Preloaded D-methionine protects from steady state and impulse noise-induced hearing loss and induces long-term cochlear and endogenous antioxidant effects

Objective Determine effective preloading timepoints for D-methionine (D-met) otoprotection from steady state or impulse noise and impact on cochlear and serum antioxidant measures. Design D-met started 2.0-, 2.5-, 3.0-, or 3.5- days before steady-state or impulse noise exposure with saline controls. Auditory brainstem response (ABRs) measured from 2 to 20 kHz at baseline and 21 days post-noise. Samples were then collected for serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels. Study sample Ten Chinchillas per group. Results Preloading D-met significantly reduced ABR threshold shifts for both impulse and steady state noise exposures but with different optimal starting time points and with differences in antioxidant measures. For impulse noise exposure, the 2.0, 2.5, and 3.0 day preloading start provide significant threshold shift protection at all frequencies. Compared to the saline controls, serum GR for the 3.0 and 3.5 day preloading groups was significantly increased at 21 days with no significant increase in SOD, CAT or GPx for any impulse preloading time point. Cochlear GSH, GSSG, and GSH/GSSG ratio were not significantly different from saline controls at 21 days post noise exposure. For steady state noise exposure, significant threshold shift protection occurred at all frequencies for the 3.5, 3.0 and 2.5 day preloading start times but protection only occurred at 3 of the 6 test frequencies for the 2.0 day preloading start point. Compared to the saline controls, preloaded D-met steady-state noise groups demonstrated significantly higher serum SOD for the 2.5–3.5 day starting time points and GPx for the 2.5 day starting time but no significant increase in GR or CAT for any preloading time point. Compared to saline controls, D-met significantly increased cochlear GSH concentrations in the 2 and 2.5 day steady-state noise exposed groups but no significant differences in GSSG or the GSH/GSSG ratio were noted for any steady state noise-exposed group. Conclusions The optimal D-met preloading starting time window is earlier for steady state (3.5–2.5 days) than impulse noise (3.0–2.0). At 21 days post impulse noise, D-met increased serum GR for 2 preloading time points but not SOD, CAT, or GpX and not cochlear GSH, GSSG or the GSH/GSSG ratio. At 21 days post steady state noise D-met increased serum SOD and GPx at select preloading time points but not CAT or GR. However D-met did increase the cochlear GSH at select preloading time points but not GSSG or the GSH/GSSG ratio.

Effect of Phlorofucofuroeckol A and Dieckol Extracted from Ecklonia cava on Noise-induced Hearing Loss in a Mouse Model

One of the well-known causes of hearing loss is noise. Approximately 31.1% of Americans between the ages of 20 and 69 years (61.1 million people) have high-frequency hearing loss associated with noise exposure. In addition, recurrent noise exposure can accelerate age-related hearing loss. Phlorofucofuroeckol A (PFF-A) and dieckol, polyphenols extracted from the brown alga Ecklonia cava, are potent antioxidant agents. In this study, we investigated the effect of PFF-A and dieckol on the consequences of noise exposure in mice. In 1,1-diphenyl-2-picrylhydrazyl assay, dieckol and PFF-A both showed significant radical-scavenging activity. The mice were exposed to 115 dB SPL of noise one single time for 2 h. Auditory brainstem response(ABR) threshold shifts 4 h after 4 kHz noise exposure in mice that received dieckol were significantly lower than those in the saline with noise group. The high-PFF-A group showed a lower threshold shift at click and 16 kHz 1 day after noise exposure than the control group. The high-PFF-A group also showed higher hair cell survival than in the control at 3 days after exposure in the apical turn. These results suggest that noise-induced hair cell damage in cochlear and the ABR threshold shift can be alleviated by dieckol and PFF-A in the mouse. Derivatives of these compounds may be applied to individuals who are inevitably exposed to noise, contributing to the prevention of noise-induced hearing loss with a low probability of adverse effects.

Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.

When Is Temporary Threshold Shift Injurious to Marine Mammals?

Evidence for synaptopathy, the acute loss of afferent auditory nerve terminals, and degeneration of spiral ganglion cells associated with temporary threshold shift (TTS) in traditional laboratory animal models (e.g., mice, guinea pigs) has brought into question whether TTS should be considered a non-injurious form of noise impact in marine mammals. Laboratory animal studies also demonstrate that both neuropathic and non-neuropathic forms of TTS exist, with synaptopathy and neural degeneration beginning over a narrow range of noise exposures differing by ~6–9 dB, all of which result in significant TTS. Most TTS studies in marine mammals characterize TTS within minutes of noise exposure cessation, and TTS generally does not achieve the levels measured in neuropathic laboratory animals, which have had initial TTS measurements made 6–24 h post-exposure. Given the recovery of the ear following the cessation of noise exposure, it seems unlikely that the magnitude of nearly all shifts studied in marine mammals to date would be sufficient to induce neuropathy. Although no empirical evidence in marine mammals exists to support this proposition, the regulatory application of impact thresholds based on the onset of TTS (6 dB) is certain to capture the onset of recoverable fatigue without tissue destruction.

Temporary threshold shift after noise exposure in hypobaric hypoxia at high altitude: results of the ADEMED expedition 2011

Objectives To evaluate whether there is an increased risk for noise-induced hearing loss at high altitude rsp. in hypobaric hypoxia. Methods Thirteen volunteers got standard audiometry at 125, 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, and 8000 Hz before and after 10 min of white noise at 90 dB. The system was calibrated for the respective altitude. Measurements were performed at Kathmandu (1400 m) and at Gorak Shep (5300 m) (Solo Khumbu/Nepal) after 10 days of acclimatization while on trek. Temporary threshold shift (TTS) was analyzed by descriptive statistics and by factor analysis. Results TTS is significantly more pronounced at high altitudes. Acclimatization does not provide any protection of the inner ear, although it increases arterial oxygen saturation. Conclusion The thresholds beyond which noise protection is recommended (> 80 dB) or necessary (> 85 dB) are not sufficient at high altitudes. We suggest providing protective devices above an altitude of 1500 m (“ear threshold altitude”) when noise level is higher than 75 dB and using them definitively above 80 dB. This takes the individual reaction on hypobaric hypoxia at high altitude into account.