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Title: The zebrafish as an in vivo model of drug-induced auditory and vestibular impairment
Author: Buck, Lauren Michelle Jenny
ISNI:       0000 0004 2735 8141
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2012
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A variety of marketed drugs are known to cause damage to the hearing and/or balance systems in humans (ototoxicity). The absence of standard testing protocols to identify ototoxic effects at the pre-clinical stage is one major reason for the incidence of these adverse effects in the clinic. The zebrafish (Danio rerio) has been proposed as a suitable model organism to determine the ototoxicity of compounds early on. Free-swimming zebrafish larvae possess rudimentary hearing and balance systems that consist of inner ear and lateral line structures, with specialised hair cells similar to those of the human inner ear. The studies described in this thesis examine the pathological and functional consequences of hair cell loss in the lateral line and otic vesicle of larval zebrafish, following exposure to a range of reported human ototoxins. The aim of these studies was to assess the validity and translational capability of the larval zebrafish as a microplate-scale in vivo model of mammalian inner ear hair cell responses to ototoxin exposure. Histological analyses of hair cell damage were performed using the vital dyes DASPEI and FM1-43FX, in addition to Tg(pou4f3::mGFP)s356t and i193 transgenic lines, which mark hair cells. Results of the histological investigations showed hair cell damage to occur in a concentration-dependent manner after exposure to representatives from a range of drug classes. These classes include the aminoglycoside antibiotics, salicylates and platinum-based chemotherapeutics. Injection of ototoxins into the ear was also sufficient to induce hair cell damage to specific sensory maculae. The functional impact of hair cell damage was investigated using startle, rheotaxis and seeker response assays, which harnessed the natural behavioural responses of the larvae. A novel semi-automated startle assay was developed and optimised to study the effects of hair cell damage on the acoustically-evoked high-speed escape response. Functional assessment revealed the significant attenuation of startle, rheotaxis and underwater motion detection following exposure to compounds that had previously induced hair cell damage. Additional investigations into the mechanisms underlying hair cell damage for one ototoxin, cisplatin, are also described. Chemical manipulation of one component of the proposed mammalian pathway of damage was able to significantly protect hair cells in the zebrafish, suggesting conservation of damage mechanisms between zebrafish and higher vertebrates. Collectively, the data described in this thesis provide evidence to support the use of zebrafish as an in vivo model of ototoxicity.
Supervisor: Whitfield, T. T. ; Winter, M. J. ; Redfern, W. S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available