Models for Assessing Risk of Occupational Hearing Loss

描述(申请人提供)：听力损失是美国最常见的职业伤害。超过3000万工人暴露在潜在的危险噪音中，900万工人暴露在耳毒性化学物质中。这项资助的重点是确定化学窒息增强噪声诱导听力的机制和条件。 损失(NIHL)。化学窒息是有用的模型化合物，因为氰化氢和一氧化碳在与工作场所相关的暴露水平下会增强大鼠的NIHL。消防员、重型设备操作员、隧道和通行费工人以及卡车司机同时暴露在噪音和化学窒息中。我们将检验一个分两个阶段的假设，即噪音和窒息“引发”活性氧物种(ROS)的产生，而窒息则通过损害内在的ROS缓冲机制来“促进”这种应激。使用电生理和声学方法比较治疗组之间的耳蜗功能。通过琥珀酸脱氢酶活性染色检测相应的组织病理损伤。在药物治疗后，将评估窒息暴露对NIHL的增强作用，这些药物可以增强和抑制内在的ROS缓冲 系统。如果ROS促进对NIHL的增强至关重要，那么加强ROS清除的治疗将降低易感性。此外，减少ROS清除的治疗将增加易感性。生化研究将证实药物治疗对内在ROS缓冲的有效性。将使用电子顺磁共振波谱(EPR)在耳蜗处直接测量ROS。最后，免疫组织化学方法将被用来确定混合暴露在耳蜗中选定的应激途径上的后果。

DESCRIPTION (provided by applicant): Hearing loss is the most common occupational injury in the United States. More than 30 million workers are exposed to potentially hazardous noise and 9 million workers have exposure to ototoxic chemicals. The focus of this grant is identifying the mechanisms and conditions under which chemical asphyxiates potentiate noise induced hearing loss (NIHL). Chemical asphyxiates serve as useful model compounds because hydrogen cyanide and carbon monoxide potentiate NIHL in rats at exposure levels relevant to the workplace. Fire fighters, operators of heavy equipment, tunnel and toll workers, and truck drivers are exposed to noise and chemical asphyxiants simultaneously. A two-stage hypothesis will be tested whereby noise and asphyxiant "initiate" reactive oxygen species (ROS) generation and asphyxiants "promote" this stress by impairing intrinsic ROS buffering mechanisms. Cochlear function will be compared among treatment groups using electrophysiological and acoustic methods. Corresponding histopathological injury will be detected by staining for succinate dehydrogenase activity. Potentiation of NIHL by asphyxiant exposure will be assessed following pharmacological treatments that enhance and depress intrinsic ROS buffering systems. If ROS promotion is critical to potentiation of NIHL, then treatments that enhance ROS scavenging will reduce susceptibility. Also, treatments that decrease ROS scavenging will increase susceptibility. Biochemical studies will confirm the effectiveness of drug treatment on intrinsic ROS buffering. Direct measurement of ROS will be performed in the cochlea using electron paramagnetic spin resonance spectrometry (EPR). Finally, immunohistochemical methods will be used to define the consequences of mixed exposures on selected stress pathways in the cochlea.