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).
| Pouyatos, Benoit; Gearhart, Caroline A; Fechter, Laurence D (2005) Acrylonitrile potentiates hearing loss and cochlear damage induced by moderate noise exposure in rats. Toxicol Appl Pharmacol 204:46-56 |
| Fechter, Laurence D; Gearhart, Caroline; Shirwany, Najeeb A (2004) Acrylonitrile potentiates noise-induced hearing loss in rat. J Assoc Res Otolaryngol 5:90-8 |
| Fechter, Laurence D; Klis, Sjaak F L; Shirwany, Najeeb A et al. (2003) Acrylonitrile produces transient cochlear function loss and potentiates permanent noise-induced hearing loss. Toxicol Sci 75:117-23 |
