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

Buck, L.M., Winter, M.J., Redfern, W.S., and Whitfield, T.T.
Hearing Research   284(1-2): 67-81 (Journal)
Registered Authors
Buck, Lauren, Whitfield, Tanya T.
MeSH Terms
  • Acoustic Stimulation
  • Aminoglycosides/toxicity
  • Animals
  • Anti-Bacterial Agents/toxicity
  • Aspirin/toxicity
  • Cisplatin/toxicity
  • Drug Evaluation, Preclinical/instrumentation
  • Drug Evaluation, Preclinical/methods
  • Evoked Potentials, Auditory/drug effects
  • Hair Cells, Auditory/drug effects*
  • Hair Cells, Auditory/pathology
  • Hair Cells, Auditory/physiology
  • Humans
  • Larva
  • Lateral Line System/drug effects*
  • Lateral Line System/pathology*
  • Lateral Line System/physiopathology
  • Reflex, Startle/drug effects
  • Zebrafish
22183155 Full text @ Hear. Res.
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.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes