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d-Galactose and Hypoxia Induce the Early Onset of Age-Related Hearing Loss Deterioration in a Mouse Model

  • Original Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

We previously showed that aging accelerates after 3 months of exposure to hypoxia and environmental change but not genetic modifications. Here, we aimed to simply induce early-onset age-related hearing loss within a short period based on our previous method.

Methods:

We randomly divided 16 C57BL/6 mice into four groups that were maintained under conditions of normoxia and hypoxia with or without injected d-galactose for 2 months. Deteriorated hearing, the expression of age-related factors, and oxidative stress responses were detected using the click and tone burst auditory brainstem response test, reverse transcription-polymerase chain reaction, and by measuring superoxide dismutase (SOD).

Results:

The group maintained under hypoxia combined with d-galactose lost hearing particularly at 24 Hz and 32 Hz at 6 weeks compared with the other groups. Aging-related factors were also significantly decreased in the hypoxia and d-galactose groups. However, SOD levels did not significantly differ among the groups.

Conclusion:

Age-related hearing loss is an environmental disorder induced by chronic oxidative stress associated with genetic backgrounds. Our findings suggested that d-galactose and hypoxia can induce the phenotypes of age-related hearing loss and aging-associated molecules in a murine model within a short time with environmental stimulation alone.

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References

  1. World Health O. Addressing the rising prevalence of hearing loss. Geneva: World Health Organization; 2018.

    Google Scholar 

  2. Shen Y, Ye B, Chen P, Wang Q, Fan C, Shu Y, et al. Cognitive decline, dementia, Alzheimer’s disease and presbycusis: examination of the possible molecular mechanism. Front Neurosci. 2018;12:394.

    Article  PubMed  PubMed Central  Google Scholar 

  3. McDaid D, Park AL, Chadha S. Estimating the global costs of hearing loss. Int J Audiol. 2021;60:162–70.

    Article  PubMed  Google Scholar 

  4. Wang J, Puel JL. Presbycusis: an update on cochlear mechanisms and therapies. J Clin Med. 2020;9:218.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ohlemiller KK. Mouse methods and models for studies in hearing. J Acoust Soc Am. 2019;146:3668–80.

    Article  PubMed  Google Scholar 

  6. Park DJ, Ha S, Choi JS, Lee SH, Park JE, Seo YJ. Induced short-term hearing loss due to stimulation of age-related factors by intermittent hypoxia, high-fat diet, and galactose injection. Int J Mol Sci. 2020;21:7068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Seo YJ, Ju HM, Lee SH, Kwak SH, Kang MJ, Yoon JH, et al. Damage of inner ear sensory hair cells via mitochondrial loss in a murine model of sleep apnea with chronic intermittent hypoxia. Sleep. 2017. https://doi.org/10.1093/sleep/zsx106.

    Article  PubMed  Google Scholar 

  8. Jaiganesh A, De-la-Torre P, Patel AA, Termine DJ, Velez-Cortes F, Chen C, et al. Zooming in on Cadherin-23: structural diversity and potential mechanisms of inherited deafness. Structure. 2018;26:1210-25.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Manji SS, Miller KA, Williams LH, Andreasen L, Siboe M, Rose E, et al. An ENU-induced mutation of Cdh23 causes congenital hearing loss, but no vestibular dysfunction, in mice. Am J Pathol. 2011;179:903–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miyasaka Y, Suzuki S, Ohshiba Y, Watanabe K, Sagara Y, Yasuda SP, et al. Compound heterozygosity of the functionally null Cdh23(v-ngt) and hypomorphic Cdh23(ahl) alleles leads to early-onset progressive hearing loss in mice. Exp Anim. 2013;62:333–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guo B, Guo Q, Wang Z, Shao JB, Liu K, Du ZD, et al. d-Galactose-induced oxidative stress and mitochondrial dysfunction in the cochlear basilar membrane: an in vitro aging model. Biogerontology. 2020;21:311–23.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yeo EJ. Hypoxia and aging. Exp Mol Med. 2019;51:1–15.

    CAS  PubMed  Google Scholar 

  13. Ju HM, Lee SH, Choi JS, Seo YJ. A simple model for inducing optimal increase of SDF-1 with aminoglycoside ototoxicity. Biomed Res Int. 2017;2017:4630241.

  14. Youn CK, Jun Y, Jo ER, Cho SI. Age-related hearing loss in C57BL/6J mice is associated with mitophagy impairment in the central auditory system. Int J Mol Sci. 2020;21:7202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhao C, Yang Z, Chen Z, Liang W, Gong S, Du Z. AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo. Mol Med. 2022;28:124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Du Z, Yang Q, Zhou T, Liu L, Li S, Chen S, et al. d-galactose-induced mitochondrial DNA oxidative damage in the auditory cortex of rats. Mol Med Rep. 2014;10:2861–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Elham T, Ghassem M. Evaluation of the effects of chronic injection of D-galactose on auditory brainstem responses as a model for studying age-related hearing loss. Acta Med Iran. 2019;57:281–8.

    Google Scholar 

  18. Du ZD, Han SG, Qu TF, Guo B, Yu SK, Wei W, et al. Age-related insult of cochlear ribbon synapses: an early-onset contributor to d-galactose-induced aging in mice. Neurochem Int. 2020;133:104649.

    Article  CAS  PubMed  Google Scholar 

  19. Koide Y, Teranishi M, Sugiura S, Uchida Y, Nishio N, Kato K, et al. Association between uncoupling protein 2 gene Ala55val polymorphism and sudden sensorineural hearing loss. J Int Adv Otol. 2018;14:166–9.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kim MJ, White K, Walker L, Han C, Someya S. Age-related hearing loss: mitochondrial biochemical pathways and molecular targets. In: Miller J, Le Prell CG, Rybak L, editors., et al., Free radicals in ENT pathology. Cham: Springer International Publishing; 2015. p. 273–88.

    Chapter  Google Scholar 

  21. Bouzid A, Smeti I, Dhouib L, Roche M, Achour I, Khalfallah A, et al. Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis. Biomarkers. 2018;23:347–56.

    Article  CAS  PubMed  Google Scholar 

  22. Wang J, Shen J, Guo L, Cheng C, Chai R, Shu Y, et al. A humanized mouse model, demonstrating progressive hearing loss caused by MYO6 p.C442Y, is inherited in a semi-dominant pattern. Hear Res. 2019;379:79–88.

    Article  CAS  PubMed  Google Scholar 

  23. Seki Y, Shitara H, Ishii R, Ouchi T, Yasuda SP, Kikkawa Y. Myosin VI haploinsufficiency reduced hearing ability in mice. Neuroscience. 2021;478:100–11.

    Article  CAS  PubMed  Google Scholar 

  24. Uchida Y, Teranishi M, Nishio N, Sugiura S, Hiramatsu M, Suzuki H, et al. Endothelin-1 gene polymorphism in sudden sensorineural hearing loss. Laryngoscope. 2013;123:E59-65.

    Article  CAS  PubMed  Google Scholar 

  25. Vasilyeva ON, Frisina ST, Zhu X, Walton JP, Frisina RD. Interactions of hearing loss and diabetes mellitus in the middle age CBA/CaJ mouse model of presbycusis. Hear Res. 2009;249:44–53.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fujita T, Yamashita D, Uehara N, Inokuchi G, Hasegawa S, Otsuki N, et al. A high-fat diet delays age-related hearing loss progression in C57BL/6J mice. PLoS One. 2015;10:e0117547.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Espino Guarch M, Font-Llitjós M, Murillo-Cuesta S, Errasti-Murugarren E, Celaya AM, Girotto G, et al. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. eLife. 2018;7:e31511.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Suzuki J, Inada H, Han C, Kim MJ, Kimura R, Takata Y, et al. “Passenger gene” problem in transgenic C57BL/6 mice used in hearing research. Neurosci Res. 2020;158:6–15.

    Article  CAS  PubMed  Google Scholar 

  29. Sugiura S, Uchida Y, Nakashima T, Ando F, Shimokata H. The association between gene polymorphisms in uncoupling proteins and hearing impairment in Japanese elderly. Acta Otolaryngol. 2010;130:487–92.

    Article  CAS  PubMed  Google Scholar 

  30. Liu Y, Chu H, Chen J, Zhou L, Chen Q, Yu Y, et al. Age-related change in the expression of NKCC1 in the cochlear lateral wall of C57BL/6J mice. Acta Otolaryngol. 2014;134:1047–51.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by the Korean Fund for Regenerative Medicine(KFRM) grant funded by the Korea government(the Ministry of Science and ICT, the Ministry of Health & Welfare, 21A0101L0) and supported by "Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(MOE)(2022RIS-005).

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Authors and Affiliations

  1. Department of Otorhinolaryngology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea

    Temuulen Batsaikhan, Jin Sil Choi, Sun Mok Ha, Yeji Ahn & Young Joon Seo

  2. Research Institute of Hearing Enhancement, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, 26426, South Korea

    Temuulen Batsaikhan, Jin Sil Choi, Sun Mok Ha, Yeji Ahn & Young Joon Seo

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  1. Temuulen Batsaikhan
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Each author had equally contributed on this study.

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Correspondence to Young Joon Seo.

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The animal studies were approved by the Institutional Animal Care and Use Committee of the Animal laboratory of Yonsei University, Wonju College of Medicine (Approval No: YWC-181001-2).

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Batsaikhan, T., Choi, J.S., Ha, S.M. et al. d-Galactose and Hypoxia Induce the Early Onset of Age-Related Hearing Loss Deterioration in a Mouse Model. Tissue Eng Regen Med 20, 779–787 (2023). https://doi.org/10.1007/s13770-023-00547-8

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  • DOI: https://doi.org/10.1007/s13770-023-00547-8

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