Protective Effect Of Inhibition Of DNA Methyltransferase 1 On Noise-induced Hearing Loss And Its Mechanism

Background:Noise-induced hearing loss(NIHL)is a common form of hearing impairment severely impacting the quality of individuals.While many molecular mechanisms such as transcriptional dysregulation and oxidative damage are known to play important roles in the pathogenesis of NIHL but epigenetic regulation remains unclear.In the current study,we investigated the effects of the DNA methylation,a key epigenetic mechanism that often responses to intracellular and environmental cues and plays a crucial role in regulating gene expression,on NIHL in adult C57BL/6J mice.Results:Auditory brainstem responses(ABR)were measured at baseline and 2 days after trauma in mice to assess the auditory functions.Scanning electron microscopy(SEM)assay,whole-mount immunofluorescence staining and confocal microcopy of the mice inner ear were performed to analyze the noise-induced damage in inner ear and the auditory nerve at 2 days after the noise exposure.Our results showed that the noise exposure caused the ABR threshold elevations and cochlear hair cell(HC)loss throughout the basal and middle turns of the cochlea;SEM images confirmed persistent damage to the surviving OHC stereocilia.Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells(IHCs)and spiral ganglion neurons(SGN).Inhibition of DNA methyltransferase 1(DNMT1)activity via a non-nucleoside specific pharmacological inhibitor,RG108,or silencing of DNMT1 with siRNA significantly attenuated ABR threshold elevations,HC damage and auditory synapses loss.Conclusions:This study explores the role of DNA methylation in the pathogenesis of noiseinduced hair cell damage,cochlear synaptopathy,and subsequent hearing loss,implying that certain epigenetic manipulations may have potential therapeutic significance in the prevention and treatment of NIHL.