Intratympanically Delivered Steroids Impact Thousands More Inner Ear Genes Than Systemic Delivery

Dennis Trune, Katherine D. Shives, Fran Hausman, J. Beth Kempton, Carol Macarthur, Dongseok Choi

Research output: Contribution to journalArticle

Abstract

Objectives: Glucocorticoids are given for sensorineural hearing loss, but little is known of their molecular impact on the inner ear. Furthermore, in spite of claims of improved hearing recovery with intratympanic delivery of steroids, no studies have actually documented the inner ear molecular functions that are enhanced with this delivery method. Methods: To assess steroid-driven processes in the inner ear, gene chip analyses were conducted on mice treated systemically with the glucocorticoids prednisolone or dexamethasone or the mineralocorticoid aldosterone. Other mice were given the same steroids intratympanically. Inner ears were harvested at 6 hours and processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34 000 genes. Results were statistically analyzed for up or down expression of each gene against control (untreated) mice. Results: Analyses showed approximately 17 500 genes are normally expressed in the inner ear and steroids alter expression of 55% to 82% of these. Dexamethasone changed expression of 9424 (53.9%) inner ear genes following systemic injection but 14 899 ear genes (85%) if given intratympanically. A similar pattern was seen with prednisolone, as 7560 genes were impacted by oral delivery and 11 164 genes (63.8%) when given intratympanically. The mineralocorticoid aldosterone changed expression of only 268 inner ear genes if given orally, but this increased to 10 124 genes (57.9%) if injected intratympanically. Furthermore, the glucocorticoids given actually impacted more inner ear genes via the mineralocorticoid receptor than the glucocorticoid receptor. Conclusions: Thousands of inner ear genes were affected by steroids, and this number increased significantly if steroids were delivered intratympanically. Also, the impact of glucocorticoids on inner ear mineralocorticoid functions is more substantial than previously known. Thus, the application of therapeutic steroids for hearing loss needs to be reassessed in light of their more comprehensive impact on inner ear genes. Furthermore, simply ascribing the efficacy of steroids to immunosuppression no longer appears to be warranted.

Original languageEnglish (US)
Pages (from-to)134S-138S
JournalAnnals of Otology, Rhinology and Laryngology
Volume128
Issue number6_suppl
DOIs
StatePublished - Jun 1 2019

Fingerprint

Inner Ear
Steroids
Genes
Mineralocorticoids
Glucocorticoids
Prednisolone
Oligonucleotide Array Sequence Analysis
Aldosterone
Dexamethasone
Gene Expression
Mineralocorticoid Receptors
Sensorineural Hearing Loss
Glucocorticoid Receptors
Hearing Loss
Immunosuppression
Hearing
Ear
Injections

Keywords

  • gene microarray
  • glucocorticoid
  • inner ear
  • intratympanic steroids
  • mineralocorticoid
  • steroid therapy

ASJC Scopus subject areas

  • Otorhinolaryngology

Cite this

Intratympanically Delivered Steroids Impact Thousands More Inner Ear Genes Than Systemic Delivery. / Trune, Dennis; Shives, Katherine D.; Hausman, Fran; Kempton, J. Beth; Macarthur, Carol; Choi, Dongseok.

In: Annals of Otology, Rhinology and Laryngology, Vol. 128, No. 6_suppl, 01.06.2019, p. 134S-138S.

Research output: Contribution to journalArticle

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abstract = "Objectives: Glucocorticoids are given for sensorineural hearing loss, but little is known of their molecular impact on the inner ear. Furthermore, in spite of claims of improved hearing recovery with intratympanic delivery of steroids, no studies have actually documented the inner ear molecular functions that are enhanced with this delivery method. Methods: To assess steroid-driven processes in the inner ear, gene chip analyses were conducted on mice treated systemically with the glucocorticoids prednisolone or dexamethasone or the mineralocorticoid aldosterone. Other mice were given the same steroids intratympanically. Inner ears were harvested at 6 hours and processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34 000 genes. Results were statistically analyzed for up or down expression of each gene against control (untreated) mice. Results: Analyses showed approximately 17 500 genes are normally expressed in the inner ear and steroids alter expression of 55{\%} to 82{\%} of these. Dexamethasone changed expression of 9424 (53.9{\%}) inner ear genes following systemic injection but 14 899 ear genes (85{\%}) if given intratympanically. A similar pattern was seen with prednisolone, as 7560 genes were impacted by oral delivery and 11 164 genes (63.8{\%}) when given intratympanically. The mineralocorticoid aldosterone changed expression of only 268 inner ear genes if given orally, but this increased to 10 124 genes (57.9{\%}) if injected intratympanically. Furthermore, the glucocorticoids given actually impacted more inner ear genes via the mineralocorticoid receptor than the glucocorticoid receptor. Conclusions: Thousands of inner ear genes were affected by steroids, and this number increased significantly if steroids were delivered intratympanically. Also, the impact of glucocorticoids on inner ear mineralocorticoid functions is more substantial than previously known. Thus, the application of therapeutic steroids for hearing loss needs to be reassessed in light of their more comprehensive impact on inner ear genes. Furthermore, simply ascribing the efficacy of steroids to immunosuppression no longer appears to be warranted.",
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