Integrative Functional Transcriptomic Analyses Implicate Shared Molecular Circuits in Sensorineural Hearing Loss.

Peng Chen,Jun-Jun Hao,Meng-Wen Li,Zhen Liu,Yuan-Ting Guo,Jing Bai,Peng Shi

doi:10.3389/fncel.2022.857344

Abstract

Sensorineural hearing loss (SNHL) is referred to as the most common type of hearing loss and typically occurs when the inner ear or the auditory nerve is damaged. Aging, noise exposure, and ototoxic drugs represent three main causes of SNHL, leading to substantial similarities in pathophysiological characteristics of cochlear degeneration. Although the common molecular mechanisms are widely assumed to underlie these similarities, its validity lacks systematic examination. To address this question, we generated three SNHL mouse models from aging, noise exposure, and cisplatin ototoxicity, respectively. Through constructing gene co-expression networks for the cochlear transcriptome data across different hearing-damaged stages, the three models are found to significantly correlate with each other in multiple gene co-expression modules that implicate distinct biological functions, including apoptosis, immune, inflammation, and ion transport. Bioinformatics analyses reveal several potential hub regulators, such as IL1B and CCL2, both of which are verified to contribute to apoptosis accompanied by the increase of (ROS) in in vitro model system. Our findings disentangle the shared molecular circuits across different types of SNHL, providing potential targets for the broad effective therapeutic agents in SNHL.

Highlights

Sensorineural hearing loss (SNHL) refers to a type of hearing loss resulting from the structurally and functionally damaged inner ear and vestibulocochlear nerve, mainly including cochlear hair cells (HCs), stria vascularis (SV), and spiral ganglion neurons (SGNs) (Liberman and Kujawa, 2017)
To systematically investigate the shared molecular circuits involved in SNHL, we generated three SNHL models in C57BL/6 mice strain from aging, noise exposure, and cisplatin ototoxicity, respectively (Figure 1A)
It is notable that more damaged out hair cells (OHCs) were observed at the basal region than at the apex when exposed to the excessive intense noises even with relatively low frequencies (120 decibel sound pressure level (dB SPL), 4-24 kHz), which may result from the more susceptibility of OHCs at the basal region as shown in the previous studies (Sanz et al, 2015; Miao et al, 2021)

Summary

Introduction

Sensorineural hearing loss (SNHL) refers to a type of hearing loss resulting from the structurally and functionally damaged inner ear and vestibulocochlear nerve, mainly including cochlear hair cells (HCs), stria vascularis (SV), and spiral ganglion neurons (SGNs) (Liberman and Kujawa, 2017). Compared to other kinds of hearing loss, SNHL is usually permanent and accounts for approximately 90% of reported hearing loss cases (Li et al, 2017). Sudden SNHL affects 5 to 27 per 100,000 people each year, with approximately 66,000 new annual cases in the United States (Alexander and Harris, 2013). Among various causes of SNHL, aging, noise exposure, and ototoxic drugs are widely believed to play predominant roles Ototoxicity is well-established toxicity associated with therapeutic agents for causing cochlear impairment and the prevalence of ototoxicity-induced hearing loss ranges from 4 to 90% in patients who have received the therapies with potential ototoxicity (Landier, 2016)

Methods

Results

Conclusion