This research will identify fundamental mechanisms by which environmental toxicants produce cochlear dysfunction and injury. This will improve prediction of ototoxic chemicals and instances where environmental contaminants potentiate the damaging effect of noise on hearing. Two central hypotheses drive this research. The first hypothesis states that the initial synapse in the auditory system formed by the inner hair cell (IHC) and Type 1 spiral ganglion cell (SGC1) is vulnerable to glutamate excitotoxicity. This hypothesis will be tested by measuring changes in spontaneous and sound-elicited firing rates of auditory nerve units following trimethyltin (TMT) and by assessing whether glutamate receptor antagonists protect against synaptic dysfunction and post-synaptic injury. Sub-hypotheses, that the excessive release of glutamate from the IHC is dependent on increased extracellular Ca++ uptake and that SGC1 dysfunction results from elevated Ca++ will be tested by determining cytosolic Ca++ levels using Ca++ sensitive fluorescent dyes, determining the source of the Ca++ elevation, and whether Ca++ channel antagonists can protect against TMT dysfunction. The second hypothesis states that elevated Ca++ levels within the outer hair cell (OHC) are responsible for dysfunction and injury observed following TMT. This hypothesis will be tested by establishing that TMT's effects at the OHC are independent of its excitotoxic action and then by relating the elevation in cytosolic Ca++ with subsequent disruption of OHC shape. Ca++ sensitive dyes will be used to assess cytosolic Ca++ levels. TMT will be used as a model compound to test these hypotheses because data from the central nervous system implicate excitotoxicity and enhanced cytosolic Ca++ levels in its neurotoxicity. While several other environmental chemicals are also important excitotoxic candidates, TMT has well established toxic effects in the cochlea at the two different targets. Further TMT provokes a very rapid toxic action in the cochlea at a dose level approximately a full order of magnitude lower than that used to detect CNS dysfunction and pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002852-12
Application #
2153201
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1983-08-01
Project End
1996-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
12
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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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