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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002852-05
Application #
3250099
Study Section
Toxicology Study Section (TOX)
Project Start
1983-08-01
Project End
1992-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Liu, Y; Fechter, L D (1997) Toluene disrupts outer hair cell morphometry and intracellular calcium homeostasis in cochlear cells of guinea pigs. Toxicol Appl Pharmacol 142:270-7
Liu, Y; Rao, D; Fechter, L D (1997) Correspondence between middle frequency auditory loss in vivo and outer hair cell shortening in vitro. Hear Res 112:134-40
Fechter, L D; Liu, Y; Pearce, T A (1997) Cochlear protection from carbon monoxide exposure by free radical blockers in the guinea pig. Toxicol Appl Pharmacol 142:47-55
Liu, Y; Fechter, L D (1996) Comparison of the effects of trimethyltin on the intracellular calcium levels in spiral ganglion cells and outer hair cells. Acta Otolaryngol 116:417-21
Liu, Y; Fechter, L D (1995) Trimethyltin disrupts loudness recruitment and auditory threshold sensitivity in guinea pigs. Neurotoxicol Teratol 17:281-7
Fechter, L D; Liu, Y (1995) Elevation of intracellular calcium levels in spiral ganglion cells by trimethyltin. Hear Res 91:101-9
Liu, Y; Fechter, L D (1995) MK-801 protects against carbon monoxide-induced hearing loss. Toxicol Appl Pharmacol 132:196-202
Fechter, L D; Liu, Y (1994) Trimethyltin disrupts N1 sensitivity, but has limited effects on the summating potential and cochlear microphonic. Hear Res 78:189-96
Fechter, L D (1993) Effects of acute styrene and simultaneous noise exposure on auditory function in the guinea pig. Neurotoxicol Teratol 15:151-5
Clerici, W J; Chertoff, M E; Brownell, W E et al. (1993) In vitro organotin administration alters guinea pig cochlear outer hair cell shape and viability. Toxicol Appl Pharmacol 120:193-202

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