Prolonged dexamethasone exposure enhances zebrafish lateral-line regeneration but disrupts mitochondrial homeostasis and hair cell function

Abstract

The synthetic glucocorticoid dexamethasone is commonly used to treat inner ear disorders. Previous work in larval zebrafish has shown that dexamethasone treatment enhances hair cell regeneration, yet dexamethasone has also been shown to inhibit regeneration of peripheral nerves after lesion. We therefore used the zebrafish model to determine the impact of dexamethasone treatment on lateral-line hair cells and primary afferents. To explore dexamethasone in the context of regeneration, we used copper sulfate (CuSO4) to induce hair cell loss and retraction of nerve terminals, and then allowed animals to recover in dexamethasone for 48 hours. Consistent with previously work, we observed significantly more regenerated hair cells in dexamethasone-treated larvae. Importantly, we found that the afferent processes beneath neuromasts also regenerated in the presence of dexamethasone and formed an appropriate number of synapses, indicating that innervation of hair cells was not inhibited by dexamethasone. In addition to regeneration, we also explored the effects of prolonged dexamethasone exposure on lateral-line homeostasis and function. Following dexamethasone treatment, we observed more negatively charged mitochondrial membrane potentials (ΔΨm) in neuromast hair cells and supporting cells. Hair cells exposed to dexamethasone were also more vulnerable to neomycin-induced cell death. In response to a fluid-jet delivered saturating stimulus, calcium influx through hair cell mechanotransduction channels was significantly reduced, yet presynaptic calcium influx was unchanged. Cumulatively, these observations indicate that dexamethasone enhances hair cell regeneration in lateral-line neuromasts, yet also disrupts mitochondrial homeostasis, making hair cells more vulnerable to ototoxic insults and possibly impacting hair cell function.

Hair cell toxicology: With the help of a little fish

“…Glucocorticoids have been proposed to treat hearing loss (Meltser and Canlon, 2011). However, using zebrafish larvae it was demonstrated that previous exposure to glucocorticoids like cortisol or dexamethasone increased neomycin damage to hair cells (Hayward et al, 2019;Saettele et al, 2022). On a positive note, testing the ototoxicity of new semisynthetic aminoglycoside antibiotics has shown that etimicin exerts less damage to lateral line hair cells in zebrafish larvae than gentamicin (Shao et al, 2021), so this antibiotic could become an alternative for the ototoxic members of the family.…”