Calcitriol alleviates noise-induced hearing loss by regulating the ATF3/DUSP1 signalling pathway

  • Ecotoxicol Environ Saf. 2024 Oct 1:284:116906. doi: 10.1016/j.ecoenv.2024.116906.
Rui Liang  1 ,  Weilong Wang  2 ,  Wei Gao  1 ,  Siyu Li  1 ,  Peiheng Lu  1 ,  Jiawei Chen  1 ,  Xuerui Ding  1 ,  Pengwei Ma  1 ,  Hao Yuan  1 ,  Yuqiang Lun  1 ,  Jianing Guo  1 ,  Zi Wang  1 ,  Hongkai Mei  1 ,  Lianjun Lu  3
Affiliations
  • 1. Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
  • 2. Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 3. Department of Otolaryngology Head and Neck Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China. Electronic address: [email protected].
PMID: 39182283 DOI: 10.1016/j.ecoenv.2024.116906
Abstract

Background: Calcitriol (Cal) is the most active metabolite of vitamin D and has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the role of Cal in noise-induced hearing loss (NIHL) to further elucidate the mechanism of noise-induced oxidative stress in the mouse cochlea.

Methods: C57BL/6 J mice were given six intraperitoneal injections of Cal (500 ng/kg/d). After 14 days of noise exposure, auditory brainstem response (ABR) thresholds, and the cochlear outer hair cell loss rate were analysed to evaluate auditory function. Real-time fluorescence quantitative PCR, immunofluorescence and western blotting were performed in vitro after the treatment of cochlear explants with 100 µM tert-butyl hydroperoxide (TBHP) for 2.5 h and HEI-OC1 cells with 250 µM TBHP for 1.5 h.

Results: In vivo experiments confirmed that Cal pretreatment mitigated NIHL and outer hair cell death. The in vitro results demonstrated that Cal significantly reduced TBHP-induced cochlear auditory nerve fibre degradation and spiral ganglion neuron damage. Moreover, treatment with Cal inhibited the expression of oxidative stress-related factors (3-NT and 4-HNE) and DNA damage-related factors (γ-H2A.X) and attenuated TBHP-induced Apoptosis in cochlear explants and HEI-OC1 cells. A total of 1479 upregulated genes and 1443 downregulated genes were screened in cochlear tissue 1 h after noise exposure. The level of transcription factor 3 (ATF3) was significantly elevated in HEI-OC1 cells after TBHP stimulation. Gene Transcription Regulation Database （GTRD）and Cistrome database analyses revealed that the downstream target gene of ATF3 is dual specificity Phosphatase 1 (DUSP1). Cistrome DB Toolkit database results showed that the transcription factor of DUSP1 was ATF3. In addition, the ChIP-PCR results indicated that ATF3 might be a direct transcription factor of DUSP1.

Conclusion: The results of our study suggest that Cal attenuates NIHL and inhibits noise-induced Apoptosis by regulating the ATF3/DUSP1 signalling pathway.

Keywords
ATF3; Calcitriol; DNA repair; DUSP1; Noise-induced hearing loss; Oxidative stress.
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