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Age related changes in gene expression within the cochlea of C57BL/6J mice

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Abstract

Background and aims: Hearing loss as a unique symptom is highly prevalent in the elderly and while there exists several pathologies that would result in age related hearing loss (ARHL), most agree it is multifactorial with environmental, metabolic and genetic components. However, no research to date has discovered a definitive genetic cause. This paper describes the use of microarray to address this issue. Methods: The left cochlea of laboratory aged C57BL6J mice at 4, 15 and 45 weeks was extracted from pooled, agematched animals and the RNA extracted for use in microarray analysis. The contralateral cochlea was also removed and used for immunohistochemical analysis. Results: Microarray revealed 116 genes to be up or down regulated between young and old animals, the most prominent being prolactin (108.2 fold increase) and growth hormone (43.94 fold increase). The prolactin inhibitor calcitonin was also down regulated over 2 fold. Immunohistochemistry revealed prolactin to be weakly expressed within the spiral ganglion, whilst its receptor was widely distributed throughout the cochlea. Conclusion: This is the first study demonstrating the cochlea as a site for extrapituitary prolactin expression and that this expression is related to age. Combined with the widespread distribution of prolactin receptor, there may be implications for prolactin’s role in ARHL.

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References

  1. Schuknecht HF, Gacek MR. Cochlear pathology in presbycusis. Ann Otol Rhinol Laryngol 1993; 102: 1–16.

    Article  CAS  PubMed  Google Scholar 

  2. Gates GA, Mills JH. Presbycusis. Lancet 2005; 366: 1111–20.

    Article  PubMed  Google Scholar 

  3. Huang T. Age-related hearing loss. Minn Med 2007; 90: 48–50.

    PubMed  Google Scholar 

  4. Ohlemiller KK. Mechanisms and genes in human strial presbycusis from animal models. Brain Res 2009; 314: 70–83.

    Article  Google Scholar 

  5. Syka J. The Fischer 344 rat as a model of presbycusis. Hear Res 2010; 264: 70–8. doi: 10.1016/j.heares.2009.11.003. Epub 2009 Nov 10.

    Article  PubMed  Google Scholar 

  6. Liu XZ, Yan D. Ageing and hearing loss. J Pathol 2007; 211: 188–97.

    Article  CAS  PubMed  Google Scholar 

  7. D’Souza M, Zhu X, Frisina RD. Novel approach to select genes from RMA normalized microarray data using functional hearing tests in aging mice. J Neurosci Methods 2008; 171: 279–87.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kurniawan C, Westendorp RG, de Craen AJ, Gussekloo J, de Laat J, van Exel E. Gene dose of apolipoprotein E and age-related hearing loss. Neurobiol Aging 2012; 33: 2230.e7–2230.e12. doi: 10.1016/j.

    Article  CAS  PubMed  Google Scholar 

  9. Van Laer L, Van Eyken E, Fransen E et al. The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment. Hum Mol Genet 2008; 17: 159–69.

    Article  PubMed  Google Scholar 

  10. Dufva M. Introduction to microarray technology. Methods Mol Biol 2009; 529: 1–22.

    Article  CAS  PubMed  Google Scholar 

  11. Henry KR, Chole RA. Genotypic differences in behavioral, physiological and anatomical expressions of age-related hearing loss in the laboratory mouse. Audiology 1980; 19: 369–83.

    Article  CAS  PubMed  Google Scholar 

  12. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–8.

    Article  CAS  Google Scholar 

  13. Ries PW. Prevalence and characteristics of persons with hearing trouble: United States, 1990–91. Vital Health Stat 10. 1994; 1–75.

    Google Scholar 

  14. Bai U, Seidman MD, Hinojosa R, Quirk WS. Mitochondrial DNA deletions associated with aging and possibly presbycusis: a human archival temporal bone study. Am J Otol 1997; 18: 449–53.

    CAS  PubMed  Google Scholar 

  15. Fischel-Ghodsian N, Bykhovskaya Y, Taylor K et al. Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations. Hear Res 1997; 110: 147–54.

    Article  CAS  PubMed  Google Scholar 

  16. Manwaring N, Jones MM, Wang JJ et al. Mitochondrial DNA haplogroups and age-related hearing loss. Arch Otolaryngol Head Neck Surg 2007; 133: 929–33.

    Article  PubMed  Google Scholar 

  17. Markaryan A, Nelson EG, Hinojosa R. Detection of mitochondrial DNA deletions in the cochlea and its structural elements from archival human temporal bone tissue. Mutat Res 2008; 640: 38–45.

    Article  CAS  PubMed  Google Scholar 

  18. Someya S, Yamasoba T, Kujoth GC et al. The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiol Aging 2008; 29: 1080–92.

    Article  CAS  PubMed  Google Scholar 

  19. Op de Beeck K, Schacht J, Van Camp G. Apoptosis in acquired and genetic hearing impairment: The programmed death of the hair cell. Hear Res 2011; 281: 18–27.

    Article  PubMed Central  Google Scholar 

  20. Someya S, Xu J, Kondo K et al. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc Natl Acad Sci USA 2009; 106: 19432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ohlemiller KK, Lett JM, Gagnon PM. Cellular correlates of agerelated endocochlear potential reduction in a mouse model. Hear Res 2006; 220: 10–26.

    Article  PubMed  Google Scholar 

  22. Ohlemiller KK, Rice ME, Gagnon PM. Strial microvascular pathology and age-associated endocochlear potential decline in NOD congenic mice. Hear Res 2008; 244: 85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Horner KC, Cazals Y, Guieu R, Lenoir M, Sauze N. Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig. Am J Physiol Endocrinol Metab 2007; 293: E1224–32.

    Article  CAS  PubMed  Google Scholar 

  24. Horner KC. The effect of sex hormones on bone metabolism of the otic capsule — an overview. Hear Res 2009; 252: 56–60.

    Article  CAS  PubMed  Google Scholar 

  25. Sziklai I, Grof J, Ribari O, Menyhart J. Possible role of peptides derived from otosclerotic bone in the mechanism of sensorineural hearing loss. Acta Otolaryngol 1985; 100: 253–9.

    Article  CAS  PubMed  Google Scholar 

  26. Sziklai I, Batta TJ, Karosi T. Otosclerosis: an organ-specific inflammatory disease with sensorineural hearing loss. Eur Arch Otorhinolaryngol 2009; 266: 1711–8.

    Article  PubMed  Google Scholar 

  27. Zehnder AF, Kristiansen AG, Adams JC, Kujawa SG, Merchant SN, McKenna MJ. Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss. Laryngoscope 2006; 116: 201–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bovo R, Ciorba A, Martini A. Environmental and genetic factors in age-related hearing impairment. Aging Clin Exp Res 2011; 23: 3–10.

    Article  PubMed  Google Scholar 

  29. Erway LC, Willott JF, Archer JR, Harrison DE. Genetics of age-related hearing loss in mice: I. Inbred and F1 hybrid strains. Hear Res 1993; 65: 125–32.

    Article  CAS  PubMed  Google Scholar 

  30. Fetoni AR, Picciotti PM, Paludetti G, Troiani D. Pathogenesis of presbycusis in animal models: a review. Exp Gerontol 2011; 46: 413–25.

    Article  PubMed  Google Scholar 

  31. Shnerson A, Devigne C, Pujol R. Age-related changes in the C57BL/6J mouse cochlea. II. Ultrastructural findings. Brain Res 1981; 254: 77–88.

    Article  CAS  PubMed  Google Scholar 

  32. Shnerson A, Pujol R. Age-related changes in the C57BL/6J mouse cochlea. I. Physiological findings. Brain Res 1981; 254: 65–75.

    Article  CAS  PubMed  Google Scholar 

  33. Willott JF, Erway LC. Genetics of age-related hearing loss in mice. IV. Cochlear pathology and hearing loss in 25 BXD recombinant inbred mouse strains. Hear Res 1998; 119: 27–36.

    Article  CAS  PubMed  Google Scholar 

  34. Zheng QY, Johnson KR. Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice. Hear Res 2001; 154: 45–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Baranowska B, Wolinska-Witort E, Bik W et al. Evaluation of neuroendocrine status in longevity. Neurobiol Aging 2007; 28: 774–83.

    Article  CAS  PubMed  Google Scholar 

  36. Gong TW, Karolyi IJ, Macdonald J et al. Age-related changes in cochlear gene expression in normal and shaker 2 mice. J Assoc Res Otolaryngol 2006; 7: 317–28.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Someya S, Yamasoba T, Prolla TA, Tanokura M. Genes encoding mitochondrial respiratory chain components are profoundly down-regulated with aging in the cochlea of DBA/2J mice. Brain Res 2007; 1182: 26–33.

    Article  CAS  PubMed  Google Scholar 

  38. Tadros SF, D’Souza M, Zettel ML, Zhu X, Waxmonsky NC, Frisina RD. Glutamate-related gene expression changes with age in the mouse auditory midbrain. Brain Res 2007; 1127: 1–9.

    Article  CAS  PubMed  Google Scholar 

  39. Tadros SF, D’Souza M, Zhu X, Frisina RD. Apoptosis-related genes change their expression with age and hearing loss in the mouse cochlea. Apoptosis 2008; 13: 1303–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zou J, Minasyan A, Keisala T et al. Progressive hearing loss in mice with a mutated vitamin D receptor gene. Audiol Neurootol 2008; 13: 219–30.

    Article  CAS  PubMed  Google Scholar 

  41. Ben-Jonathan N, Mershon JL, Allen DL, Steinmetz RW. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev 1996; 17: 639–69.

    CAS  PubMed  Google Scholar 

  42. Ben-Jonathan N, LaPensee CR, LaPensee EW. What can we learn from rodents about prolactin in humans? Endocr Rev 2008; 29: 1–41.

    Article  CAS  PubMed  Google Scholar 

  43. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 1998; 19: 225–68.

    Article  CAS  PubMed  Google Scholar 

  44. Brandebourg T, Hugo E, Ben-Jonathan N. Adipocyte prolactin: regulation of release and putative functions. Diabetes Obes Metab 2007; 9: 464–76.

    Article  CAS  PubMed  Google Scholar 

  45. Egli M, Leeners B, Kruger TH. Prolactin secretion patterns: basic mechanisms and clinical implications for reproduction. Reproduction 2010; 140: 643–54.

    Article  CAS  PubMed  Google Scholar 

  46. Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000; 80: 1523–631.

    Article  CAS  PubMed  Google Scholar 

  47. Emanuele NV, Jurgens JK, Halloran MM, Tentler JJ, Lawrence AM, Kelley MR. The rat prolactin gene is expressed in brain tissue: detection of normal and alternatively spliced prolactin messenger RNA. Mol Endocrinol 1992; 6: 35–42.

    CAS  PubMed  Google Scholar 

  48. Ramesh R, Kuenzel WJ, Buntin JD, Proudman JA. Identification of growth-hormone- and prolactin-containing neurons within the avian brain. Cell Tissue Res 2000; 299: 371–83.

    Article  CAS  PubMed  Google Scholar 

  49. Roselli CE, Bocklandt S, Stadelman HL, Wadsworth T, Vilain E, Stormshak F. Prolactin expression in the sheep brain. Neuroendocrinology 2008; 87: 206–15.

    Article  CAS  PubMed  Google Scholar 

  50. Torner L, Maloumby R, Nava G, Aranda J, Clapp C, Neumann ID. In vivo release and gene upregulation of brain prolactin in response to physiological stimuli. Eur J Neurosci 2004; 19: 1601–8.

    Article  PubMed  Google Scholar 

  51. Shah GV, Pedchenko V, Stanley S, Li Z, Samson WK. Calcitonin is a physiological inhibitor of prolactin secretion in ovariectomized female rats. Endocrinology 1996; 137: 1814–22.

    Article  CAS  PubMed  Google Scholar 

  52. Amara JF, Van Itallie C, Dannies PS. Regulation of prolactin production and cell growth by estradiol: difference in sensitivity to estradiol occurs at level of messenger ribonucleic acid accumulation. Endocrinology 1987; 120: 264–71.

    Article  CAS  PubMed  Google Scholar 

  53. Lloyd HM, Meares JD, Jacobi J. Effects of oestrogen and bromocryptine on in vivo secretion and mitosis in prolactin cells. Nature 1975; 255: 497–8.

    Article  CAS  PubMed  Google Scholar 

  54. Raymond V, Beaulieu M, Labrie F et al. Potent antidopaminergic activity of estradiol at the pituitary level on prolactin release.

  55. Regulation of prolactin production and cell growth by estradiol: difference in sensitivity to estradiol occurs at level of messenger ribonucleic acid accumulation. Sci Endocrinol 1978; 200: 1173–5–1264–71.

  56. Stenberg AE, Wang H, Fish J 3rd, Schrott-Fischer A, Sahlin L, Hultcrantz M. Estrogen receptors in the normal adult and developing human inner ear and in Turner’s syndrome. Hear Res 2001; 157: 87–92.

    Article  CAS  PubMed  Google Scholar 

  57. Willott JF. Effects of sex, gonadal hormones, and augmented acoustic environments on sensorineural hearing loss and the central auditory system: insights from research on C57BL/6J mice. Hear Res 2009; 252: 89–99.

    Article  CAS  PubMed  Google Scholar 

  58. Royster M, Driscoll P, Kelly PA, Freemark M. The prolactin receptor in the fetal rat: cellular localization of messenger ribonucleic acid, immunoreactive protein, and ligand-binding activity and induction of expression in late gestation. Endocrinology 1995; 136: 3892–900.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Robert Jeffery Marano.

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Marano, R.J., Tickner, J. & Redmond, S.L. Age related changes in gene expression within the cochlea of C57BL/6J mice. Aging Clin Exp Res 24, 603–611 (2012). https://doi.org/10.1007/BF03654841

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