Noise-induced Permanent Threshold Shift Research Articles

The Role of Connexin26 and Connexin30 in the Mouse Cochlea of Noise-Induced Hearing Loss.

We aimed to explore the role of connexin26 (Cx26) and connexin30 (Cx30) in the cochlea in noise-induced permanent threshold shifts (PTS) and temporary threshold shift (TTS). Prospective, controlled. Laboratory. A mouse model of noise-induced PTS and TTS was constructed. Western blots were used to detect the expression of Cx26 and Cx30 in the cochlea. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to assess the potential biological pathways. Both the expression of Cx26 and Cx30 showed a trend of first rising and then falling in noise-induced PTS. The expression of Cx26 increased greatly in the 24 hours noise exposure (P < .05) and reached the highest level in the 4 hours after noise exposure (P < .05), then decreased gradually and returned to the control level on the seventh day after the noise exposure, when compared with the control group. The expression of Cx30 showed a similar trend in noise-induced PTS. However, both the expression of Cx26 and Cx30 showed a trend of first falling and then rising in noise induced TTS. The expression of Cx26/Cx30 reached its lowest level in the 4 hours after noise exposure (P < .05), and then increased to the control level on the second day after noise exposure (P > .05), compared with the control group. The first KEGG and GO pathway may be related with oxidative phosphorylation. Cx26 and Cx30 may have an effect in noise induced PTS and TTS. Future studies are needed to confirm the results.

Therapeutic effect of intraperitoneal dexamethasone on noise-induced permanent threshold shift in mice model.

The purpose of the study was to which investigate whether dexamethasone, which has anti-inflammatory and immune response suppression roles, could treat noise-induced hearing loss caused by damage to hair cells in the cochlea. The experiment used 8-week-old CBA mice exposed to white noise at an intensity of 110 dB SPL for 2 h, with hearing loss confirmed by the auditory brainstem response test. Dexamethasone was administered by intraperitoneal injection for 5 days, and the therapeutic effect was investigated for 3 weeks. The experimental groups were 3 mg/kg of dexamethasone (3 mpk) and 10 mg/kg of dexamethasone (10 mpk), and the control group was a saline-administered group. The results showed that compared to the control group, the hearing threshold value was recovered by 10 dB SPL compared to the saline group from the 14th day in the 3 mpk group. In the 10 mpk group, thresholds were recovered from the 7th day compared to the saline group. This difference was similar at 4 kHz, and in the case of the 10 mpk group, the threshold was recovered by 20 dB SPL compared to the saline group. The study also confirmed the restoration of nerve cell activity and showed a recovery effect of about 20 µV in the amplitude value change in the 10 mpk group. In conclusion, the study suggests that dexamethasone has a therapeutic effect for noise-induced hearing loss by increasing the activity of nerve cells and showing a recovery effect from hair cells damaged by noise.

Investigation of critical factors influencing the underestimation of hearing loss predicted by the ISO 1999 predicting model.

To analyze factors influencing the underestimation of noise-induced permanent threshold shift (NIPTS) among manufacturing workers, providing baseline data for revising noise exposure standard. A cross-sectional study was designed with 2702 noise-exposed workers from 35 enterprises from 10 industries. Personal noise exposure level(LAeq,8h) and noise kurtosis level were determined by a noise dosimeter. Questionnaires and hearing loss tests were performed for each subject. The predicted NIPTS was calculated using the ISO 1999:2013 model for each participant, and the actual measured NIPTS was corrected for age and sex. The factors influencing the underestimation of NIPTS were investigated. The predicted NIPTS at each test frequency (0.5, 1, 2, 3, 4, or 6kHz) and mean NIPTS at 2, 3, 4, and 6kHz (NIPTS2346) using the ISO 1999:2013 model were significantly lower than their corresponding measured NIPTS, respectively (P < 0.001). The ISO model significantly underestimated the NIPTS2346 by 12.36 dB HL. The multiple linear regression analysis showed that noise exposure level, exposure duration, age, and kurtosis could affect the degree of underestimation of NIPTS2346. The generalized additive model (GAM) with (penalized) spline components showed nonlinear relationships between critical factors (age, exposure duration, noise level, and kurtosis) and the underestimated NIPTS2346.The underestimated NIPTS2346 decreased with an increase in exposure duration (especially over ten years). There was no apparent trend in the underestimated NIPTS2346 with age. The underestimated NIPTS2346 decreased with the increased noise level [especially > 90 dB(A)]. The underestimated NIPTS2346 increased with an increase in noise kurtosis after adjusting for the noise exposure level and exposure duration and ultimately exhibiting a linear regression relationship. The ISO 1999 predicting model significantly underestimated the noise-induced hearing loss among manufacturing workers. The degree of underestimation became more significant at the noise exposure condition of fewer than ten years, less than 90 dB(A), and higher kurtosis levels. It is necessary to apply kurtosis to adjust the underestimation of hearing loss and consider the applying condition of noise energy metrics when using the ISO predicting model.

The role of kurtosis and kurtosis-adjusted energy metric in occupational noise-induced hearing loss among metal manufacturing workers.

Noise energy has been well-established to increase the risk of occupational noise-induced hearing loss (NIHL). However, the role of noise temporal structure (expressed by kurtosis) or its combination with energy metrics (e.g., kurtosis-adjusted cumulative noise exposure, adj-CNE) in occupational NIHL was still unclear. A cross-sectional survey of 867 Chinese workers, including 678 metal manufacturing workers and 189 workers exposed to Gaussian noise, was conducted. Noise energy metrics, including LAeq,8h and CNE, kurtosis (β), and adj-CNE were used to quantify noise exposure levels. Noise-induced permanent threshold shift at frequencies 3, 4, and 6 kHz (NIPTS346) and the prevalence of high-frequency NIHL (HFNIHL%) were calculated for each participant. The dose-response relationship between kurtosis or adj-CNE and occupational NIHL was observed. Among 867 workers, different types of work had specific and independent noise energy and kurtosis values (p > 0.05). HFNIHL% increased with an increase in exposure duration (ED), LAeq,8h, CNE, or kurtosis (p < 0.01), and there were strong linear relationships between HFNIHL% and ED (coefficient of determination [R2] = 0.963), CNE (R2 = 0.976), or kurtosis (R2 = 0.938, when CNE < 100 dB(A)∙year). The "V" shape notching extent in NIPTS became deeper with increasing kurtosis when CNE < 100 dB(A)∙year and reached the notching bottom at the frequency of 4 or 6 kHz. The workers exposed to complex noise (β ≥ 10) had a higher risk of NIHL than those exposed to Gaussian noise (β < 10) at the frequencies of 3, 4, 6, and 8 kHz (OR > 2, p < 0.01). Moreover, HFNIHL% increased with adj-CNE (p < 0.001). There were strong linear relationships between NIHL and adj-CNE or CNE when β ≥ 10 (R2adj-CNE > R2CNE). After CNE was adjusted by kurtosis, average differences in NIPTS346 or HFNIHL% between the complex and Gaussian noise group were significantly reduced (p < 0.05). Kurtosis was a key factor influencing occupational NIHL among metal manufacturing workers, and its combination with energy metrics could assess the risk of NIHL more effectively than CNE alone.

Effectiveness of Kurtosis-Adjusted Cumulative Noise Exposure in Assessing Occupational Hearing Loss Associated With Complex Noise.

Occupational noise-induced hearing loss (NIHL) is one of the most prevalent occupational diseases worldwide. Few studies have been reported on applying kurtosis-adjusted noise energy (e.g., kurtosis-adjusted cumulative noise exposure, CNE-K) as a joint indicator for assessing NIHL. This study aimed to analyze the effectiveness of CNE-K in assessing occupational hearing loss associated with complex noise in typical manufacturing industries. A cross-sectional survey of 1404 Chinese manufacturing workers from typical manufacturing industries was conducted. General demographic characteristics, noise exposure data, and noise-induced permanent threshold shifts (NIPTS) at 3, 4, and 6 kHz (NIPTS 346 ) were collected and analyzed. The role of kurtosis in high-frequency noise-induced hearing loss (HFNIHL) was also analyzed. The degree of overlap of the two logistic curves (i.e., between complex noise CNE-K and HFNIHL%, and between Gaussian noise CNE and HFNIHL%) was used to evaluate the effectiveness of CNE-K, using a stratified analysis based on age, sex, industry, or job type. The binary logistic regression analysis showed that in addition to age, sex, exposure duration, and Eight-hour Continuous Equivalent A-weighted Sound Pressure Level (L Aeq,8h ), kurtosis was a key factor influencing HFNIHL% in workers (odds ratio = 1.18, p < 0.05), and its odds ratio increased with an increase in kurtosis value. Multiple linear regression analysis demonstrated that the contribution of kurtosis to NIPTS 346 was second to L Aeq,8h . Complex noise led to a higher risk of NIHL than Gaussian noise at frequencies of 3, 4, 6, and 8 kHz after adjusting for age, sex, and CNE ( p < 0.05). As kurtosis increased, the notch in the audiogram became deeper, and the frequency at which the notch began to deepen shifted from 3 to 1 kHz. The logistic curve between complex noise CNE-K and HFNIHL% nearly overlapped with that between Gaussian noise CNE and HFNIHL%, and the average difference in HFNIHL% between the two curves decreased from 8.1 to 0.4%. Moreover, the decrease of average difference in HFNIHL% between the two logistic curves was evident in several subgroups, such as male workers, aged <30 and 30 to 50 years, furniture and woodworking industries and gunning and nailing job types with relatively high kurtosis values. Kurtosis, as an indirect metric of noise temporal structure, was an important risk factor for occupational NIHL. Kurtosis-adjusted CNE metric could be more effective than CNE alone in assessing occupational hearing loss risk associated with complex noise.

Estimation of Occupational Noise-Induced Hearing Loss Using Kurtosis-Adjusted Noise Exposure Levels.

Objectives:Studies have shown that in addition to energy, kurtosis plays an important role in the assessment of hearing loss caused by complex noise. The objective of this study was to investigate how to use noise recordings and audiometry collected from workers in industrial environments to find an optimal kurtosis-adjusted algorithm to better evaluate hearing loss caused by both continuous noise and complex noise.Design:In this study, the combined effects of energy and kurtosis on noise-induced hearing loss (NIHL) were investigated using data collected from 2601 Chinese workers exposed to various industrial noises. The cohort was divided into three subgroups based on three kurtosis (β) levels (K1: 3 ≤ β ≤ 10, K2: 10 <β ≤ 50, and K3: β > 50). Noise-induced permanent threshold shift at test frequencies 3, 4, and 6 kHz (NIPTS346) was used as the indicator of NIHL. Predicted NIPTS346 was calculated using the ISO 1999 model for each participant, and the actual NIPTS was obtained by correcting for age and sex using non-noise-exposed Chinese workers (n = 1297). A kurtosis-adjusted A-weighted sound pressure level normalized to a nominal 8-hour working day (LAeq,8h) was developed based on the kurtosis categorized group data sets using multiple linear regression. Using the NIPTS346 and the LAeq.8h metric, a dose-response relationship for three kurtosis groups was constructed, and the combined effect of noise level and kurtosis on NIHL was investigated.Results:An optimal kurtosis-adjusted LAeq,8h formula with a kurtosis adjustment coefficient of 6.5 was established by using the worker data. The kurtosis-adjusted LAeq,8h better estimated hearing loss caused by various complex noises. The analysis of the dose-response relationships among the three kurtosis groups showed that the NIPTS of K2 and K3 groups was significantly higher than that of K1 group in the range of 70 dBA ≤ LAeq,8h < 85 dBA. For 85 dBA ≤ LAeq,8h ≤ 95 dBA, the NIPTS346 of the three groups showed an obvious K3 > K2 > K1. For LAeq,8h >95 dBA, the NIPTS346 of the K2 group tended to be consistent with that of the K1 group, while the NIPTS346 of the K3 group was significantly larger than that of the K1 and K2 groups. When LAeq,8h is below 70 dBA, neither continuous noise nor complex noise produced significant NIPTS346.Conclusions:Because non-Gaussian complex noise is ubiquitous in many industries, the temporal characteristics of noise (i.e., kurtosis) must be taken into account in evaluating occupational NIHL. A kurtosis-adjusted LAeq,8h with an adjustment coefficient of 6.5 allows a more accurate prediction of high-frequency NIHL. Relying on a single value (i.e., 85 dBA) as a recommended exposure limit does not appear to be sufficient to protect the hearing of workers exposed to complex noise.

Assessment of Occupational Hearing Loss Associated With Non-Gaussian Noise Using the Kurtosis-Adjusted Cumulative Noise Exposure Metric: A Cross-Sectional Survey.

ObjectiveThere is little literature on the validity of kurtosis-adjusted noise energy metrics in human studies. Therefore, this study aimed to validate the application of cumulative noise exposure (CNE) adjusted by kurtosis in evaluating occupational hearing loss associated with non-Gaussian noise among manufacturing workers.MethodsA cross-sectional survey was conducted on 1,558 manufacturing workers exposed to noise from five industries to collect noise exposure and hearing loss data. Both CNE and kurtosis-adjusted CNE (CNE′) were collapsed into 2-dB(A)∙year bins, and the mean noise-induced permanent threshold shifts at 3, 4, and 6 kHz (NIPTS346) in each bin were calculated. The contributions of CNE and CNE′ to noise-induced hearing loss (NIHL) were compared using the multiple linear regression. The degree of overlap of two linear regression equations (i.e., between CNE′ and NIPTS346 for non-Gaussian noise and between CNE and NIPTS346 for Gaussian noise) was used to evaluate the validity of the CNE′ using a stratified analysis based on age and sex.ResultsMultiple linear regression models showed that after kurtosis adjustment, the standardized regression coefficient of CNE increased from 0.230 to 0.255, and R2 increased from 0.147 to 0.153. The linear relationship between NIPTS346 and CNE′ or CNE showed that the regression line of non-Gaussian noise was closer to that of Gaussian noise when using CNE′ than using CNE. The mean difference in NIPTS346 between the equations of non-Gaussian noise and Gaussian noise was significantly reduced from 4.32 to 1.63 dB HL after kurtosis adjustment (t = 12.00, p < 0.001). Through a stratified analysis, these significant decreases were observed in male and female workers, and workers aged ≥30 years old.ConclusionAs a noise exposure metric combining noise energy and temporal characteristics, the kurtosis-adjusted-CNE metric was more effective than CNE alone in assessing occupational hearing loss among manufacturing workers in non-Gaussian noise environment. However, more studies are needed to verify the validity of the kurtosis-adjusted-CNE metric.

D-methionine administered as late as 36 hours post-noise exposure rescues from permanent threshold shift and dose-dependently increases serum antioxidant levels

Objective To elucidate D-methionine’s (D-met) dose and time rescue parameters from steady-state or impulse noise-induced permanent threshold shift (PTS) and determine D-met rescue’s influence on serum and cochlear antioxidant levels. Design Five D-met doses at 0, 50, 100, or 200 mg/kg/dose administered starting at 1, 24, or 36 hours post steady-state or impulse noise exposure. Auditory brainstem responses at baseline and 21 days post-noise measured PTS. Serum (superoxide dismutase [SOD], catalase [CAT],, glutathione reductaseand glutathione peroxidase [GPx]) and cochlear (Glutathione [GSH] and glutathione disulphide [GSSG]) antioxidant levels measured physiological impact. Study Sample Chinchillas (10/study group; 6–8/confirmatory groups). Results D-met significantly reduced PTS for impulse noise (100 mg [2, 6, 14 and 20 kHz]; 200 mg [2, 14 and 20 kHz]) and steady-state noise (all dosing groups, time parameters and tested frequencies). PTS reduction did not significantly vary by rescue time. D-met significantly increased serum SOD (100 and 200 mg for 24 hour rescue) and GPx (50 mg/kg at 24 hour rescue) at 21 days post-noise. Cochlear GSH and GSSG levels were unaffected relative to control. Conclusion D-met rescues from steady-state and impulse noise-induced PTS even when administered up to 36 hours post-noise and dose-dependently influences serum antioxidant levels even 21 days post-noise. D-met’s broad and effective dose/time window renders it a promising antioxidant rescue agent.

Applying Kurtosis as an Indirect Metric of Noise Temporal Structure in the Assessment of Hearing Loss Associated With Occupational Complex Noise Exposure.

Objective:The association of occupational noise-induced hearing loss (NIHL) with noise energy was well documented, but the relationship between occupational noise and noise temporal structure is rarely reported. The objective of this study was to investigate the principal characteristics of the relationship between occupational NIHL and the temporal structure of noise.Methods:Audiometric and shift-long noise exposure data were collected from 3102 Chinese manufacturing workers from six typical industries through a cross-sectional survey. In data analysis, A-weighted 8-h equivalent SPL (LAeq.8h), peak SPL, and cumulative noise exposure (CNE) were used as noise energy indicators, while kurtosis (β) was used as the indicator of noise temporal structure. Two NIHL were defined: (1) high-frequency noise-induced hearing loss (HFNIHL) and (2) noise-induced permanent threshold shift at test frequencies of 3, 4, and 6 kHz (noise-induced permanent threshold shift [NIPTS346]). The noise characteristics of different types of work and the relationship between these characteristics and the prevalence of NIHL were analyzed.Results:The noise waveform shape, with a specific noise kurtosis, was unique to each type of work. Approximately 27.92% of manufacturing workers suffered from HFNIHL, with a mean NIPTS346 of 24.16 ± 14.13 dB HL. The Spearman correlation analysis showed that the kurtosis value was significantly correlated with the difference of peak SPL minus its LAeq.8h across different types of work (p < 0.01). For a kurtosis-adjusted CNE, the linear regression equation between HFNIHL% and CNE for complex noise almost overlapped with Gaussian noise. Binary logistic regression analysis showed that LAeq.8h, kurtosis, and exposure duration were the key factors influencing HFNIHL% (p < 0.01). The notching extent in NIPTS at 4 kHz became deeper with the increase in LAeq.8h and kurtosis. HFNIHL% increased most rapidly during the first 10 years of exposure. HFNIHL% with β ≥ 10 was significantly higher than that with β < 10 (p < 0.05), and it increased with increasing kurtosis across different CNE or LAeq.8h levels. When LAeq.8h was 80 to 85 dB(A), the HFNIHL% at β ≥ 100 was significantly higher than that at 10 ≤ β < 100 or β < 10 (p < 0.05 and p < 0.01, respectively).Conclusions:In the evaluation of hearing loss caused by complex noise, not only noise energy but also the temporal structure of noise must be considered. Kurtosis of noise is an indirect metric that is sensitive to the presence of impulsive components in complex noise exposure, and thus, it could be useful for quantifying the risk for NIHL. It is necessary to re-evaluate the safety of permissible exposure limit of 85 dB(A) as noise with a high kurtosis value can aggravate or accelerate early NIHL.

Dose-response relationship between noise kurtosis and noise-induced hearing loss

Objective: To analyse the dose-response relationships between the kurtosis metric of noise and noise-induced hearing loss (NIHL) and study the role of kurtosis in the evaluation of NIHL associated with non-Gaussian noise. Methods: From January 2012 to December 2017, a total of 1869 workers in seven manufacturing industries were selected as the study subjects. The basic data of the workers were investigated by questionnaire, personal noise waveform was collected for a long time, and pure tone hearing threshold was tested. The 8-hour continuous equivalent A sound level (L(Aeq, 8 h)) , cumulative noise exposure (CNE) and kurtosis structure indexes were calculated. The dose-response relationships between kurtosis and NIHL were analyzed by stratification analysis method, which controlled the influence of CNE, L(Aeq, 8 h), exposure duration, age and sex on hearing loss using high-frequency noise-induced permanent threshold shift (NIPTS(346)) and high-frequency noise-induced hearing loss (HFNIHL) as outcome indicators. Results: When CNE was <90 dB (A) ·year and ≥100 dB (A) ·year, NIPTS(346) in the extremely high kurtosis group was significantly greater than that in the Gaussian kurtosis, low kurtosis and medium kurtosis group (P<0.05) . In the workers exposed to L(Aeq, 8 h)<85 dB (A) and ≥94 dB (A) , NIPTS(346) in the extremely high kurtosis group was significantly greater than that in the Gaussian kurtosis group (P<0.05) . Among workers under the age of 50 or male workers, NIPTS(346) in the extremely high kurtosis group was significantly greater than that in the Gaussian kurtosis, low kurtosis and medium kurtosis group (P<0.05) . Kurtosis was positively correlated with NIPTS(346) (r=0.121, P<0.05) . When CNE was <100 dB (A) ·year, the detection rate of HFNIHL increased with the increase of kurtosis level (P<0.01) . Logistic regression analysis showed that kurtosis was an important influencing factor for HFNIHL (OR=1.321) . Conclusion: Kurtosis has a dose-response relationship with the detection rate of HFNIHL in noise exposed workers, and noise kurtosis is an influencing factor of NIHL.

Assessment of noise impact on coal mine workers including way to/from workplace

Purpose. Determination of the noise induced permanent threshold shift for a coal miners in five main working professions, taking into account the noise impact on the way to the workplace and back based on data obtained from personal sound level meters. Methodology. A strategy is selected for measuring the level of noise exposure at workplaces No. 3 per workday (GOST ISO 9612-2016) in a coal mine. Personal sound level meters were attached to the miners shoulders; they measured the noise level on the way to the workplace, during the work shift (8 hours) and on the way back. The processing of the measurement results was carried out on the basis of a quantitative assessment of the noise impact on workers according to the noise induced permanent threshold shift (NIPTS). The NIPTS values were calculated for a period from 3 to 30 years for 5 main professions, taking into account the noise impact when moving to the workplace and back. Findings. The values of the equivalent noise level at miners workplaces of are determined, which are 15 to 20 dBA above the maximum permissible equivalent level (80 dBA). Based on the results obtained, a constant shift in the hearing threshold was forecast for workers of five occupations with seniority of 3 to 30 years. A reduction in the hearing threshold of a sinker will amount to 25 dB in 30 years, which corresponds to the occupational disease Stage 3. Originality. Constant displacement of the hearing threshold for workers in coal mines, caused by the effect of an increased noise level during the journey to the place of work and back, was revealed. Practical value. It was found that in order to prevent the development of an occupational disease (sensorineural hearing loss) in underground miners, it is necessary to measure the noise level by using personal sound level meters for an 8-hour working day, taking into account the way time to the workplace and back. Noise exposure assessment should be based on a continuous decrease in the hearing threshold.

Regulator of G Protein Signalling 4 (RGS4) as a Novel Target for the Treatment of Sensorineural Hearing Loss.

We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.

Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss.

Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1, Per2, Rev-erbα, Bmal1, and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light–dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.

New Metrics Needed in the Evaluation of Hearing Hazard Associated With Industrial Noise Exposure

To evaluate (1) the accuracy of the International Organization for Standardization (ISO) standard ISO 1999 [(2013), International Organization for Standardization, Geneva, Switzerland] predictions of noise-induced permanent threshold shift (NIPTS) in workers exposed to various types of high-intensity noise levels, and (2) the role of the kurtosis metric in assessing noise-induced hearing loss (NIHL). Audiometric and shift-long noise exposure data were acquired from a population (N = 2,333) of screened workers from 34 industries in China. The entire cohort was exclusively divided into subgroups based on four noise exposure levels (85 ≤ LAeq.8h < 88, 88 ≤ LAeq.8h < 91, 91 ≤ LAeq.8h < 94, and 94 ≤ LAeq.8h ≤ 100 dBA), two exposure durations (D ≤ 10 years and D > 10 years), and four kurtosis categories (Gaussian, low-, medium-, and high-kurtosis). Predicted NIPTS was calculated using the ISO 1999 model for each participant and the actual measured NIPTS was corrected for age and sex also using ISO 1999. The prediction accuracy of the ISO 1999 model was evaluated by comparing the NIPTS predicted by ISO 1999 with the actual NIPTS. The relation between kurtosis and NIPTS was also investigated. Overall, using the average NIPTS value across the four audiometric test frequencies (2, 3, 4, and 6 kHz), the ISO 1999 predictions significantly (p < 0.001) underestimated the NIPTS by 7.5 dB on average in participants exposed to Gaussian noise and by 13.6 dB on average in participants exposed to non-Gaussian noise with high kurtosis. The extent of the underestimation of NIPTS by ISO 1999 increased with an increase in noise kurtosis value. For a fixed range of noise exposure level and duration, the actual measured NIPTS increased as the kurtosis of the noise increased. The noise with kurtosis greater than 75 produced the highest NIPTS. The applicability of the ISO 1999 prediction model to different types of noise exposures needs to be carefully reexamined. A better understanding of the role of the kurtosis metric in NIHL may lead to its incorporation into a new and more accurate model of hearing loss due to noise exposure.

Long-term evidence of noise-induced permanent threshold shift in a harbor seal (Phoca vitulina).

In psychophysical studies of noise-induced hearing loss with marine mammals, exposure conditions are often titrated from levels of no effect to those that induce significant but recoverable loss of auditory sensitivity [temporary threshold shift (TTS)]. To examine TTS from mid-frequency noise, a harbor seal was exposed to a 4.1-kHz underwater tone that was incrementally increased in sound pressure level (SPL) and duration. The seal's hearing was evaluated at the exposure frequency and one-half octave higher (5.8 kHz) to identify the noise parameters associated with TTS onset. No reliable TTS was measured with increasing sound exposure level until the second exposure to a 60-s fatiguing tone of 181 dB re 1 μPa SPL (sound exposure level 199 dB re 1 μPa2s), after which an unexpectedly large threshold shift (>47 dB) was observed. While hearing at 4.1 kHz recovered within 48 h, there was a permanent threshold shift of at least 8 dB at 5.8 kHz. This hearing loss was evident for more than ten years. Furthermore, a residual threshold shift of 11 dB was detected one octave above the tonal exposure, at 8.2 kHz. This hearing loss persisted for more than two years prior to full recovery.

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

The endocochlear potential (EP) provides part of the electrochemical drive for sound-driven currents through cochlear hair cells. Intense noise exposure (110 dB SPL, 2 h) differentially affects the EP in three inbred mouse strains (C57BL/6 [B6], CBA/J [CBA], BALB/cJ [BALB]) (Ohlemiller and Gagnon, 2007, Hearing Research 224:34-50; Ohlemiller et al., 2011, JARO 12:45-58). At least for mice older than 3 mos, B6 mice are unaffected, CBA mice show temporary EP reduction, and BALB mice may show temporary or permanent EP reduction. EP reduction was well correlated with histological metrics for injury to stria vascularis and spiral ligament, and little evidence was found for holes or tears in the reticular lamina that might ‘short out’ the EP. Thus we suggested that the genes and processes that underlie the strain EP differences primarily impact cochlear lateral wall, not the organ of Corti. Our previous work did not test the range of noise exposure conditions over which strain differences apply. It therefore remained possible that the relation between exposure severity and acute EP reduction simply has a higher exposure threshold in B6 mice compared to CBA and BALB. We also did not test for age dependence. It is well established that young adult animals are especially vulnerable to noise-induced permanent threshold shifts (NIPTS). It is unknown, however, whether heightened vulnerability of the lateral wall contributes to this condition. The present study extends our previous work to multiple noise exposure levels and durations, and explicitly compares young adult (6–7 wks) and older mice (>4 mos). We find that the exposure level-versus-acute EP relation is dramatically strain-dependent, such that B6 mice widely diverge from both CBA and BALB. For all three strains, however, acute EP reduction is greater in young mice. Above 110 dB SPL, all mice exhibited rapid and severe EP reduction that is likely related to tearing of the reticular lamina. By contrast, EP-versus-noise duration examined at 104 dB suggested that different processes contribute to EP reduction in young and older mice. The average EP falls to a constant level after ∼7.5 min in older mice, but progressively decreases with further exposure in young mice. Confocal microscopy of organ of Corti surface preparations stained for phalloidin and zonula occludens-1 (ZO-1) indicated this corresponds to rapid loss of outer hair cells (OHCs) and formation of both holes and tears in the reticular lamina of young mice. In addition, when animals exposed at 119 dB were allowed to recover for 1 mo, only young B6 mice showed collapse of the EP to ≤5 mV. Confocal analysis suggested novel persistent loss of tight junctions in the lateral organ of Corti. This may allow paracellular leakage that permanently reduces the EP. From our other findings, we propose that noise-related lateral wall pathology in young CBA and BALB mice promotes hair cell loss and opening of the reticular lamina. The heightened vulnerability of young adult animals to noise exposure may in part reflect special sensitivity of the organ of Corti to acute lateral wall dysfunction at younger ages. This feature appears genetically modifiable.

The histone deacetylase inhibitor sodium butyrate protects against noise-induced hearing loss in Guinea pigs.

Noise-induced hearing loss (NIHL) severely impacts the quality of life of affected individuals. Oxidative stress resulting from noise exposure is a significant cause of NIHL. Although histone deacetylase (HDAC) inhibitors were shown to protect against NIHL, the underlying mechanism remains unclear, and it is not known how they act on noise-induced oxidative stress. In the current study, we investigated the expression levels of acetyl-histone H3 (Lys9) (H3-AcK9), histone deacetylase 1 (HDAC1), and 3-nitrotyrosine (3-NT), an oxidative stress marker, in a guinea pig model of NIHL using immunohistology and Western blotting. We then assessed the effects of systemic administration of the HDAC inhibitor, sodium butyrate (SB), on noise-induced permanent threshold shifts (PTS), hair cell (HC) loss, and changes in the above mentioned markers. The results showed that SB attenuated noise-induced PTS and outer hair cell loss. SB treatment promoted H3-AcK9 expression and repressed HDAC1 expression in the nuclei of HCs and Hensen's cells after noise exposure. Furthermore, SB attenuated the noise-induced increase of 3-NT expression in HCs and Hensen's cells. These findings suggest that SB protects against NIHL by reversing the noise-induced histone acetylation imbalance and inhibiting oxidative stress in cochlear HCs and Hensen's cells. SB treatment may represent a potential strategy to prevent and treat NIHL.

Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss.

Loss of auditory sensory hair cells is the major pathological feature of noise-induced hearing loss (NIHL). Currently, no established clinical therapies for prevention or amelioration of NIHL are available. The absence of treatments is due to our lack of a comprehensive understanding of the molecular mechanisms underlying noise-induced damage. Our previous study indicates that epigenetic modification of histones alters hair cell survival. In this study, we investigated the effect of noise exposure on histone H3 lysine 9 acetylation (H3K9ac) in the inner ear of adult CBA/J mice and determined if inhibition of histone deacetylases by systemic administration of suberoylanilide hydroxamic acid (SAHA) could attenuate NIHL. Our results showed that H3K9ac was decreased in the nuclei of outer hair cells (OHCs) and marginal cells of the stria vascularis in the basal region after exposure to a traumatic noise paradigm known to induce permanent threshold shifts (PTS). Consistent with these results, levels of histone deacetylases 1, 2, and 3 (HDAC1, HDAC2 and HDAC3) were increased predominately in the nuclei of cochlear cells. Silencing of HDAC1, HDAC2, or HDAC3 with siRNA reduced the expression of the target HDAC in OHCs, but did not attenuate noise-induced PTS, whereas treatment with the pan-HDAC inhibitor SAHA, also named vorinostat, reduced OHC loss, and attenuated PTS. These findings suggest that histone acetylation is involved in the pathogenesis of noise-induced OHC death and hearing loss. Pharmacological targeting of histone deacetylases may afford a strategy for protection against NIHL.

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice.

We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50mV in BALBs. In about 25% of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.

Rescuing Noise‐Induced Permanent Threshold Shift by D‐Methionine in Guinea Pigs

Objectives: This study examined the effectiveness of D-methionine (D-met) in rescuing a noise-induced permanent threshold shift (PTS) and cochlear biochemistry following noise exposure. Methods: One hour after being exposed to continuous white noise at 105 ± 2 dB SPL for 6 hours, guinea pigs were treated 5 times at 12-hour intervals with 200, 400, or 600 mg/kg D-met or sterile 0.9% saline by intraperitoneal injection. Auditory brainstem responses were examined before and 14 days after noise exposure. Six guinea pigs with normal hearing that were not exposed to noise served as control animals. The level of D-met in rescuing noise-induced hearing loss and the changes in cochlear biochemistry, including membranous Na+, K+-ATPase, and Ca2+-ATPase, lipid peroxidation, and nitric oxide, were evaluated. Results: Hearing acuity had no significant differences before and 14 days after noise exposure for the animals treated with 600 mg/kg D-met, compared with the control animals, whereas significant differences occurred among the animals in the other treatment groups. The level of rescue from noise-induced PTS following treatment with D-met was dose-dependent. No significant differences in the mean enzyme activities were observed between the controls and the D-met 600 mg/kg treatment group. The attenuation of the noise-induced decreases in the enzyme activities was dose-dependent. Likewise, D-met-dose-dependent decreases in oxidative stress were observed in the D-met treated groups. Conclusions: Treatment with D-met significantly rescued noise-induced PTS in a dose-dependent manner. Significant attenuation of increased oxidative stress and decreased ATPase activities were concurrent with the D-met-mediated improvements in noise-induced auditory dysfunction.