessing whether glutamate receptor antagonists protect against synaptic dysfunction and post-synaptic injury. Sub-hypotheses, that the excessive release of glutamate from the IHC is dependent on increased extracellular Ca++ uptake and that SGC1 dysfunction results from elevated Ca++ will be tested by determining cytosolic Ca++ levels using Ca++ sensitive fluorescent dyes, determining the source of the Ca++ elevation, and whether Ca++ channel antagonists can protect against TMT dysfunction. The second hypothesis states that elevated Ca++ levels within the outer hair cell (OHC) are responsible for dysfunction and injury observed following TMT. This hypothesis will be tested by establishing that TMT's effects at the OHC are independent of its excitotoxic action and then by relating the elevation in cytosolic Ca++ with subsequent disruption of OHC shape. Ca++ sensitive dyes will be used to assess cytosolic Ca++ levels. TMT will be used as a model compound to test these hypotheses because data from the central nervous system implicate excitotoxicity and enhanced cytosolic Ca++ levels in its neurotoxicity. While several other environmental chemicals are also important excitotoxic candidates, TMT has well established toxic effects in the cochlea at the two different targets. Further TMT provokes a very rapid toxic action in the cochlea at a dose level approximately a full order of magnitude lower than that used to detect CNS dysfunction and pathology.