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      Estrogen-related receptor gamma and hearing function: evidence of a role in humans and mice

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          Abstract

          Since estrogen is thought to protect pre-menopausal women from age-related hearing loss, we investigated whether variation in estrogen-signalling genes is linked to hearing status in the 1958 British Birth Cohort. This analysis implicated the estrogen-related receptor gamma ( ESRRG) gene in determining adult hearing function and was investigated further in a total of 6134 individuals in 3 independent cohorts: (i) the 1958 British Birth Cohort; (ii) a London ARHL case-control cohort; and (iii) a cohort from isolated populations of Italy and Silk Road countries. Evidence of an association between the minor allele of single nucleotide polymorphism (SNP) rs2818964 and hearing status was found in females, but not in males in 2 of these cohorts: p = 0.0058 (London ARHL) and p = 0.0065 (Carlantino, Italy). Furthermore, assessment of hearing in Esrrg knock-out mice revealed a mild 25-dB hearing loss at 5 weeks of age. At 12 weeks, average hearing thresholds in female mice (-/-) were 15 dB worse than in males (-/-). Together these data indicate ESRRG plays a role in maintenance of hearing in both humans and mice.

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          Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.

          A. Nagy, J Rossant, R. Nagy … (1993)
          Several newly generated mouse embryonic stem (ES) cell lines were tested for their ability to produce completely ES cell-derived mice at early passage numbers by ES cell tetraploid embryo aggregation. One line, designated R1, produced live offspring which were completely ES cell-derived as judged by isoenzyme analysis and coat color. These cell culture-derived animals were normal, viable, and fertile. However, prolonged in vitro culture negatively affected this initial totipotency of R1, and after passage 14, ES cell-derived newborns died at birth. However, one of the five subclones (R1-S3) derived from single cells at passage 12 retained the original totipotency and gave rise to viable, completely ES cell-derived animals. The total in vitro culture time of the sublines at the time of testing was equivalent to passage 24 of the original line. Fully potent early passage R1 cells and the R1-S3 subclone should be very useful not only for ES cell-based genetic manipulations but also in defining optimal in vitro culture conditions for retaining the initial totipotency of ES cells.
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            ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.

            William A. Alaynick, Richard Kondo, Wen Xie … (2007)
            At birth, the heart undergoes a critical metabolic switch from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life, although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRgamma gene (Esrrg), which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch, resulting in lactatemia, electrocardiographic abnormalities, and death during the first week of life. Genomic ChIP-on-chip and expression analysis identifies ERRgamma as both a direct and an indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRgamma in the study of cardiac hypertrophy and failure.
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              Gender differences in a longitudinal study of age-associated hearing loss.

              William Klein, Andrew Pearson, Adam S. Gordon … (1995)
              Current studies are inconclusive regarding specific patterns of gender differences in age-associated hearing loss. This paper presents results from the largest and longest longitudinal study reported to date of changes in pure-tone hearing thresholds in men and women screened for otological disorders and noise-induced hearing loss. Since 1965, the Baltimore Longitudinal Study of Aging has collected hearing thresholds from 500 to 8000 Hz using a pulsed-tone tracking procedure. Mixed-effects regression models were used to estimate longitudinal patterns of change in hearing thresholds in 681 men and 416 women with no evidence of otological disease, unilateral hearing loss, or noise-induced hearing loss. The results show (1) hearing sensitivity declines more than twice as fast in men as in women at most ages and frequencies, (2) longitudinal declines in hearing sensitivity are detectable at all frequencies among men by age 30, but the age of onset of decline is later in women at most frequencies and varies by frequency in women, (3) women have more sensitive hearing than men at frequencies above 1000 Hz but men have more sensitive hearing than women at lower frequencies, (4) learning effects bias cross-sectional and short-term longitudinal studies, and (5) hearing levels and longitudinal patterns of change are highly variable, even in this highly selected group. These longitudinal findings document gender differences in hearing levels and show that age-associated hearing loss occurs even in a group with relatively low-noise occupations and with no evidence of noise-induced hearing loss.
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                Author and article information

                Contributors
                Sally J. Dawson
                Journal
                Journal ID (nlm-ta): Neurobiol Aging
                Journal ID (iso-abbrev): Neurobiol. Aging
                Title: Neurobiology of Aging
                Publisher: Elsevier
                ISSN (Print): 0197-4580
                ISSN (Electronic): 1558-1497
                Publication date PMC-release: 1 August 2013
                Publication date (Print): August 2013
                Volume: 34
                Issue: 8
                Pages: 2077.e1-2077.e9
                Affiliations
                [a ]UCL Ear Institute, University College London, London, UK
                [b ]Institute of Audioneurotechnology (VIANNA) and Department of Experimental Otology, ENT-Clinics, Medical University Hannover, Hannover, Germany
                [c ]Centre for Molecular Neurobiology (ZMNH), Hamburg and Institute of Human Genetics, Jena, Germany
                [d ]Institute for Maternal and Child Health- IRCCS “Burlo Garofolo”-DMS, University of Trieste, Trieste, Italy
                [e ]Division of Community Health Sciences, St George's University of London, London, UK
                Author notes
                [∗ ]Corresponding author at: UCL Ear Institute, 332 Gray's Inn Road, London WC1X 8EE, UK. Tel.: +44 (0)20 76798935; fax: +44 (0)20 7679 8990. sally.dawson@ 123456ucl.ac.uk
                Article
                Publisher ID: S0197-4580(13)00082-1
                DOI: 10.1016/j.neurobiolaging.2013.02.009
                PMC ID: 4330334
                PubMed ID: 23540940
                SO-VID: 706de74b-de24-40cc-8cfd-1cb53036e3d8
                Copyright © © 2013 Elsevier Inc. All rights reserved.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                Date received : 16 October 2012
                Date revision received : 5 February 2013
                Date accepted : 15 February 2013
                Categories
                Subject: Genetic Reports Abstract

                ScienceOpen disciplines: Neurosciences
                Keywords: age-related hearing loss,estrogen,gene,esrrg
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: age-related hearing loss, estrogen, gene, esrrg

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