430
In an experimental tour de force , two recent studies examined transcriptomelevel changes in isolated lateral line supporting cells from ototoxin-treated larval
zebrafi sh as a major step towards identifying the complete set of molecular factors
responsible for innate regenerative capacity (Jiang et al. 2014 ; Steiner et al. 2014 ).
These studies saw changes in several signaling pathways important for hair cell
development and regeneration, including Notch and Wnt signaling, consistent with
previous pharmacologic and genetic manipulation studies demonstrating the importance of these pathways for hair cell regeneration (Ma et al. 2008 ; Head et al. 2013 ;
Wada et al. 2013 ; Jacques et al. 2014 ). Genomics tools have also been applied to
insightful regeneration studies in the adult zebrafi sh inner ear. These studies, which
used intense noise exposure to ablate hair cells, found that activation of stat3/socs3
and growth hormone signaling pathways were involved in proliferative regeneration
in the adult zebrafi sh saccule (Schuck et al. 2011 ; Liang et al. 2012 ). It is unclear if
these pathways are also important for lateral line regeneration, and conversely if
pathways identifi ed in the lateral line are required for regeneration of inner ear hair
cells. Moreover, it is possible that different ototoxins activate different regenerative
mechanisms, although this hypothesis has not been fully tested (but see Mackenzie
and Raible 2012 ).
5 Environmental Toxins
While many in the auditory fi eld think of “chemical ototoxicity” as it relates to
aminoglycoside antibiotics and platinum-based chemotherapy agents, some environmental contaminants, particularly metals, have damaging effects on hair cells.
Exposure to these contaminants may have long-term consequences for the fi sh by
disrupting lateral line function and reducing lateral line-mediated behaviors.
Environmentally relevant concentrations of cadmium (0.5–2 μg/ml) damage hair
bundles and reduce rheotaxis and startle responses in banded kokopu ( Galaxias
fasciatus ) and sea bass ( Dicentrarchus labrax ), respectively (Baker and Montgomery
2001 ; Faucher 2006 , 2008b ). Copper concentrations as low as 10 μM rapidly kill
hair cells in larval zebrafi sh, likely by inducing oxidative stress (Linbo et al. 2006 ;
Olivari et al. 2008 ). Zinc may similarly damage hair cells, while other metals such
as silver or manganese have no visible effect. Both cadmium and copper are also
toxic to fi sh olfactory receptors (Hansen et al. 1999 ; Baker and Montgomery 2001 ;
Blechinger et al. 2007 ), suggesting that direct contact with the aquatic environment
plays an important role in sensory receptor susceptibility to toxins. Recent evidence
suggests that the ubiquitous contaminant bisphenol-A, a component of many plastics, is also a hair cell toxin and may impede hair cell regeneration (Hayashi et al.
2015). Collectively, these fi ndings underscore the vulnerability of the lateral line to
aquatic pollutants. Furthermore, these studies inform human health, as environmental contaminants in food and water sources may exert similar effects on mammalian
hair cells.
A.B. Coffi n and J. Ramcharitar
In an experimental tour de force , two recent studies examined transcriptomelevel changes in isolated lateral line supporting cells from ototoxin-treated larval
zebrafi sh as a major step towards identifying the complete set of molecular factors
responsible for innate regenerative capacity (Jiang et al. 2014 ; Steiner et al. 2014 ).
These studies saw changes in several signaling pathways important for hair cell
development and regeneration, including Notch and Wnt signaling, consistent with
previous pharmacologic and genetic manipulation studies demonstrating the importance of these pathways for hair cell regeneration (Ma et al. 2008 ; Head et al. 2013 ;
Wada et al. 2013 ; Jacques et al. 2014 ). Genomics tools have also been applied to
insightful regeneration studies in the adult zebrafi sh inner ear. These studies, which
used intense noise exposure to ablate hair cells, found that activation of stat3/socs3
and growth hormone signaling pathways were involved in proliferative regeneration
in the adult zebrafi sh saccule (Schuck et al. 2011 ; Liang et al. 2012 ). It is unclear if
these pathways are also important for lateral line regeneration, and conversely if
pathways identifi ed in the lateral line are required for regeneration of inner ear hair
cells. Moreover, it is possible that different ototoxins activate different regenerative
mechanisms, although this hypothesis has not been fully tested (but see Mackenzie
and Raible 2012 ).
5 Environmental Toxins
While many in the auditory fi eld think of “chemical ototoxicity” as it relates to
aminoglycoside antibiotics and platinum-based chemotherapy agents, some environmental contaminants, particularly metals, have damaging effects on hair cells.
Exposure to these contaminants may have long-term consequences for the fi sh by
disrupting lateral line function and reducing lateral line-mediated behaviors.
Environmentally relevant concentrations of cadmium (0.5–2 μg/ml) damage hair
bundles and reduce rheotaxis and startle responses in banded kokopu ( Galaxias
fasciatus ) and sea bass ( Dicentrarchus labrax ), respectively (Baker and Montgomery
2001 ; Faucher 2006 , 2008b ). Copper concentrations as low as 10 μM rapidly kill
hair cells in larval zebrafi sh, likely by inducing oxidative stress (Linbo et al. 2006 ;
Olivari et al. 2008 ). Zinc may similarly damage hair cells, while other metals such
as silver or manganese have no visible effect. Both cadmium and copper are also
toxic to fi sh olfactory receptors (Hansen et al. 1999 ; Baker and Montgomery 2001 ;
Blechinger et al. 2007 ), suggesting that direct contact with the aquatic environment
plays an important role in sensory receptor susceptibility to toxins. Recent evidence
suggests that the ubiquitous contaminant bisphenol-A, a component of many plastics, is also a hair cell toxin and may impede hair cell regeneration (Hayashi et al.
2015). Collectively, these fi ndings underscore the vulnerability of the lateral line to
aquatic pollutants. Furthermore, these studies inform human health, as environmental contaminants in food and water sources may exert similar effects on mammalian
hair cells.
A.B. Coffi n and J. Ramcharitar