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 following acute insults and to contribute to cumulative injury that presents as age-related hearing loss. We examined whether genetically based deficiency of cellular glutathione peroxidase, a major antioxidant enzyme, increases noise-induced hearing loss in mice. Two-month-old "knockout" mice with a targeted inactivating mutation of the gene coding for glutathione peroxidase (Gpx1) and wild type controls were exposed to broadband noise for one hour at 110 dB SPL. Auditory brainstem response (ABR) thresholds at test frequencies ranging from 5 to 40 kHz were obtained two and four weeks after exposure to determine the stable permanent component of the hearing loss. Depending 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 the 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 results support a link between genetic impairment of antioxidant defenses, vulnerability of the cochlea injury, and cochlear degeneration. Such impairment produces characteristics expected of some mutations associated with age-related hearing loss and offers one possible mechanism for their action.
Ohlemiller
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KK
Fay and Carl Simons Center for the Biology of Hearing and Deafness, Central Institute for the Deaf, St. Louis, MO 63110, USA. kohlemiller@cid.wustl.edu
McFadden
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Ding
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Lear
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Ho
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D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D001309:Auditory Threshold; D002477:Cells / Q000201:enzymology*; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D018390:Gene Targeting; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout / Q000235:genetics; D009154:Mutation; D009412:Nerve Fibers / Q000473:pathology; D000094765:Glutathione Peroxidase GPX1
D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse