dB Threshold Shift Research Articles

Complications of Cochleostomy Versus Round Window Surgical Approaches: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to compare round window (RW) and cochleostomy (C) surgical approaches for the placement of cochlear implants (CIs). After obtaining the Institutional Review Board (IRB) approval, 213 peer-reviewed articles published between January 1, 2000, and August 1, 2021, comparing RW and C approaches were identified via a search on Google Scholar, Cochrane, and PubMed. The inclusion criteria were articles having an English version and involving only human subjects (cadaveric or alive). Statistical analysis of compiled electrode-to-modiolus distances was performed with two-sample independent t-tests. Live patients were categorized as having complete hearing preservation (<10 dB threshold shift), partial hearing preservation (10-20 dB shift), or minimal hearing preservation (>20 dB shift). Chi-squared testing was used to compare the distribution of hearing preservation categories between surgical approaches. Due to the heterogeneous nature of the data, only summative information was provided on the effects of approaches on trauma, electrical impedance, speech perception, vestibular dysfunction, ease of scala tympani insertion, and scalar shift. A total of 3,797 CI patients were evaluated. The RW approach resulted in a smaller (0.15 mm smaller on average, p<0.05) electrode-to-modiolus distance when compared to the C approach. The RW approach (93.0%) led to statistically better hearing preservation than the C approach (84.3%) (p<0.05). The RW approach was also associated with better outcomes in terms of speech perception, ease of scala tympani insertion, and reduced scalar shift. No difference between approaches was found with regard to trauma, electrical impedance, and vestibular dysfunction. Based on our findings, the RW approach appears to have several benefits compared to the C approach.

Transtympanic Sodium Thiosulfate for Prevention of Cisplatin-Induced Ototoxicity: A Randomized Clinical Trial.

To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL).DESIGN Randomized controlled trial.SETTING Tertiary cancer hospital.PATIENTS Adults to be treated with high-dose cisplatin (≥ 75 mg/m2).INTERVENTION Selected by randomization, 0.1 M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated. Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a ≥ 10 dB threshold shift at pure-tone average 8-10-12.5 kHz (PTA8-12.5). Response to STS was defined as a threshold shift at PTA8-12.5 in the STS-treated ear of ≥ 10 dB smaller than the untreated ear. Twelve patients were treated. Average CIHL at PTA8-12.5 was 12.7 dB in untreated ears and 8.8 dB SPL in STS-treated ears (p = 0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA8-12.5 in STS-treated ears was 18.4 dB less compared to untreated ears (p = 0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients. Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale.

Hearing Preservation Outcomes Using a Precurved Electrode Array Inserted With an External Sheath.

Describe audiologic outcomes in hearing preservation cochlear implantation (CI) using a precurved electrode array inserted using an external sheath and evaluate association of electrode positioning and preservation of residual hearing. Retrospective review. Tertiary otologic center. Twenty-four adult patients who underwent hearing preservation CI with precurved electrode array. CI, intraoperative computed tomography (CT) OUTCOME MEASURES:: Audiologic measures (consonant-nucleus-consonant [CNC] words, AzBio sentences, low-frequency pure tone averages [LFPTA]) and electrode location (scalar location, electrode-to-modiolus distance ((Equation is included in full-text article.)), angular insertion depth). Twenty-four adults with less than 80 dB LFPTA with a precurved electrode array inserted using an external sheath; 16 underwent intraoperative CT. LFPTA was 58.5 dB HL preoperatively, with a 17.3 dB threshold shift at CI activation (p = 0.005). CNC word scores improved from 6% preoperatively to 64% at 6 months postoperatively (p < 0.0001). There was one scalar translocation and no tip fold-overs. The average angular insertion depth was 388.2 degrees, and the average (Equation is included in full-text article.)across all electrodes was 0.36 mm. Multivariate regression revealed a significant correlation between CNC scores at 6 months and angular insertion depth (p = 0.0122; r = 0.45, adjusted r = 0.35). Change in LFPTA was not significantly associated with angular insertion depth or (Equation is included in full-text article.). A low rate of translocation allows a precurved electrode array inserted using an external sheath to maintain hearing preservation rates comparable to straight electrode arrays. With scala tympani insertion, angular insertion depth is a positive marker of improved speech performance postoperatively but may be a confounder variable based on individual cochlear size.

Reduction of sound-evoked midbrain responses observed by functional magnetic resonance imaging following acute acoustic noise exposure.

Short duration and high intensity acoustic exposures can lead to temporary hearing loss and auditory nerve degeneration. This study investigates central auditory system function following such acute exposures after hearing loss recedes. Adult rats were exposed to 100 dB sound pressure level noise for 15 min. Auditory brainstem responses (ABRs) were recorded with click sounds to check hearing thresholds. Functional magnetic resonance imaging (fMRI) was performed with tonal stimulation at 12 and 20 kHz to investigate central auditory changes. Measurements were performed before exposure (0D), 7 days after (7D), and 14 days after (14D). ABRs show an ∼6 dB threshold shift shortly after exposure, but no significant threshold differences between 0D, 7D, and 14D. fMRI responses are observed in the lateral lemniscus (LL) and inferior colliculus (IC) of the midbrain. In the IC, responses to 12 kHz are 3.1 ± 0.3% (0D), 1.9 ± 0.3% (7D), and 2.9 ± 0.3% (14D) above the baseline magnetic resonance imaging signal. Responses to 20 kHz are 2.0 ± 0.2% (0D), 1.4 ± 0.2% (7D), and 2.1 ± 0.2% (14D). For both tones, responses at 7D are less than those at 0D (p < 0.01) and 14D (p < 0.05). In the LL, similar trends are observed. Acute exposure leads to functional changes in the auditory midbrain with timescale of weeks.

The Auditory Nerve Overlapped Waveform (ANOW) Detects Small Endolymphatic Manipulations That May Go Undetected by Conventional Measurements.

Electrocochleography (ECochG) has been used to assess Ménière's disease, a pathology associated with endolymphatic hydrops and low-frequency sensorineural hearing loss. However, the current ECochG techniques are limited for use at high-frequencies only (≥1 kHz) and cannot be used to assess and understand the low-frequency sensorineural hearing loss in ears with Ménière's disease. In the current study, we use a relatively new ECochG technique to make measurements that originate from afferent auditory nerve fibers in the apical half of the cochlear spiral to assess effects of endolymphatic hydrops in guinea pig ears. These measurements are made from the Auditory Nerve Overlapped Waveform (ANOW). Hydrops was induced with artificial endolymph injections, iontophoretically applied Ca2+ to endolymph, and exposure to 200 Hz tones. The manipulations used in this study were far smaller than those used in previous investigations on hydrops. In response to all hydropic manipulations, ANOW amplitude to moderate level stimuli was markedly reduced but conventional ECochG measurements of compound action potential thresholds were unaffected (i.e., a less than 2 dB threshold shift). Given the origin of the ANOW, changes in ANOW amplitude likely reflect acute volume disturbances accumulate in the distensible cochlear apex. These results suggest that the ANOW could be used to advance our ability to identify initial stages of dysfunction in ears with Ménière's disease before the pathology progresses to an extent that can be detected with conventional measures.

A faceoff with hazardous noise: Noise exposure and hearing threshold shifts of indoor hockey officials

ABSTRACTNoise exposure and hearing thresholds of indoor hockey officials of the Western States Hockey League were measured to assess the impact of hockey game noise on hearing sensitivity. Twenty-nine hockey officials who officiated the league in an arena in southeastern Wyoming in October, November, and December 2014 participated in the study. Personal noise dosimetry was conducted to determine if officials were exposed to an equivalent sound pressure level greater than 85 dBA. Hearing thresholds were measured before and after hockey games to determine if a 10 dB or greater temporary threshold shift in hearing occurred. Pure-tone audiometry was conducted in both ears at 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz. All noise exposures were greater than 85 dBA, with a mean personal noise exposure level of 93 dBA (SD = 2.2), providing 17.7% (SD = 6.3) of the officials' daily noise dose according to the OSHA criteria. Hearing threshold shifts of 10 dB or greater were observed in 86.2% (25/29) of officials, with 36% (9/25) of those threshold shifts equaling 15 dB or greater. The largest proportion of hearing threshold shifts occurred at 4000 Hz, comprising 35.7% of right ear shifts and 31.8% of left ear shifts. The threshold shifts between the pre- and post-game audiometry were statistically significant in the left ear at 500 (p=.019), 2000 (p=.0009), 3000 (p<.0001) and 4000 Hz (p=.0002), and in the right ear at 2000 (p=.0001), 3000 (p=.0001) and 4000 Hz (p<.0001), based on Wilcoxon-ranked sum analysis. Although not statistically significant at alpha = 0.05, logistic regression indicated that with each increase of one dB of equivalent sound pressure measured from personal noise dosimetry, the odds of a ≥ 10 dB TTS were increased in the left ear at 500 (OR=1.33, 95% CI 0.73-2.45), 3000 (OR=1.02, 95% CI 0.68-1.51), 4000 (OR=1.26, 95% CI 0.93-1.71) and 8000 Hz (OR=1.22, 95% CI 0.76-1.94) and in the right ear at 6000 (OR=1.03, 95% CI 0.14-7.84) and 8000 Hz (OR=1.29, 95% CI 0.12-13.83). These findings suggest that indoor hockey officials are exposed to hazardous levels of noise, experience temporary hearing loss after officiating games, and a hearing conservation program is warranted. Further temporary threshold shift research has the potential to identify officials of other sporting events that are at an increased risk of noise-induced hearing loss.

Longitudinal Changes in Audiometric Phenotypes of Age-Related Hearing Loss.

Presbyacusis, or age-related hearing loss, can be characterized in humans as metabolic and sensory phenotypes, based on patterns of audiometric thresholds that were established in animal models. The metabolic phenotype is thought to result from deterioration of the cochlear lateral wall and reduced endocochlear potential that decreases cochlear amplification and produces a mild, flat hearing loss at lower frequencies coupled with a gradually sloping hearing loss at higher frequencies. The sensory phenotype, resulting from environmental exposures such as excessive noise or ototoxic drugs, involves damage to sensory and non-sensory cells and loss of the cochlear amplifier, which produces a 50-70dB threshold shift at higher frequencies. The mixed metabolic + sensory phenotype exhibits a mix of lower frequency, sloping hearing loss similar to the metabolic phenotype, and steep, higher frequency hearing loss similar to the sensory phenotype. The current study examined audiograms collected longitudinally from 343 adults 50-93years old (n=686 ears) to test the hypothesis that metabolic phenotypes increase with increasing age, in contrast with the sensory phenotype. A Quadratic Discriminant Analysis (QDA) was used to classify audiograms from each of these ears as (1) Older-Normal, (2) Metabolic, (3) Sensory, or (4) Metabolic + Sensory phenotypes. Although hearing loss increased systematically with increasing age, audiometric phenotypes remained stable for the majority of ears (61.5%) over an average of 5.5years. Most of the participants with stable phenotypes demonstrated matching phenotypes for the left and right ears. Audiograms were collected over an average period of 8.2 years for ears with changing audiometric phenotypes, and the majority of those ears transitioned to a Metabolic or Metabolic + Sensory phenotype. These results are consistent with the conclusion that the likelihood of metabolic presbyacusis increases with increasing age in middle to older adulthood.

Plastic changes along auditory pathway during salicylate-induced ototoxicity: Hyperactivity and CF shifts

High dose of salicylate, the active ingredient in aspirin, has long been known to induce transient hearing loss, tinnitus and hyperacusis making it a powerful experimental tool. These salicylate-induced perceptual disturbances are associated with a massive reduction in the neural output of the cochlea. Paradoxically, the diminished neural output of the cochlea is accompanied by a dramatic increase in sound-evoked activity in the auditory cortex (AC) and several other parts of the central nervous system. Exactly where the increase in neural activity begins and builds up along the central auditory pathway are not fully understood. To address this issue, we measured sound-evoked neural activity in the cochlea, cochlear nucleus (CN), inferior colliculus (IC), and AC before and after administering a high dose of sodium salicylate (SS, 300 mg/kg). The SS-treatment abolished low-level sound-evoked responses along the auditory pathway resulting in a 20–30 dB threshold shift. While the neural output of the cochlea was substantially reduced at high intensities, the neural responses in the CN were only slightly reduced; those in the IC were nearly normal or slightly enhanced while those in the AC considerably enhanced, indicative of a progress increase in central gain. The SS-induced increase in central response in the IC and AC was frequency-dependent with the greatest increase occurring in the mid-frequency range the putative pitch of SS-induced tinnitus. This frequency-dependent hyperactivity appeared to result from shifts in the frequency receptive fields (FRF) such that the response areas of many FRF shifted/expanded toward the mid-frequencies. Our results suggest that the SS-induced threshold shift originates in the cochlea. In contrast, enhanced central gain is not localized to one region, but progressively builds up at successively higher stage of the auditory pathway either through a loss of inhibition and/or increased excitation.

Loss of function of Ywhah in mice induces deafness and cochlear outer hair cell’s degeneration

Loss of function of Ywhah in mice induces deafness and cochlear outer hair cell’s degeneration

Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice.

Numerous proteins act as buffers, sensors, or pumps to control calcium levels in cochlear hair cells. In the inner ear, EF-hand calcium buffers may play a significant role in hair cell function but have been very difficult to study. Unlike other reports of genetic disruption of EF-hand calcium buffers, deletion of oncomodulin (Ocm), which is predominately found in outer hair cells, leads to a progressive hearing loss after 1 month, suggesting that Ocm critically protects hearing in the mature ear.

Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin.

Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-β-cyclodextrin (HPβCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1week of subcutaneous drug treatment. In the current study, the impact of HPβCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPβCD caused up to 60dB threshold shifts and widespread OHC loss in a dose-dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPβCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism.

Aging after noise exposure: acceleration of cochlear synaptopathy in "recovered" ears.

Cochlear synaptic loss, rather than hair cell death, is the earliest sign of damage in both noise- and age-related hearing impairment (Kujawa and Liberman, 2009; Sergeyenko et al., 2013). Here, we compare cochlear aging after two types of noise exposure: one producing permanent synaptic damage without hair cell loss and another producing neither synaptopathy nor hair cell loss. Adult mice were exposed (8-16 kHz, 100 or 91 dB SPL for 2 h) and then evaluated from 1 h to ∼ 20 months after exposure. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses (ABRs). Cochlear whole mounts and plastic sections were studied to quantify hair cells, cochlear neurons, and the synapses connecting them. The synaptopathic noise (100 dB) caused 35-50 dB threshold shifts at 24 h. By 2 weeks, thresholds had recovered, but synaptic counts and ABR amplitudes at high frequencies were reduced by up to ∼ 45%. As exposed animals aged, synaptopathy was exacerbated compared with controls and spread to lower frequencies. Proportional ganglion cell losses followed. Threshold shifts first appeared >1 year after exposure and, by ∼ 20 months, were up to 18 dB greater in the synaptopathic noise group. Outer hair cell losses were exacerbated in the same time frame (∼ 10% at 32 kHz). In contrast, the 91 dB exposure, producing transient threshold shift without acute synaptopathy, showed no acceleration of synaptic loss or cochlear dysfunction as animals aged, at least to ∼ 1 year after exposure. Therefore, interactions between noise and aging may require an acute synaptopathy, but a single synaptopathic exposure can accelerate cochlear aging.

Ubiquitous aspirin: a systematic review of its impact on sensorineural hearing loss.

This systematic review evaluates the impact of aspirin on audiometric outcomes with respect to: (1) doses exceeding 325 mg daily, (2) doses of 325 mg daily or less, (3) studies applicable to the general populace, and (4) studies applicable to those with inflammatory conditions. It also assesses the impact of aspirin on (a) self-reported hearing loss, (b) noise-induced audiometric changes, and (c) the adverse otological effects of aminoglycoside therapy. Computerized searches of MEDLINE, PubMed, Cochrane, and EMBASE databases were performed, updated through January 2014, and supplemented by manual searches and inquiries to topic experts. A systematic review was performed according to an a priori protocol. Data extraction was performed by 2 independent parties and focused on relevant audiological measurements, potential confounders, and study design elements associated with risk of bias, including utilization of randomization, prospective/retrospective data collection, and incorporation of blinding. The 37 criterion-meeting studies included a combined total of 185,155 participants. Aspirin ingestion ≥ 1.95 g/d was associated with worse audiometric results (4-112 dB threshold shift); the effect was dose dependent and reversible in the short term. There were no audiometric data that confirm that long-term doses of 81 mg or 325 mg daily have no hearing consequences. Paradoxically, aspirin (in doses shown to be detrimental in isolation) had a protective effect when co-administered with intravenous gentamicin. With the large-scale population utilization of aspirin for cardiovascular prophylaxis, the potential risks to hearing health should be considered for future longitudinal study, particularly given that short-term effects may be reversible.

Prolonged noise exposure-induced auditory threshold shifts in rats

Noise-induced hearing loss (NIHL) initially increases with exposure duration, but eventually reaches an asymptotic threshold shift (ATS) once the exposure duration exceeds 18–24 h. Equations for predicting the ATS have been developed for several species, but not for rats, even though this species is extensively used in noise exposure research. To fill this void, we exposed rats to narrowband noise (NBN, 16–20 kHz) for 5 weeks starting at 80 dB SPL in the first week and then increasing the level by 6 dB per week to a final level of 104 dB SPL. Auditory brainstem responses (ABR) were recorded before, during, and following the exposure to determine the amount of hearing loss. The noise induced threshold shift to continuous long-term exposure, defined as compound threshold shift (CTS), within and above 16–20 kHz increased with noise level at the rate of 1.82 dB threshold shift per dB of noise level (NL) above a critical level (C) of 77.2 dB SPL i.e. CTS = 1.82(NL-77.2). The normalized amplitude of the largest ABR peak measured at 100 dB SPL decreased at the rate of 3.1% per dB of NL above the critical level of 76.9 dB SPL, i.e., %ABR Reduction = 3.1%(NL-76.9). ABR thresholds measured >30 days post-exposure only partially recovered resulting in a permanent threshold shift of 30–40 dB along with severe hair cell loss in the basal, high-frequency region of the cochlea. In the rat, CTS increases with noise level with a slope similar to humans and chinchillas. The critical level (C) in the rat is similar to that of humans, but higher than that of chinchillas.

Diaphanous homolog 3 (Diap3) Overexpression Causes Progressive Hearing Loss and Inner Hair Cell Defects in a Transgenic Mouse Model of Human Deafness

We previously demonstrated that a mutation in the 5′ untranslated region of Diaphanous homolog 3 (DIAPH3) results in 2 to 3-fold overexpression of the gene, leading to a form of delayed onset, progressive human deafness known as AUNA1 (auditory neuropathy, nonsyndromic, autosomal dominant, 1). To investigate the mechanism of deafness, we generated two lines of transgenic mice overexpressing Diap3, the murine ortholog of DIAPH3, on an FVB/NJ background. Line 771 exhibits a relatively mild 20 dB hearing loss at 12 kHz at 4 and 8 weeks of age, progressing to 40 dB and 60 dB losses at 16 and 24 weeks, respectively, at 12 and 24 kHz. Line 924 shows no hearing loss at 4 or 8 weeks, but manifests 35 and 50 dB threshold shifts at 16 and 24 weeks, respectively, at both 12 and 24 kHz. Notably, mice from the two transgenic lines retain distortion product otoacoustic emissions, indicative of normal cochlear outer hair cell (OHC) function despite elevation of auditory thresholds. Scanning electron microscopy of the organ of Corti demonstrates striking anomalies of the inner hair cell (IHC) stereocilia, while OHCs are essentially intact. Over time, IHCs of both lines develop elongated stereocilia that appear fused with neighboring stereocilia, in parallel to the time course of hearing loss in each line. Furthermore, we observe significant reduction in the number of IHC ribbon synapses over 24 weeks in both lines, although this reduction does not correlate temporally with onset and progression of hearing loss or stereociliary anomalies. In summary, overexpression of wild-type Diap3 in two lines of transgenic mice results in hearing loss that recapitulates human AUNA1 deafness. These findings suggest an essential role of Diap3 in regulating assembly and/or maintenance of actin filaments in IHC stereocilia, as well as a potential role at the IHC ribbon synapse.

A new connection: Enhanced hearing ability in the New Zealand bigeye, Pempheris adspersa.

Recently the bigeye, Pempheris adspersa, has been found to be one of the few sound producing fish found in the temperate marine waters of New Zealand. An initial crude morphological examination of this species found a special connection, analogous to that of the well-defined laterophysic connection, between the otic capsule and the lateral line recess. The aim of the present study was to characterize the hearing ability of the bigeye using auditory evoked potentials, understand the role of this special connection, and describe the morphology of the hearing structures using microCT and MRI techniques. The novel connection consists of a robust ligament directly connecting the otic capsule to the lateral recess, with the swim bladder running directly posterior to the ligament. Pempheris adspersa could hear in the frequency range 100–1000 Hz, with greatest sensitivity between 100–800 Hz. Cutting the connecting ligament resulted in a 15–20 dB threshold shift, with a further 5–10 dB shift after swim bladder puncture. This connection represents a completely novel hearing specialization and shows that the lateral line is directly connected to the otic capsule, enhancing the hearing ability of this species especially at low frequencies (100–200 Hz).

The effect of stimulus type and background noise on hearing abilities of the round goby Neogobius melanostomus

The auditory abilities of the round goby Neogobius melanostomus were quantified using auditory evoked potential recordings, using tone bursts and conspecific call stimuli. Fish were tested over a range of sizes to assess effects of growth on hearing ability. Tests were also run with and without background noise to assess the potential effects of masking in a natural setting. Neogobius melanostomus detected tone bursts from 100 to 600 Hz with no clear best frequency in the pressure domain but were most sensitive to 100 Hz tone stimuli when examined in terms of particle acceleration. Responses to a portion of the N. melanostomus call occurred at a significantly lower threshold than responses to pure tone stimulation. There was no effect of size on N. melanostomus hearing ability, perhaps due to growth of the otolith keeping pace with growth of the auditory epithelium. Neogobius melanostomus were masked by both ambient noise and white noise, but not until sound pressure levels were relatively high, having a 5-10 dB threshold shift at noise levels of 150 dB re 1 µPa and higher but not at lower noise levels.

Expression of Insulin-like Growth Factors in a Mouse Model of Salicylate Ototoxicity

ObjectivesInsulin-like growth factors (IGFs) are known to be neurotrophic factors, and they efficiently signal to cells to grow, differentiate and survive. The purpose of study was to identify the expressions of IGFs in mice with salicylate ototoxicity, which is a typical reversible hearing loss model.MethodsThe mice were given intraperitoneal injections of salicylate (400 mg/kg) and about a 30 dB threshold shift was achieved at 3 hours. The expressions of IGF-1 and 2 were confirmed by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Localization of IGFs was confirmed using confocal immunofluorescence imaging. For in-vitro study on the HEI-OC1 auditory cells, the cell viability was calculated and the apoptotic features of the nuclei were observed with Hoechst staining.ResultsThe expressions of the IGFs mRNA and protein were significantly increased in the salicylate ototoxicity groups compared with that of the normal control group. Salicylate induced apoptosis and decreased viability of the HEI-OC1 auditory cells in a time- and dose-dependent manner. The expressions of IGFs were localized in the stria vascularis, and these IGFs play a protective role in the in-vivo condition of salicylate ototoxicity.ConclusionIGFs were highly expressed in the mice with salicylate ototoxicity, and this expression was mainly focused in the stria vascularis in the salicylate intoxicated mice. The systemic action of IGFs, which were expressed in the vascular-rich stria vascularis, can act as a major protective mechanism in a mouse model of salicylate ototoxicity.

Differential protein expression profiles in salicylate ototoxicity of the mouse cochlea

The purpose of this study was to investigate protein expression profiles of salicylate ototoxicity using proteomic analysis, and to identify whether salicylates induce apoptosis in organotypic culture of mouse cochlear cells. The adult mice were injected intraperitoneally with 400 mg/kg of sodium salicylate. Approximately 30 dB threshold shift was observed 3 h after the injection, and the hearing threshold returned to normal range within 3 days. Proteomic analysis of mouse cochlea was performed 3 h after salicylate injection, because this was the time to show maximal ototoxic effect in salicylate intoxication. Expression pattern of proteomic analysis at 3 h was compared with those of normal cochlea and cochlea 3 days after salicylate injection. Sixteen proteins were transiently up-regulated threefolds or more at 3 h after the injection compared with normal cochlea, and three proteins were down-regulated at 3 h. Similar protein expression profiles were also observed between normal and 3 days group. These up-regulated and down-regulated proteins at 3 h were analyzed by MALDI-TOF MS. The mRNA expressions of nine selected genes from 16 up-regulated protein profiles were also investigated by RT-PCR, and their expression levels at 3 h were found to be higher than those of normal cochlea. We also confirmed the ototoxicity of salicylate in organotypic culture of cochlear cells using MTT assay, Hoechst staining and DNA laddering assay in vitro, and found that salicylate decreased the viability of cells in a time and dose-dependent manner, and that induced apoptosis in organotypic culture of cochlear cells. This study demonstrated that some proteins can be related to salicylate ototoxicity, and provides basic information about candidate proteins which are related to pathologic changes in salicylate-induced ototoxicity.

Differential expression of apoptosis-related genes in the cochlea of noise-exposed rats

Exposure to intense noise induces apoptosis in hair cells in the cochlea. To identify the molecular changes associated with noise-induced apoptosis, we used quantitative real-time PCR to evaluate the changes in 84 apoptosis-related genes in cochlear samples from the sensory epithelium and lateral wall. Sprague–Dawley rats exposed to a continuous noise at 115 dB SPL for 2 h. The exposure caused a 40–60 dB threshold shift 4 h post-exposure that decreased to 20–30 dB 7 days post-exposure. These functional changes were associated with apoptotic markers including nuclear condensation and fragmentation and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Immediately after the noise exposure, 12 genes were downregulated, whereas only one gene (Traf4) was upregulated. At 4 h post-exposure, eight genes were upregulated; three (Tnrsf1a, Tnfrsf1b, Tnfrst5) belonged to the Tnfrsf family, three (Bir3, Mcl1 and Prok2) have anti-apoptotic properties and one (Gadd45a) is a target of p53. At 7 days post-exposure, all the upregulated genes returned to pre-noise levels. Interestingly, the normal control cochlea had high constitutive levels of several apoptosis-related genes. These constitutively expressed genes, together with the inducible genes, may participate in the induction of cochlear apoptotic activity.