Glucococorticoid receptor activation exacerbates aminoglycoside-induced damage to the zebrafish lateral line

• Published in: Hearing research 2019-06, Vol.377, p.12-23
• Main Authors: Hayward, Tamasen, Young, Alexander, Jiang, Abigail, Crespi, Erica J., Coffin, Allison B.
• Format: Article
• Language: English
• Subjects: Aminoglycoside; Animals; Anti-Bacterial Agents - toxicity; Cortisol; Gentamicins - toxicity; Glucocorticoids - toxicity; Hair cell; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - metabolism; Hair Cells, Auditory - pathology; Hydrocortisone - toxicity; Lateral Line System - drug effects; Lateral Line System - embryology; Lateral Line System - metabolism; Neomycin - toxicity; Ototoxin; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Signal Transduction; Transcription, Genetic - drug effects; Zebrafish; Zebrafish - embryology; Zebrafish Proteins - agonists; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/j.heares.2019.03.002

Aminoglycoside antibiotics have potent antibacterial properties but cause hearing loss in up to 25% of patients. These drugs are commonly administered in patients with high glucocorticoid stress hormone levels and can be combined with exogenous glucocorticoid treatment. However, the interaction of stress and aminoglycoside-induced hearing loss has not been fully explored. In this study, we investigated the effect of the glucocorticoid stress hormone cortisol on hair cells in the zebrafish lateral line as an important step toward understanding how physiological stressors modulate hair cell survival. We found that 24-hr cortisol incubation sensitized hair cells to neomycin damage. Pharmacological and genetic manipulation demonstrates that sensitization depended on the action of the glucocorticoid receptor but not the mineralocorticoid receptor. Blocking endogenous cortisol production reduced hair cell susceptibility to neomycin, further evidence that glucocorticoids modulate aminoglycoside ototoxicity. Glucocorticoid transcriptional activity was apparent in lateral line hair cells, suggesting a direct action of cortisol in these aminoglycoside-sensitive cells. Our work shows that the stress hormone cortisol can increase hair cell sensitivity to aminoglycoside damage, which highlights the importance of recognizing stress and the impacts of glucocorticoid signaling in both ototoxicity research and clinical practice. [Display omitted] •Cortisol sensitizes hair cells to aminoglycoside toxicity in the lateral line.•Inhibition of glucocorticoid synthesis attenuates neomycin damage.•Glucocorticoid receptor transcriptional activity occurs in hair cells.•Cortisol sensitization relies on the glucocorticoid receptor.