Abstract
The reactive oxygen species (ROS)-generating NADPH oxidase NOX3 isoform is highly and specifically expressed in the inner ear. NOX3 is needed for normal vestibular development but NOX-derived ROS have also been implicated in the pathophysiology of sensorineural hearing loss. The role of NOX-derived ROS in noise-induced hearing loss, however, remains unclear and was addressed with the present study. Two different mouse strains, deficient in NOX3 or its critical subunit p22phox, were subjected to a single noise exposure of 2 h using an 8–16 kHz band noise at an intensity of 116–120 decibel sound pressure level. In the hours following noise exposure, there was a significant increase in cochlear mRNA expression of NOX3 in wild type animals. By using RNAscope in situ hybridization, NOX3 expression was primarily found in the Rosenthal canal area, colocalizing with auditory neurons. One day after the noise trauma, we observed a high frequency hearing loss in both knock-out mice, as well as their wild type littermates. At day seven after noise trauma however, NOX3 and p22phox knockout mice showed a significantly improved hearing recovery and a marked preservation of neurosensory cochlear structures compared to their wild type littermates. Based on these findings, an active role of NOX3 in the pathophysiology of noise-induced hearing loss can be demonstrated, in line with recent evidence obtained in other forms of acquired hearing loss. The present data demonstrates that the absence of functional NOX3 enhances the hearing recovery phase following noise trauma. This opens an interesting clinical window for pharmacological or molecular intervention aiming at post prevention of noise-induced hearing loss.
Highlights
Hearing loss is the most common neurosensory deficit in humans and the third most prevalent chronic disability over 65 years old, affecting over 460 million people world-wide (World Health Organization, 2022)
Sound pressure vibrations travel to the cochlea and activate inner hair cells at frequency specific locations, leading to glutamate release in the auditory synapses and generation of electrical stimuli traveling from the auditory neurons to the central nervous system, where they are perceived as sound (Wang and Puel, 2018)
We investigated the possible contribution of the reactive oxygen species (ROS) generating NADPH oxidase NOX3 in noise-induced sensorineural hearing loss using two different mice strains: the NOX3 mutant C57BL/6J-NOX3het−4J/J and a constitutive p22phox knockout (C57BL/N Cyba knockout), both deficient in NOX3 activity
Summary
Hearing loss is the most common neurosensory deficit in humans and the third most prevalent chronic disability over 65 years old, affecting over 460 million people world-wide (World Health Organization, 2022). Recent evidence suggests that the auditory neurons and their synaptic connections to the hair cells are the most vulnerable elements in the peripheral auditory system, at least for noise-induced hearing loss and presbyacusis (Liberman and Kujawa, 2017; Wu et al, 2019; Rousset et al, 2020; Peineau et al, 2021). Even moderate sound pressure levels over prolonged time periods can cause degeneration of spiral ganglion neurons and their synaptic connections (Kujawa and Liberman, 2006; Kaur et al, 2019). This so-called cochlear synapthopathy can even occur in cochleae with intact hair cell populations and normal audiograms, leading to a situation referred to as hidden hearing loss (Kujawa and Liberman, 2009; Wu et al, 2019). Sensorineural hearing loss persisting beyond few days after any insult, including neuronal apoptosis, is irreversible in humans (Rousset F et al, 2020)
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