1985 — 1996 |
Fechter, Laurence D. |
K04Activity Code Description: Undocumented code - click on the grant title for more information. R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Ototoxicity of Chemical Asphyxiants and Noise @ Johns Hopkins University
Accurate prediction of environmental agents likely to produce specific injury to the auditory system requires an understanding of general mechanisms of ototoxicity, normal physiological adaptation of the cochlea to stress and basic metabolic requirements of the inner ear. We have been studying the ototoxicity of tin compounds and have demonstrated a very long lasting, but partially reversible patterns of hearing loss which is unusual for chemical ototoxics. We propose to determine the mechanism by which TMT produces high frequency hearing loss with particular attention paid to its possible disrupting effects on energy metabolism. We have also been studying the vulnerability of the inner ear to hypoxic exposure produced by carbon monoxide (CO) under conditions of noise exposure and in quiet. We have noted a large increase in cochlear bloodflow which results from CO exposure and may serve to maintain normal cochlear oxygen tension. However, at high carboxyhemoglobin levels we have noted a transient and specific high frequency hearing loss. CO hypoxia present concurrently during noise exposure produces a more profound and longer lasting hearing loss than does noise alone. Further, co-exposure to noise and CO shifts the region of greatest auditory loss toward higher frequencies than noise alone. We will continue to address the reason that noise and hypoxia presented simultaneously produce synergistic effects. Our study of oxidative metabolism as a general mechanism of auditory dysfunction will employ measures of hearing based on reflex modification audiometry, and electrophysiological measures of cochlear function, along with measurement of oxygen delivery and cochlear blood flow. Direct measurement of oxidative phosphorylation, tin accumulation and binding in the cochlea and subsequent histopathological studies using both surface preparation of the organ of Corti and plastic embedded thick sections for light microscopy will provide biochemical and histopathological data essential to determining mechanisms of ototoxicity.
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0.991 |
1997 — 2005 |
Fechter, Laurence D. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Models For Assessing Risk of Occupational Hearing Loss @ University of Oklahoma Hlth Sciences Ctr
DESCRIPTION: (Adapted from the Investigator's Abstract) The proposed work would identify the exposure conditions that facilitate the potentiation of noise induced hearing loss (NIHL) by the chemical asphyxiants carbon monoxide and cyanide. A strong likelihood exists that these combined exposures produce greater risk of hearing loss than noise alone at permissible exposure levels in humans, based upon positive laboratory animal data, and a preliminary understanding of the mechanisms by which chemical asphyxiants disrupt hearing. Rats will be exposed to various types of noise alone or to noise in combination with carbon monoxide and cyanide to assess both temporary and permanent impairments of auditory function. The principal objective of this investigation is to prevent human hearing loss by determining the exposure conditions that facilitate a synergistic interaction chemical asphyxiants such as cyanide and carbon monoxide and noise. The investigators will determine the relationship between exposure duration, concentration of chemical asphyxiants and noise intensity in promoting a synergistic (greater than additive) interaction as indexed by functional impairment of the cochlea and histopathological investigation. The investigators will also determine the relationship between the noise frequency spectrum and interactions with chemical asphyxiants so that accurate predictions can be applied to work place settings where band limited noise may be present.
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0.991 |
1998 — 2001 |
Fechter, Laurence D. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Organic Solvent Ototoxicity @ University of Oklahoma Hlth Sciences Ctr
DESCRIPTION: (Adapted from the Investigator's Abstract) Organic solvents can produce permanent hearing impairment in people and in laboratory animals. The widespread use of these organic solvents and the specific nature of the hearing loss that has been reported pose a significant public health risk. Laboratory investigations appear to identify two distinct patterns of cochlear dysfunction and injury following solvent exposure. One pattern, produced by toluene, involves impairment of outer hair cells that normally encode middle frequency tones and which are located in the middle turns. The ototoxicity appears to stem from a preferential perturbation in motility of these cells and thereby of sensitivity to sound. Preferential dysmorphia in these cells and impaired regulation of free intracellular calcium level occurs rapidly and at the low concentrations of toluene predicted to occur in the brain of humans exposed at permissible levels. Because the outer hair cell alone shows rapid electromotility, a process that is sensitive to intracellular free calcium ion concentrations, it may be particularly vulnerable to ototoxic agents that disrupt intracellular calcium regulation. Trichloroethylene, by contrast, preferentially impairs inner hair cell-spiral ganglion cell function. It will be determined whether this reflects excitotoxic injury at this synapse. This proposal will characterize the development of cochlear impairment by toluene and trichloroethylene using repeated within subject assessment of distortion product otacoustic emission and the compound action potential to determine targets of injury and the lowest exposure concentrations and durations that are ototoxic. Comprehensive acute cochlear assessment of auditory nerve saturation, cochlear microphonic and endocochlear potential measures will specify the target cells. Non-ototoxic solvents will be used as controls to identify selective mechanisms of ototoxicity. Toluene preferentially disrupts slow motility in outer hair cells that encode middle frequency hearing and elevates intracellular calcium by disrupting intracellular storage and/or release mechanisms. In vitro experiments will identify the specific calcium sequestration mechanism that is impaired by this ototoxic solvent and determine the relationship between changes in outer hair cell morphometry and outer hair cell and spiral ganglion cell calcium homeostasis.
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0.991 |
2002 — 2003 |
Fechter, Laurence D. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Potentiation--Noise Induced Hearing Loss--Acrylonitrile @ University of Oklahoma Hlth Sciences Ctr
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).
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0.991 |