Assessment of cochlear toxicity in response to chronic 3,3'-iminodipropionitrile in mice reveals early and reversible functional loss that precedes overt histopathology.

The peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3'-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss.

Assessment criteria for rotated stereociliary bundles in the guinea pig cochlea.

OBJECTIVE: Our study examined the relationship between variant stereociliary bundles of cochlear outer hair cells (OHCs) and auditory function to analyze assessment criteria for rotated stereociliary bundles in the guinea pig cochlea. METHODS: Auditory brainstem response and distortion product otoacoustic emission (DPOAE) were recorded on 100 guinea pigs. Variant hair cells were identified and counted by scanning electron and light microscopy. RESULTS: The most common variation observed was rotation of stereociliary bundles in the first-row OHCs (OHC1), with most 13.3% variant OHC1 rotated 90 degrees and a few 2.5% rotated 180 degrees. Occasionally, the length and angle of the 2 arms of an OHC deviated from the norm. The auditory brainstem response threshold of affected animals increased only slightly, 20- to 30-dB sound pressure level. More importantly, amplitude of DPOAE increased significantly (40.5 dB sound pressure level). CONCLUSION: Our study suggests that rotation of stereociliary bundles in the cochlear OHC was found to be prevalent in 28% of the animals. We established the assessment criteria for rotated stereociliary bundles that were more than 10% OHC1 rotated. This hair bundle seemed to be rotated by 90 degrees from the normal orientation and was accompanied with changes of auditory function. Increased amplitude of DPOAE is associated with the variation of rotated OHC that might result in hearing loss.

Assessment of outer hair cell function and blood antioxidant status of rabbits exposed to noise and metal welding fumes.

OBJECTIVES: To investigate the interaction between welding fumes and noise in causation of hearing impairment. METHODS: Groups of rabbits (n=6) were exposed to noise, welding fumes or combination of both prior to Distortion Product Otoacoustic-Emissions (DPOAEs) analysis. The function of outer hair cells (OHCs) was examined by DPOAE assessment over a broad range of frequencies. Variations in DPOAE amplitude were compared between control (n=6) and exposed (n=18) groups. RESULTS: The DPOAEs levels measured at different frequencies (1379-6299 Hz) were found to decrease significantly (P<0.05) in rabbits exposed to 110 dB sound pressure level (SPL) broadband noise (8h/day, 12 days). In rabbits, exposed to carbon-steel welding fumes alone (157 mg/m(3)), the threshold shift was limited to the high frequencies (2759-6299 Hz), whereas, mixed exposure to noise and fumes resulted in reduction of DPOAEs at all the frequencies. Changes in DPOAEs were associated with increased susceptibility of erythrocytes to oxidation (P<0.05). Exposure to noise or fumes alone or simultaneously, suppressed total antioxidant ability of plasma as measured by ferric reducing ability of plasma (FRAP). Noise alone or in combination with fumes resulted in depletion of blood glutathione (GSH). Despite suppression of FRAP in the exposed groups, GSH was found to remain unchanged due to welding fumes suggesting that antioxidants other than GSH are affected by toxicants present in metal welding fumes. CONCLUSION: Exposure to very high levels of welding fumes can increase noise-related effects on OHC function by extending hearing threshold shift to wide band frequencies.