OTOTOXICITY OF CHEMICAL ASPHYXIANTS AND NOISE

这项研究将确定环境保护的基本机制 毒物会导致耳蜗功能障碍和损伤。这将会有所改善 耳毒性化学物质的预测和环境 污染物会加重噪音对听力的损害作用。二 中心假设推动了这项研究。第一种假设认为 内毛细胞在听觉系统中形成的初始突触 (IHC)和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变化来检验 听神经单位的自发和声诱发放电率 在三甲基锡(TMT)之后，通过评估谷氨酸受体 拮抗剂保护突触功能障碍和突触后 受伤。次假说，谷氨酸的过度释放 IHC依赖于细胞外钙摄取的增加，而SGC1 钙离子升高导致的功能障碍将通过检测 用钙离子敏感的荧光染料测定细胞内钙离子水平 钙离子升高的来源，以及钙离子通道拮抗剂 可以防止TMT功能障碍。第二种假设认为 外毛细胞(OHC)内钙离子水平升高是 观察TMT后的功能障碍和损伤情况。这一假设将是 通过建立TMT在OHC的影响独立于 它的兴奋毒性作用，然后通过联系胞浆中的升高 Ca++，随后OHC形状被破坏。CA++敏感染料将 可用来评估细胞内钙离子水平。TMT将被用作模型 来检验这些假说的化合物是因为来自中枢神经系统的数据 系统涉及兴奋性毒性和ITS细胞内钙离子水平升高 神经毒性。而其他几种环境化学品也在 重要的兴奋性毒性候选物质，TMT具有良好的毒性作用 在两个不同的目标耳蜗处。进一步的TMT激起了非常大的 耳蜗内的快速毒性作用，剂量水平约为 低于用于检测中枢神经系统功能障碍的数量级 病理学。

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.