Potentiation--noise induced hearing loss--acrylonitrile

描述（由申请人提供）：氧化应激被认为是 在噪声暴露相关耳蜗损伤中的重要作用 耳毒性暴露我们假设接触药物和化学制剂 破坏活性氧（ROS）的内在缓冲区， 噪声性听力损失的危险因素，通过促进 被噪音吓到了我们建议化学中间体丙烯腈将 以这种方式增强噪声引起的听力损失。的代谢 已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（ROS）。丙烯腈代谢也可以产生 氰化物，在体内，这是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， 每年数十亿磅的数量。为了生成足够的数据 为了支持R01赠款申请的成功，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 丙烯腈和听觉障碍之间的关系这 将需要使用畸变产物耳声发射（DPOAE）测试 沿着通过测量化合物来评估听觉阈值 动作电位（CAP）的圆窗。我们还将确定一个剂量 丙烯腈给药与程度的反应关系 耳蜗中谷胱甘肽的消耗以及氰化物的产生。最后我们 将确定是否氧化应激在大鼠接受 噪声与丙烯腈联合暴露对耳蜗活性氧的捕获作用 匀浆并通过电子顺磁自旋共振测量加合物 （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).