title: Zebrafish swimming behavior as a biomarker for ototoxicity-induced hair cell damage: a high-throughput drug development platform targeting hearing loss.
abstract: Hearing loss is one of the most common human sensory disabilities, adversely affecting communication, socialization, mood, physical functioning, and quality of life. In addition to age and noise-induced damage, ototoxicity is a common cause of sensorineural hearing loss with chemotherapeutic agents, for example, cisplatin, being a major contributor. Zebrafish (Danio rerio) are an excellent model to study hearing loss as they have neurosensory hair cells on their body surface that are structurally similar to those within the human inner ear. Anatomic assays of toxin-mediated hair cell damage in zebrafish have been established; however, using fish swimming behavior--rheotaxis--as a biomarker for this anatomic damage was only recently described. We hypothesized that, in parallel, multilane measurements of rheotaxis could be used to create a high-throughput platform for drug development assessing both ototoxic and potentially otoprotective compounds in real time. Such a device was created, and results demonstrated a clear dose response between cisplatin exposure, progressive hair cell damage, and reduced rheotaxis in zebrafish. Furthermore, pre-exposure to the otoprotective medication dexamethasone, before cisplatin exposure, partially rescued rheotaxis swimming behavior and hair cell integrity. These results provide the first evidence that rescued swimming behavior can serve as a biomarker for rescued hair cell function. Developing a drug against hearing loss represents an unmet clinical need with global implications. Because hearing loss from diverse etiologies may result from common end-effects at the hair cell level, lessons learned from the present study may be broadly used.
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; Department of Otolaryngology, The University of Arizona, Tucson, Ariz; The University of Arizona Cancer Center, The University of Arizona, Tucson, Ariz.
authors.forename: Maki
authors.initials: M
authors.lastname: Niihori
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; The University of Arizona College of Medicine, The University of Arizona, Tucson, Ariz.
authors.forename: Terry
authors.initials: T
authors.lastname: Platto
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; Department of Otolaryngology, The University of Arizona, Tucson, Ariz; The University of Arizona Cancer Center, The University of Arizona, Tucson, Ariz.
authors.forename: Suzu
authors.initials: S
authors.lastname: Igarashi
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; The University of Arizona College of Medicine, The University of Arizona, Tucson, Ariz.
authors.forename: Audriana
authors.initials: A
authors.lastname: Hurbon
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; Department of Otolaryngology, The University of Arizona, Tucson, Ariz; The University of Arizona Cancer Center, The University of Arizona, Tucson, Ariz.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Dunn
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; The University of Arizona College of Medicine, The University of Arizona, Tucson, Ariz.
authors.forename: Phi
authors.initials: P
authors.lastname: Tran
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; The University of Arizona College of Medicine, The University of Arizona, Tucson, Ariz.
authors.forename: Hung
authors.initials: H
authors.lastname: Tran
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; The University of Arizona College of Medicine, The University of Arizona, Tucson, Ariz.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Mudery
authors.affiliation: The University of Arizona College of Medicine, The University of Arizona, Tucson, Ariz; The University of Arizona Sarver Heart Center, The University of Arizona, Tucson, Ariz; Department of Biomedical Engineering, The University of Arizona, Tucson, Ariz.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Slepian
authors.affiliation: University of Arizona Ear Institute, The University of Arizona, Tucson, Ariz; Department of Otolaryngology, The University of Arizona, Tucson, Ariz; The University of Arizona Cancer Center, The University of Arizona, Tucson, Ariz; The University of Arizona Bio5 Institute, The University of Arizona, Tucson, Ariz. Electronic address: ajacob@oto.arizona.edu.
authors.forename: Abraham
authors.initials: A
authors.lastname: Jacob
mesh_terms: D000818:Animals; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions; D006198:Hair Cells, Auditory / Q000187:drug effects*; D034381:Hearing Loss / Q000188:drug therapy*; D013550:Swimming; D015027:Zebrafish / Q000502:physiology*