Targeted Mutation of the Gene for Cellular Glutathione Peroxidase (Gpx1) Increases Noise-Induced Hearing Loss in Mice

Ohlemiller, Kevin K.; McFadden, Sandra L.; Ding, Dalian; Lear, Patricia M.; Ho, Ye-Shih

doi:10.1007/s101620010043

Cited by 211 publications

(155 citation statements)

References 32 publications

(3 reference statements)

Supporting

Mentioning

147

Contrasting

Unclassified

Order By: Relevance

“…Impaired function of antioxidant enzymes caused by genetic variation has been postulated as leading to failure of cellular responses against the toxic effects of ROS and subsequent peroxidative cell injury. Studies of knock-out models of Gpx1 and Sod1 have shown that deletion in the two antioxidant genes can lead to both age-related and noise-induced HL [51][52][53]. These mice show the phenotypic characteristics of ARHL.…”

Section: Oxidative Stressmentioning

confidence: 99%

Ageing and hearing loss

Yan

2007

The Journal of Pathology

270

178

View full text Add to dashboard Cite

Although many adults retain good hearing as they age, hearing loss associated with ageing is common among elderly persons. There are a number of pathophysiolological processes underlying age-related changes to functional components in the inner ear. Genetic factors determine the ageing process but are under the influence of intrinsic and environmental factors. It is difficult to distinguish changes of normal ageing from those of other contributing factors. The effects of age-related deafness can have significant physical, functional and mental health consequences. Although a deficit in hearing can be corrected to some degree by a hearing aid or other appropriate amplification devices, hearing-related rehabilitative needs are much more than simply amplifying external sound. Only by better understanding the process of ageing and its effect on the auditory function can we better accommodate elderly people in our day-to-day interactions. We review here the structure and function of the inner ear, pathophysiology associated with age-related hearing loss (ARHL), heritability, allelism and modifier genes of ARHL, and evaluate the genetic analyses for identification of genetic factors that are involved.

show abstract

Section: Oxidative Stressmentioning

confidence: 99%

Ageing and hearing loss

Yan

2007

The Journal of Pathology

270

178

View full text Add to dashboard Cite

show abstract

“…Keywords cochlea; free radical; noise; hearing; antioxidant; vasodilation Mechanical destruction of cells in the organ of Corti was once assumed to be the primary cause of noise-induced hearing loss (NIHL) [1][2][3][4][5][6][7][8], with perhaps some effect of reduced blood flow to the inner ear [9][10][11][12][13][14][15][16][17][18]. We now know that another key factor is intense metabolic activity that results in production of excess free radicals [19][20][21][22][23] and lipid peroxidation products [24]. Noise-induced production of reactive oxygen species (ROS) in the cochlea has now been well characterized, and several recent reviews are available [25][26][27].…”

mentioning

confidence: 99%

“…Upregulation of the endogenous antioxidant glutathione reduces NIHL and cell pathology [44,45], whereas the opposite is observed with reduced endogenous antioxidants [20,22,23,44]. That exogenous antioxidant agents reduce sensory cell death and NIHL has been well demonstrated in animal studies using a variety of free radical scavengers [24,[44][45][46][47][48][49][50][51][52][53][54][55][56], including several studies with dietary antioxidants [50,[57][58][59][60].…”

mentioning

confidence: 99%

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Prell

Hughes

Miller

2007

Free Radical Biology and Medicine

198

188

View full text Add to dashboard Cite

Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7-10 days following noise exposure. Reduction in cochlear blood flow as a result of free radical formation has also been described. Here we report that the antioxidant agents, vitamins A, C, and E, act in synergy with magnesium to effectively prevent noise-induced trauma. Neither the antioxidant agents nor magnesium reliably reduced NIHL or sensory cell death with the doses we used when these agents were delivered alone. In combination, however, they were highly effective in reducing both hearing loss and cell death even with treatment initiated just one hour prior to noise exposure. This study supports roles for both free radical formation and noise-induced vasoconstriction in the onset and progression of NIHL. Identification of this safe and effective antioxidant intervention that attenuates NIHL provides a compelling rationale for human trials in which free radical scavengers are used to eliminate this single major cause of acquired hearing loss. Keywords cochlea; free radical; noise; hearing; antioxidant; vasodilation Mechanical destruction of cells in the organ of Corti was once assumed to be the primary cause of noise-induced hearing loss (NIHL) [1][2][3][4][5][6][7][8], with perhaps some effect of reduced blood flow to the inner ear [9][10][11][12][13][14][15][16][17][18]. We now know that another key factor is intense metabolic activity that results in production of excess free radicals [19][20][21][22][23] and lipid peroxidation products [24]. Noise-induced production of reactive oxygen species (ROS) in the cochlea has now been well characterized, and several recent reviews are available [25][26][27]. Mitochodrial dysfunction and ROS production have been implicated in numerous neurodegenerative syndromes and diseases [28-34, see 35,36]. The use of antioxidant agents holds significant therapeutic promise for many neurodegenerative processes [32,33,[37][38][39][40][41][42], and there is some suggestion that Correspondence to: C. G. Le Prell, Kresge Hearing Research Institute, University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109-0506, USA. Tel: +1-734-763-5104; fax +1-734-764-0014. E-mail address: colleeng@umich.edu. Disclosure. Dr. Miller is a founding member and Chairman of the Board of Directors at OtoMedicine, Inc., a company that has an option to license the intellectual property described in this report. Dr. Le Prell is a paid consultant to OtoMedicine, Inc. Drs. Miller and Le Prell have disclosed these relationships to the Medical School Conflict of Interest Board at the University of Michigan; conflict management plans including semi-annual review by the Board are in place.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publicatio...

show abstract

“…Repeated blast exposure in mice showed significant increase in the expression of antioxidant enzymes, superoxide dismutase 3, and glutathione peroxidase 4 in the hippocampus and midbrain, suggesting a protective mechanism in central auditory processing (Tables 1 and 4). The influence of glutathione peroxidase and superoxide dismutase in noiseinduced hearing loss has also been reported [12,31,[33][34]. Reactive oxygen species showed an increase in the brain following repeated blast exposures [36].…”

Section: Discussionmentioning

confidence: 81%

“…Another large class of molecules involved in auditory signaling is centered on the calcium regulating proteins, which are known to have broad functions in age-and noise-related hearing loss or protection [18,[22][23][24][25][26]. The significance of reactive oxygen species and heat shock proteins in age-and noise-related auditory impairments are also reviewed in detail [10,[27][28][29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Preliminary studies on differential expression of auditory functional genes in the brain after repeated blast exposures

Valiyaveettil

Alamneh²,

Miller³

et al. 2012

JRRD

View full text Add to dashboard Cite

Abstract-The mechanisms of central auditory processing involved in auditory/vestibular injuries and subsequent tinnitus and hearing loss in Active Duty servicemembers exposed to blast are not currently known. We analyzed the expression of hearingrelated genes in different regions of the brain 6 h after repeated blast exposures in mice. Preliminary data showed that the expression of the deafness-related genes otoferlin and otoancorin was significantly changed in the hippocampus after blast exposures. Differential expression of cadherin and protocadherin genes, which are involved in hearing impairment, was observed in the hippocampus, cerebellum, frontal cortex, and midbrain after repeated blasts. A series of calcium-signaling genes that are known to be involved in auditory signal processing were also found to be significantly altered after repeated blast exposures. The hippocampus and midbrain showed significant increase in the gene expression of hearing loss-related antioxidant enzymes. Histopathology of the auditory cortex showed more significant injury in the inner layer compared to the outer layer. In summary, mice exposed to repeated blasts showed injury to the auditory cortex and significant alterations in multiple genes in the brain known to be involved in age-or noise-induced hearing impairment.

show abstract

Targeted Mutation of the Gene for Cellular Glutathione Peroxidase (Gpx1) Increases Noise-Induced Hearing Loss in Mice

Cited by 211 publications

References 32 publications

Ageing and hearing loss

Ageing and hearing loss

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Preliminary studies on differential expression of auditory functional genes in the brain after repeated blast exposures

Contact Info

Product

Resources

About