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Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity

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Abstract

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin’s ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.

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Acknowledgments

The authors would like to thank Dr. Mincheol Kang for his help. The project was supported by a grant to J.B. from the National Institute on Deafness and Other Communication Disorders (R41DC017108).

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Authors and Affiliations

  1. Translational Research Center, Department of Neurobiology and Anatomy, Northeast Ohio Medical University, Rootstown, OH, 44272, USA

    Yingying Chen, Jeffrey G. Mellott, Weijie Wang, Amir M. Mafi & Jianxin Bao

  2. Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, NV, 95616, USA

    Yingying Chen & Ebenezer N. Yamoah

  3. Department of Speech and Hearing Science, The Ohio State University, 110 Pressey Hall, 1070 Carmack Road, Columbus, OH, 43210, USA

    Eric C. Bielefeld

  4. School of Pharmacy, Anhui Medical University, Hefei, China

    Weijie Wang

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  1. Yingying Chen
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J.B. is one of the co-founders of Gateway Biotechnology Inc. and has disclosed potential interests fully to Northeast Ohio Medical University. Other authors declare that they have no conflict of interest.

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Chen, Y., Bielefeld, E.C., Mellott, J.G. et al. Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity. JARO 22, 107–126 (2021). https://doi.org/10.1007/s10162-020-00782-z

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