Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2025, Vol. 39 ›› Issue (6): 46-53.doi: 10.6040/j.issn.1673-3770.0.2024.517

• Original Article • Previous Articles    

Correlation between aromatase and estrogen receptor expression in the primary auditory cortex of mice at different developmental stages and hearing ability

TANG Xi1, HUANG Maoling1, ZHANG Jiqiang2, ZHONG Cheng1   

  1. 1. Department of Otolaryngology Head and Neck Surgery, the First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China2. Department of Neurobiology, College of Basic Sciences, Army Military Medical University, Chongqing, 400038, China
  • Published:2025-11-19

Abstract: Objective To investigate the expression and potential regulatory roles of aromatase(AROM)and three estrogen receptors(ERs)—estrogen receptor alpha(ERα), estrogen receptor beta(ERβ), and G protein-coupled receptor 30(GPR30)—in the primary auditory cortex(A1)during auditory development. Methods Male C57BL/6J mice at different postnatal stages—postnatal day 7(P7), P14, P21, P30, and P60-were selected. Auditory thresholds were measured by auditory brainstem response(ABR), and qRT-PCR, Western bloting, and immunohistochemistry were performed to examine the expression changes of AROM and ERs in the A1. Spearman correlation analysis was conducted between expression levels and hearing thresholds. Results ABR thresholds decreased significantly from P14 onward(P<0.05), reaching maturity at P30. qPCR revealed that the expression of AROM, GPR30, and ERβ increased with age(P<0.05)while ERα peaked at P30(P<0.05). Protein levels(Western bloting and immunohistochemistry)confirmed a significant developmental increase in AROM and ERs expression(P<0.05). Spearman correlation analysis showed strong correlations between the developmental changes in hearing thresholds and the expression of AROM(∣rs∣=0.75)and ERβ(∣rs∣=0.72), a weak correlation with GPR30(∣rs∣=0.64), and no significant correlation with ERα. Conclusion Postnatal auditory development in mice progressively matures, accompanied by increasing expression levels of AROM, GPR30, and ERβ in the A1. The AROM-GPR30/ERβ axis is suggested to potentially facilitate the establishment and maturation of auditory function in mice.

Key words: Aromatase, 17β-Estradiol, Estrogen receptors, ERα, ERβ, G protein coupled receptor 30, Auditory cortex

CLC Number: 

  • R339.16
[1] 杨旻, 朱晓燕, 王旭. 感音神经性聋的代谢组学研究进展[J]. 山东大学耳鼻喉眼学报, 2024, 38(2): 113-121. doi:10.6040/j.issn.1673-3770.0.2023.263 YANG Min, ZHU Xiaoyan, WANG Xu. Progress in metabolomics research in sensorineural hearing loss[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2024, 38(2): 113-121. doi:10.6040/j.issn.1673-3770.0.2023.263
[2] Pearson JD, Morrell CH, Gordon-Salant S, et al. Gender differences in a longitudinal study of age-associated hearing loss[J]. J Acoust Soc Am, 1995, 97(2): 1196-1205.
[3] Pottoo FH, Bhowmik M, Vohora D. Raloxifene protects against seizures and neurodegeneration in a mouse model mimicking epilepsy in postmenopausal woman[J]. Eur J Pharm Sci, 2014, 65: 167-173. doi: 10.1016/j.ejps.2014.09.002
[4] Hederstierna C, Hultcrantz M, Collins A, et al. Hearing in women at menopause. Prevalence of hearing loss, audiometric configuration and relation to hormone replacement therapy[J]. Acta Otolaryngol, 2007, 127(2): 149-155. doi: 10.1080/00016480600794446
[5] Predná L, Habánová M, Sláviková E, et al. Hormonal contraceptives and hormone replacement therapy as a possible factor of breast cancer[J]. Rocz Panstw Zakl Hig, 2015, 66(3): 269-274.
[6] Naftolin F, Ryan KJ, Davies IJ, et al. The formation of estrogens by central neuroendocrine tissues[J]. Recent Prog Horm Res, 1975, 31: 295-319. doi: 10.1016/b978-0-12-571131-9.50012-8
[7] Santen RJ, Brodie H, Simpson ER, et al. History of aromatase: Saga of an important biological mediator and therapeutic target[J]. Endocr Rev, 2009, 30(4): 343-375.
[8] McCullough LD, Blizzard K, Simpson ER, et al. Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection[J]. J Neurosci, 2003, 23(25): 8701-8705.
[9] Nilsen J, Mor G, Naftolin F. Estrogen-regulated developmental neuronal apoptosis is determined by estrogen receptor subtype and the Fas/Fas ligand system[J]. J Neurobiol, 2000, 43(1): 64-78.
[10] Gruber CJ, Tschugguel W, Schneeberger C, et al. Production and actions of estrogens[J]. N Engl J Med, 2002, 346(5): 340-352.
[11] Meltser I, Tahera Y, Simpson E, et al. Estrogen receptor beta protects against acoustic trauma in mice[J]. J Clin Invest, 2008, 118(4): 1563-1570.
[12] Milon B, Mitra S, Song Y, et al. The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice[J]. Biol Sex Differ, 2018, 9(1): 12. doi: 10.1186/s13293-018-0171-0
[13] Shuster B, Casserly R, Lipford E, et al. Estradiol protects against noise-induced hearing loss and modulates auditory physiology in female mice[J]. Int J Mol Sci, 2021, 22(22): 12208. doi: 10.3390/ijms222212208
[14] Webster DB. A critical period during postnatal auditory development of mice[J]. Int J Pediatr Otorhinolaryngol, 1983, 6(2): 107-118.
[15] Abe T, Kakehata S, Kitani R, et al. Developmental expression of the outer hair cell motor prestin in the mouse[J]. J Membr Biol, 2007, 215(1): 49-56.
[16] Bilger RC, Matthies ML, Hammel DR, et al. Genetic implications of gender differences in the prevalence of spontaneous otoacoustic emissions[J]. J Speech Hear Res, 1990, 33(3): 418-432.
[17] Jerger J, Hall J. Effects of age and sex on auditory brainstem response[J]. Arch Otolaryngol, 1980, 106(7): 387-391.
[18] Alves C, Oliveira CS. Hearing loss among patients with Turner’s syndrome: literature review[J]. Braz J Otorhinolaryngol, 2014, 80(3): 257-263.
[19] Curhan SG, Eliassen AH, Eavey RD, et al. Menopause and postmenopausal hormone therapy and risk of hearing loss[J]. Menopause, 2017, 24(9): 1049-1056.
[20] Cornil CA, Charlier TD. Rapid behavioural effects of oestrogens and fast regulation of their local synthesis by brain aromatase[J]. J Neuroendocrinol, 2010, 22(7): 664-673.
[21] Azcoitia I, Yague JG, Garcia-Segura LM. Estradiol synthesis within the human brain[J]. Neuroscience, 2011, 191: 139-147. doi: 10.1016/j.neuroscience.2011.02.012
[22] Balthazart J, Ball GF. Is brain estradiol a hormone or a neurotransmitter?[J]. Trends Neurosci, 2006, 29(5): 241-249.
[23] Stocco C. Tissue physiology and pathology of aromatase[J]. Steroids, 2012, 77(1/2): 27-35.
[24] Naftolin F, Ryan KJ, Petro Z. Aromatization of androstenedione by the diencephalon[J]. J Clin Endocrinol Metab, 1971, 33(2): 368-370.
[25] Colciago A, Celotti F, Pravettoni A, et al. Dimorphic expression of testosterone metabolizing enzymes in the hypothalamic area of developing rats[J]. Brain Res Dev Brain Res, 2005, 155(2): 107-116.
[26] Vierk R, Brandt N, Rune GM. Hippocampal estradiol synthesis and its significance for hippocampal synaptic stability in male and female animals[J]. Neuroscience, 2014, 274: 24-32. doi: 10.1016/j.neuroscience.2014.05.003
[27] Negri-Cesi P, Poletti A, Celotti F. Metabolism of steroids in the brain: a new insight into the role of 5alpha-reductase and aromatase in brain differentiation and functions[J]. J Steroid Biochem Mol Biol, 1996, 58(5/6): 455-466.
[28] Soutar CN, Grenier P, Patel A, et al. Brain-generated 17β-estradiol modulates long-term synaptic plasticity in the primary auditory cortex of adult male rats[J]. Cereb Cortex, 2022, 32(10): 2140-2155.
[29] Yokosuka M, Okamura H, Hayashi S. Transient expression of estrogen receptor-immunoreactivity(ER-IR)in the layer V of the developing rat cerebral cortex[J]. Brain Res Dev Brain Res, 1995, 84(1): 99-108.
[30] Sharma PK, Thakur MK. Expression of estrogen receptor(ER)alpha and beta in mouse cerebral cortex: effect of age, sex and gonadal steroids[J]. Neurobiol Aging, 2006, 27(6): 880-887.
[31] Charitidi K, Canlon B. Estrogen receptors in the central auditory system of male and female mice[J]. Neuroscience, 2010, 165(3): 923-933.
[32] Montelli S, Peruffo A, Zambenedetti P, et al. Expression of aromatase P450(AROM)in the human fetal and early postnatal cerebral cortex[J]. Brain Res, 2012, 1475: 11-18. doi: 10.1016/j.brainres.2012.08.010
[33] Matsuda K, Sakamoto H, Mori H, et al. Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation[J]. Neurosci Lett, 2008, 441(1): 94-99.
[34] Krentzel AA, Macedo-Lima M, Ikeda MZ, et al. A membrane G-protein-coupled estrogen receptor is necessary but not sufficient for sex differences in Zebra finch auditory coding[J]. Endocrinology, 2018, 159(3): 1360-1376.
[35] Fan XT, Xu HW, Warner M, et al. ERbeta in CNS: new roles in development and function[J]. Prog Brain Res, 2010, 181: 233-250. doi: 10.1016/S0079-6123(08)81013-8
[36] Spencer-Segal JL, Tsuda MC, Mattei L, et al. Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation[J]. Neuroscience, 2012, 202: 131-146. doi: 10.1016/j.neuroscience.2011.11.035
[37] Tremere LA, Burrows K, Jeong JK, et al. Organization of estrogen-associated circuits in the mouse primary auditory cortex[J]. J Exp Neurosci, 2011, 2011(5): 45-60.
[38] Wilson ME, Westberry JM. Regulation of oestrogen receptor gene expression: new insights and novel mechanisms[J]. J Neuroendocrinol, 2009, 21(4): 238-242.
[1] LU Jiantao, ZHONG Jie, LIU Shaofeng. Electrophysiological characteristics of deep projections from bilateral auditory cortex [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 1-7.
[2] MA Xiao-hua,BI Hong-sheng,LI Jing-hai,XIE Xiao-feng,WU Jian-feng,JI Peng . Effect of 17β-estradiol on VEGF and HIF-1α mRNA expressions in bovine retinal vascular endothelial cells [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2008, 22(1): 6-09 .
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!