Hair cell toxicology: With the help of a little fish

Abstract

Hearing or balance loss are disabling conditions that have a serious impact in those suffering them, especially when they appear in children. Their ultimate cause is frequently the loss of function of mechanosensory hair cells in the inner ear. Hair cells can be damaged by environmental insults, like noise or chemical agents, known as ototoxins. Two of the most common ototoxins are life-saving medications: cisplatin against solid tumors, and aminoglycoside antibiotics to treat infections. However, due to their localization inside the temporal bone, hair cells are difficult to study in mammals. As an alternative animal model, zebrafish larvae have hair cells similar to those in mammals, some of which are located in a fish specific organ on the surface of the skin, the lateral line. This makes them easy to observe in vivo and readily accessible for ototoxins or otoprotective substances. These features have made possible advances in the study of the mechanisms mediating ototoxicity or identifying new potential ototoxins. Most importantly, the small size of the zebrafish larvae has allowed screening thousands of molecules searching for otoprotective agents in a scale that would be highly impractical in rodent models. The positive hits found can then start the long road to reach clinical settings to prevent hearing or balance loss.

Keywords: aminoglycoside antibiotic; cisplatin; hair cell; otoprotection; ototoxicity; zebrafish.

FIGURE 1

Images of hair cells in 5dpf zebrafish larvae. (A) Composite image obtained with laser scanning microscopy of a transgenic larva expressing cldnb::lynGFP (Haas and Gilmour, 2006), gift of Paola Bovolenta (CSIC, Madrid). Arrowheads point to some of the neuromast of the anterior (head) and posterior (trunk) lateral line. pn, pronephric duct; n, nephrons; g, distal gut. (B–D) Detail of an individual neuromast of the posterior lateral line showing (B) hair cells expressing the transgene pou4f3::mGFP (Obholzer et al., 2008), gift of Berta Alisa (Univ. Pompeu Fabra, Barcelona); (C) its afferent innervation expressing the transgene SILL1::mCherry (Pujol-Martí et al., 2012), gift of Hernán López-Schier (Helmholtz Zentrum, Munich); (D) overlay of the previous images. (E,F) Overview of the anterior lateral line showing hair cells labelled with (E) YO-PRO1 and (F) FM1-43X; neuromasts are labelled according to (Raible and Kruse, 2000). Inner ear hair cells are not labelled with these dyes; otoliths are visible behind neuromasts O2 and MI2. (G,H) Image of two anterior lateral line neuromasts labelled with the transgene pou4f3::mGFP under standard conditions (G) or after treatment with the aminoglycoside antibiotic streptomycin (H). Scale bar in A, E, (F) 100 μm; scale bar in (B,C,D,G,H) 10 μm. All images taken in the Microscopy Unit of Centres Científics i Tecnològics de la Universitat de Barcelona (CCiTUB) at the Campus de Bellvitge.