Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice

Reactive oxygen species (ROS) and oxidative stress have been implicated in cochlear injury following loud noise and ototoxins. Genetic mutations that impair antioxidant defenses would be expected to increase cochlear injury f ollowing acute insults and to contribute to cumulative injury that presents as age-related hearing loss. We examined whether genetically based deficie ncy of cellular glutathione peroxidase, a major antioxidant enzyme, increas es noise-induced hearing loss in mice. Two-month-old "knockout" mice with a targeted inactivating mutation of the gene coding for glutathione peroxida se (Gpx1) and wild type controls were exposed to broadband noise for one ho ur at 110 dB SPL. Auditory brainstem response (ABR) thresholds at test freq uencies ranging from 5 to 40 kHz were obtained two and four weeks after exp osure to determine the stable permanent component of the hearing loss. Depe nding on test frequency, (compared with controls) Gpx1 knockout mice showed up to 16 dB higher ABR thresholds prior to noise exposure, and up to 15 dB greater noise-induced hearing loss, compared with normal control. Within t he cochlear base, there was also a significant contribution of the knockout to inner and outer hair cell loss, as well as nerve fiber loss. Our result s support a link between genetic impairment of antioxidant defenses, vulner ability of the cochlea injury, and cochlear degeneration. Such impairment p roduces characteristics expected of some mutations associated with age-rela ted hearing loss and offers one possible mechanism for their action.