Potentiation--noise induced hearing loss--acrylonitrile

描述(申请人提供)：氧化应激被认为是一种 在与噪声暴露相关的耳蜗损伤中的重要作用 接触耳毒剂。我们假设接触毒品和化学制剂 扰乱活性氧物种(ROS)的内在缓冲可以作为 通过启动ROS促进噪声性听力损失的危险因素 在噪音的作用下。我们建议化学中间体，丙烯腈，将 以这种方式强化噪音引起的听力损失。的新陈代谢 众所周知，丙烯腈会耗尽谷胱甘肽，谷胱甘肽是一种重要的内在缓冲剂 对抗活性氧自由基(ROS)。丙烯腈的新陈代谢也会产生 体内的氰化物，能够抑制超氧化物歧化酶。 丙烯腈是50种最常见的化学品之一，它是在 每年数十亿英镑的数量。为了生成足够的数据 为了支持成功的R01赠款申请，我们提出了一系列有限的 旨在建立有效剂量反应关系的实验 在生理水平上，丙烯腈和听力损害之间的关系。这 将需要使用失真产品耳声发射(DPOAE)测试 以及通过测量化合物来评估听觉阈值 圆窗的动作电位(CAP)。我们还将建立一种剂量 丙烯腈给药与受累程度的反应关系 耳蜗中谷胱甘肽的耗竭以及氰化物的产生。最后，我们 将确定氧化应激是否在接受 噪声和丙烯腈联合暴露在耳蜗处捕获ROS的研究 均质和加合物的电子顺磁共振测量 (EPR)。

DESCRIPTION (provided by applicant): Oxidative stress is recognized to play an important role in cochlear injury associated with noise exposure as well as ototoxicant exposure. We hypothesize that exposure to drugs and chemical agents that disrupt intrinsic buffers of reactive oxygen species (ROS) can serve as risk factors for noise induced hearing loss by promoting ROS that are initiated by the noise. We propose that the chemical intermediary, acrylonitrile, will potentiate noise induced hearing loss in this manner. The metabolism of acrylonitrile is known to deplete glutathione, an important intrinsic buffer against reactive oxygen species (ROS). Acrylonitrile metabolism can also produce cyanide, in vivo, which is capable of inhibiting superoxide dismutase. Acrylonitrile is one of the 50 most common chemicals and it is produced in quantities of billions of pounds per year. In order to generate sufficient data to support a successful R01 grant application, we propose a limited series of experiments aimed at establishing an effective dose response relationship between acrylonitrile and auditory impairment at a physiological level. This will entail the use of distortion product otoacoustic emissions (DPOAE) testing along with assessment of auditory threshold via measurement of the compound action potential (CAP) from the round window. We will also establish a dose response relationship between acrylonitrile administration and extent of glutathione depletion in the cochlea as well as cyanide generation. Finally, we will determine whether oxidative stress is elevated among rats receiving combined exposure to noise and acrylonitrile by trapping ROS in cochlear homogenates and measuring the adducts by electron paramagnetic spin resonance (EPR).