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Ototoxin-induced cellular damage in neuromasts disrupts lateral line function in larval zebrafish

Buck, L. M. J., Winter, M. J., Redfern, W. S. and Whitfield, T. T. (2012) Ototoxin-induced cellular damage in neuromasts disrupts lateral line function in larval zebrafish. Hearing Research. ISSN 0378-5955 (In Press)

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Abstract

The ototoxicity of a number of marketed drugs is well documented, and there is an absence of convenient techniques to identify and eliminate this unwanted effect at a pre-clinical stage. We have assessed the validity of the larval zebrafish, or more specifically its lateral line neuromast hair cells, as a microplate-scale in vivo surrogate model of mammalian inner ear hair cell responses to ototoxin exposure. Here we describe an investigation of the pathological and functional consequences of hair cell loss in lateral line neuromasts of larval zebrafish after exposure to a range of well known human and non-human mammalian ototoxins. Using a previously described histological assay, we show that hair cell damage occurs in a concentration-dependent fashion following exposure to representatives from a range of drug classes, including the aminoglycoside antibiotics, salicylates and platinum-based chemotherapeutics, as well as a heavy metal. Furthermore, we detail the optimisation of a semi-automated method to analyse the stereotypical startle response in larval zebrafish, and use this to assess the impact of hair cell damage on hearing function in these animals. Functional assessment revealed robust and significant attenuation of the innate startle, rheotactic and avoidance responses of 5 day old zebrafish larvae after treatment with a number of compounds previously shown to induce hair cell damage and loss. Interestingly, a startle reflex (albeit reduced) was still present even after the apparent complete loss of lateral line hair cell fluorescence, suggesting some involvement of the inner ear as well as the lateral line neuromast hair cells in this reflex response. Collectively, these data provide evidence to support the use of the zebrafish as a pre-clinical indicator of drug-induced histological and functional ototoxicity.

Item Type: Article
Copyright, Publisher and Additional Information: © 2010 Elsevier. This is an author produced version of a paper subsequently published in Hearing Research. Uploaded in accordance with the publisher's self-archiving policy.
Keywords: zebrafish, ototoxicity, hair cell, startle reflex, hearing function, neuromast, rheotaxis, avoidance behaviour
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > School of Biological Sciences (Sheffield) > Department of Biomedical Science (Sheffield) > Centre for Developmental Genetics (Sheffield)
The University of Sheffield > University of Sheffield Research Centres and Institutes > Centre for Developmental Genetics (Sheffield)

The University of Sheffield > Faculty of Science (Sheffield) > School of Biological Sciences (Sheffield) > Department of Biomedical Science (Sheffield)
Depositing User: Dr Tanya Whitfield
Date Deposited: 11 Jan 2012 11:09
Last Modified: 08 Feb 2013 17:36
Published Version: http://dx.doi.org/10.1016/j.heares.2011.12.001
Status: In Press
Publisher: Elsevier
Refereed: Yes
Identification Number: 10.1016/j.heares.2011.12.001
Related URLs:
URI: http://eprints.whiterose.ac.uk/id/eprint/43574

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