Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4
Various factors that are important for proper hearing have been identified, including serum levels of zinc. Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltran...
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| creator | Mutai, Hideki Miya, Fuyuki Fujii, Masato Tsunoda, Tatsuhiko Matsunaga, Tatsuo |
| description | Various factors that are important for proper hearing have been identified, including serum levels of zinc. Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltransferase and histone deacetylase (Hdac) in the postnatal as well as adult mouse auditory epithelium. DBA/2J mice, which are a model for progressive hearing loss, were injected subcutaneously with one or a combination of the following reagents: L-methionine as a methyl donor, valproic acid as a pan-Hdac inhibitor, and folic acid and vitamin B12 as putative factors involved in age-related hearing loss. The mice were treated from ages 4 to 12 weeks (N ≥ 5), and auditory brainstem response (ABR) thresholds were measured at 8, 16, and 32 kHz. Treatment of the mice with a combination of L-methionine and valproic acid (M+V) significantly reduced the increase in the ABR threshold at 32 kHz. Treatment with any of these reagents individually produced no such effect. Microarray analyses detected 299 gene probes that were significantly up- or down-regulated in the cochleae of mice treated with M+V compared with the control vehicle-treated mice. Quantitative RT-PCR confirmed significant up-regulation of a zinc importer gene, Zip4, in the cochleae of mice treated with M+V. Immunohistochemistry demonstrated an intense Zip4 signal in cochlear tissues such as the lateral wall, organ of Corti, and spiral ganglion. Finally, mice treated with the Zip4 inducer (-)-epigallocatechin-3-O-gallate showed a significant reduction in the increase of the ABR threshold at 32 kHz and up-regulation of Zip4 expression in the cochlea. This study suggests that epigenetic regulatory pathways can modify auditory function and that zinc intake in the cochlea via Zip4 mediates maintenance of mammalian hearing. |
| doi_str_mv | 10.1371/journal.pone.0124301 |
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Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltransferase and histone deacetylase (Hdac) in the postnatal as well as adult mouse auditory epithelium. DBA/2J mice, which are a model for progressive hearing loss, were injected subcutaneously with one or a combination of the following reagents: L-methionine as a methyl donor, valproic acid as a pan-Hdac inhibitor, and folic acid and vitamin B12 as putative factors involved in age-related hearing loss. The mice were treated from ages 4 to 12 weeks (N ≥ 5), and auditory brainstem response (ABR) thresholds were measured at 8, 16, and 32 kHz. Treatment of the mice with a combination of L-methionine and valproic acid (M+V) significantly reduced the increase in the ABR threshold at 32 kHz. Treatment with any of these reagents individually produced no such effect. Microarray analyses detected 299 gene probes that were significantly up- or down-regulated in the cochleae of mice treated with M+V compared with the control vehicle-treated mice. Quantitative RT-PCR confirmed significant up-regulation of a zinc importer gene, Zip4, in the cochleae of mice treated with M+V. Immunohistochemistry demonstrated an intense Zip4 signal in cochlear tissues such as the lateral wall, organ of Corti, and spiral ganglion. Finally, mice treated with the Zip4 inducer (-)-epigallocatechin-3-O-gallate showed a significant reduction in the increase of the ABR threshold at 32 kHz and up-regulation of Zip4 expression in the cochlea. This study suggests that epigenetic regulatory pathways can modify auditory function and that zinc intake in the cochlea via Zip4 mediates maintenance of mammalian hearing.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0124301</identifier><identifier>PMID: 25875282</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Age ; Analysis ; Animals ; Attenuation ; Auditory system ; Brain research ; Brain stem ; Catechin - analogs & derivatives ; Catechin - pharmacology ; Cation Transport Proteins - genetics ; Cation Transport Proteins - metabolism ; Cochlea ; Cochlea - drug effects ; Cochlea - metabolism ; Cyanocobalamin ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA methyltransferase ; DNA microarrays ; DNA probes ; Down-Regulation - drug effects ; Environmental factors ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Epithelium ; Evoked Potentials, Auditory, Brain Stem - drug effects ; Folic acid ; Gene expression ; Hearing loss ; Hearing Loss - chemically induced ; Hearing Loss - metabolism ; Hearing Loss - pathology ; Hearing protection ; Histone deacetylase ; Immunohistochemistry ; Investigations ; Laboratories ; Medical research ; Methionine ; Methionine - toxicity ; Mice ; Mice, Inbred DBA ; Microscopy, Fluorescence ; Oligonucleotide Array Sequence Analysis ; Organ of Corti ; Organ of Corti - metabolism ; Polymerase chain reaction ; Proteins ; Reagents ; Real-Time Polymerase Chain Reaction ; Serum levels ; Spiral ganglion ; Spiral Ganglion - metabolism ; Stem cells ; Transferases ; Up-regulation ; Up-Regulation - drug effects ; Valproic acid ; Valproic Acid - toxicity ; Vitamin B12 ; Zinc</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0124301-e0124301</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Mutai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Mutai et al 2015 Mutai et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-62d2043a2e137dd03473671d3a5eccd008e322a0cfdd196f5d83f953e93cf5713</citedby><cites>FETCH-LOGICAL-c692t-62d2043a2e137dd03473671d3a5eccd008e322a0cfdd196f5d83f953e93cf5713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397065/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397065/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2097,2916,23848,27906,27907,53773,53775,79350,79351</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25875282$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Alsina, Berta</contributor><creatorcontrib>Mutai, Hideki</creatorcontrib><creatorcontrib>Miya, Fuyuki</creatorcontrib><creatorcontrib>Fujii, Masato</creatorcontrib><creatorcontrib>Tsunoda, Tatsuhiko</creatorcontrib><creatorcontrib>Matsunaga, Tatsuo</creatorcontrib><title>Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Various factors that are important for proper hearing have been identified, including serum levels of zinc. Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltransferase and histone deacetylase (Hdac) in the postnatal as well as adult mouse auditory epithelium. DBA/2J mice, which are a model for progressive hearing loss, were injected subcutaneously with one or a combination of the following reagents: L-methionine as a methyl donor, valproic acid as a pan-Hdac inhibitor, and folic acid and vitamin B12 as putative factors involved in age-related hearing loss. The mice were treated from ages 4 to 12 weeks (N ≥ 5), and auditory brainstem response (ABR) thresholds were measured at 8, 16, and 32 kHz. Treatment of the mice with a combination of L-methionine and valproic acid (M+V) significantly reduced the increase in the ABR threshold at 32 kHz. Treatment with any of these reagents individually produced no such effect. Microarray analyses detected 299 gene probes that were significantly up- or down-regulated in the cochleae of mice treated with M+V compared with the control vehicle-treated mice. Quantitative RT-PCR confirmed significant up-regulation of a zinc importer gene, Zip4, in the cochleae of mice treated with M+V. Immunohistochemistry demonstrated an intense Zip4 signal in cochlear tissues such as the lateral wall, organ of Corti, and spiral ganglion. Finally, mice treated with the Zip4 inducer (-)-epigallocatechin-3-O-gallate showed a significant reduction in the increase of the ABR threshold at 32 kHz and up-regulation of Zip4 expression in the cochlea. This study suggests that epigenetic regulatory pathways can modify auditory function and that zinc intake in the cochlea via Zip4 mediates maintenance of mammalian hearing.</description><subject>Acids</subject><subject>Age</subject><subject>Analysis</subject><subject>Animals</subject><subject>Attenuation</subject><subject>Auditory system</subject><subject>Brain research</subject><subject>Brain stem</subject><subject>Catechin - analogs & derivatives</subject><subject>Catechin - pharmacology</subject><subject>Cation Transport Proteins - genetics</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Cochlea</subject><subject>Cochlea - drug effects</subject><subject>Cochlea - metabolism</subject><subject>Cyanocobalamin</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA methyltransferase</subject><subject>DNA microarrays</subject><subject>DNA probes</subject><subject>Down-Regulation - drug effects</subject><subject>Environmental factors</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Epithelium</subject><subject>Evoked Potentials, Auditory, Brain Stem - drug effects</subject><subject>Folic acid</subject><subject>Gene expression</subject><subject>Hearing loss</subject><subject>Hearing Loss - chemically induced</subject><subject>Hearing Loss - metabolism</subject><subject>Hearing Loss - pathology</subject><subject>Hearing protection</subject><subject>Histone deacetylase</subject><subject>Immunohistochemistry</subject><subject>Investigations</subject><subject>Laboratories</subject><subject>Medical research</subject><subject>Methionine</subject><subject>Methionine - toxicity</subject><subject>Mice</subject><subject>Mice, Inbred DBA</subject><subject>Microscopy, Fluorescence</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Organ of Corti</subject><subject>Organ of Corti - metabolism</subject><subject>Polymerase chain reaction</subject><subject>Proteins</subject><subject>Reagents</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Serum levels</subject><subject>Spiral ganglion</subject><subject>Spiral Ganglion - metabolism</subject><subject>Stem cells</subject><subject>Transferases</subject><subject>Up-regulation</subject><subject>Up-Regulation - drug effects</subject><subject>Valproic acid</subject><subject>Valproic Acid - toxicity</subject><subject>Vitamin B12</subject><subject>Zinc</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk8tu1DAUhiMEoqXwBggsISFYzNSxc90gDeU2qFIlbgs2lmMfJ66SONhOoTwOT4pnJh1NUBcoi0TOd_6T8-c_UfQ4xsuY5vHppRltz9vlYHpY4pgkFMd3ouO4pGSREUzvHjwfRQ-cu8Q4pUWW3Y-OSFrkKSnIcfRn5T30I_fa9MgoNFhTW3BOXwFqgFvd16g1ziHdozevV6fkI-q0AFRdIwu8ht475BvuEVcKhEcw6HAIXgvUGamVFlvpUO8Qd84IzT1I9FP7Bo3DwkI9tvvmvgH0W_cC6W4w1oNF3_WQPIzuKd46eDTdT6Kv795-OfuwOL94vz5bnS9EVhIf5pQEJ5QTCPZIiWmS0yyPJeUpCCExLoASwrFQUsZlplJZUFWmFEoqVJrH9CR6utMdwsBsstexOMspLguSl4FY7whp-CUbrO64vWaGa7Y9MLZm3IbRW2ApYMULVQielElFs0IBhG4ig6zKy6oKWq-mbmPVgRTBScvbmej8Ta8bVpsrltAyx1kaBF5MAtb8GMF51mknoG15D2bcfneSlXGOaUCf_YPePt1E1TwMoHtlQl-xEWWrJCSmJCnduLS8hQqXhBCMkEWlw_ms4OWsIDAefvmaj86x9edP_89efJuzzw_YkNXWN8604zZuczDZgcKGIFtQe5NjzDardOMG26wSm1YplD05_EH7opvdoX8Bgo0b0w</recordid><startdate>20150414</startdate><enddate>20150414</enddate><creator>Mutai, Hideki</creator><creator>Miya, Fuyuki</creator><creator>Fujii, Masato</creator><creator>Tsunoda, Tatsuhiko</creator><creator>Matsunaga, Tatsuo</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150414</creationdate><title>Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4</title><author>Mutai, Hideki ; Miya, Fuyuki ; Fujii, Masato ; Tsunoda, Tatsuhiko ; Matsunaga, Tatsuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-62d2043a2e137dd03473671d3a5eccd008e322a0cfdd196f5d83f953e93cf5713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acids</topic><topic>Age</topic><topic>Analysis</topic><topic>Animals</topic><topic>Attenuation</topic><topic>Auditory system</topic><topic>Brain research</topic><topic>Brain stem</topic><topic>Catechin - analogs & derivatives</topic><topic>Catechin - pharmacology</topic><topic>Cation Transport Proteins - genetics</topic><topic>Cation Transport Proteins - metabolism</topic><topic>Cochlea</topic><topic>Cochlea - drug effects</topic><topic>Cochlea - metabolism</topic><topic>Cyanocobalamin</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA methyltransferase</topic><topic>DNA microarrays</topic><topic>DNA probes</topic><topic>Down-Regulation - drug effects</topic><topic>Environmental factors</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Epithelium</topic><topic>Evoked Potentials, Auditory, Brain Stem - drug effects</topic><topic>Folic acid</topic><topic>Gene expression</topic><topic>Hearing loss</topic><topic>Hearing Loss - chemically induced</topic><topic>Hearing Loss - metabolism</topic><topic>Hearing Loss - pathology</topic><topic>Hearing protection</topic><topic>Histone deacetylase</topic><topic>Immunohistochemistry</topic><topic>Investigations</topic><topic>Laboratories</topic><topic>Medical research</topic><topic>Methionine</topic><topic>Methionine - toxicity</topic><topic>Mice</topic><topic>Mice, Inbred DBA</topic><topic>Microscopy, Fluorescence</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Organ of Corti</topic><topic>Organ of Corti - metabolism</topic><topic>Polymerase chain reaction</topic><topic>Proteins</topic><topic>Reagents</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Serum levels</topic><topic>Spiral ganglion</topic><topic>Spiral Ganglion - metabolism</topic><topic>Stem cells</topic><topic>Transferases</topic><topic>Up-regulation</topic><topic>Up-Regulation - drug effects</topic><topic>Valproic acid</topic><topic>Valproic Acid - toxicity</topic><topic>Vitamin B12</topic><topic>Zinc</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mutai, Hideki</creatorcontrib><creatorcontrib>Miya, Fuyuki</creatorcontrib><creatorcontrib>Fujii, Masato</creatorcontrib><creatorcontrib>Tsunoda, Tatsuhiko</creatorcontrib><creatorcontrib>Matsunaga, Tatsuo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mutai, Hideki</au><au>Miya, Fuyuki</au><au>Fujii, Masato</au><au>Tsunoda, Tatsuhiko</au><au>Matsunaga, Tatsuo</au><au>Alsina, Berta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-14</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0124301</spage><epage>e0124301</epage><pages>e0124301-e0124301</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Various factors that are important for proper hearing have been identified, including serum levels of zinc. Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltransferase and histone deacetylase (Hdac) in the postnatal as well as adult mouse auditory epithelium. DBA/2J mice, which are a model for progressive hearing loss, were injected subcutaneously with one or a combination of the following reagents: L-methionine as a methyl donor, valproic acid as a pan-Hdac inhibitor, and folic acid and vitamin B12 as putative factors involved in age-related hearing loss. The mice were treated from ages 4 to 12 weeks (N ≥ 5), and auditory brainstem response (ABR) thresholds were measured at 8, 16, and 32 kHz. Treatment of the mice with a combination of L-methionine and valproic acid (M+V) significantly reduced the increase in the ABR threshold at 32 kHz. Treatment with any of these reagents individually produced no such effect. Microarray analyses detected 299 gene probes that were significantly up- or down-regulated in the cochleae of mice treated with M+V compared with the control vehicle-treated mice. Quantitative RT-PCR confirmed significant up-regulation of a zinc importer gene, Zip4, in the cochleae of mice treated with M+V. Immunohistochemistry demonstrated an intense Zip4 signal in cochlear tissues such as the lateral wall, organ of Corti, and spiral ganglion. Finally, mice treated with the Zip4 inducer (-)-epigallocatechin-3-O-gallate showed a significant reduction in the increase of the ABR threshold at 32 kHz and up-regulation of Zip4 expression in the cochlea. This study suggests that epigenetic regulatory pathways can modify auditory function and that zinc intake in the cochlea via Zip4 mediates maintenance of mammalian hearing.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25875282</pmid><doi>10.1371/journal.pone.0124301</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-04, Vol.10 (4), p.e0124301-e0124301 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1673098279 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acids Age Analysis Animals Attenuation Auditory system Brain research Brain stem Catechin - analogs & derivatives Catechin - pharmacology Cation Transport Proteins - genetics Cation Transport Proteins - metabolism Cochlea Cochlea - drug effects Cochlea - metabolism Cyanocobalamin Deoxyribonucleic acid DNA DNA methylation DNA methyltransferase DNA microarrays DNA probes Down-Regulation - drug effects Environmental factors Epigenesis, Genetic Epigenetic inheritance Epigenetics Epithelium Evoked Potentials, Auditory, Brain Stem - drug effects Folic acid Gene expression Hearing loss Hearing Loss - chemically induced Hearing Loss - metabolism Hearing Loss - pathology Hearing protection Histone deacetylase Immunohistochemistry Investigations Laboratories Medical research Methionine Methionine - toxicity Mice Mice, Inbred DBA Microscopy, Fluorescence Oligonucleotide Array Sequence Analysis Organ of Corti Organ of Corti - metabolism Polymerase chain reaction Proteins Reagents Real-Time Polymerase Chain Reaction Serum levels Spiral ganglion Spiral Ganglion - metabolism Stem cells Transferases Up-regulation Up-Regulation - drug effects Valproic acid Valproic Acid - toxicity Vitamin B12 Zinc |
| title | Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-17T09%3A40%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Attenuation%20of%20progressive%20hearing%20loss%20in%20DBA/2J%20mice%20by%20reagents%20that%20affect%20epigenetic%20modifications%20is%20associated%20with%20up-regulation%20of%20the%20zinc%20importer%20Zip4&rft.jtitle=PloS%20one&rft.au=Mutai,%20Hideki&rft.date=2015-04-14&rft.volume=10&rft.issue=4&rft.spage=e0124301&rft.epage=e0124301&rft.pages=e0124301-e0124301&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0124301&rft_dat=%3Cgale_plos_%3EA425892531%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1673098279&rft_id=info:pmid/25875282&rft_galeid=A425892531&rft_doaj_id=oai_doaj_org_article_5e0fa8f8ca494b368feef95c6e6b79bb&rfr_iscdi=true |