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Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age\u2010related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2\u2010mo\u2010old C57BL\/6J mice (\n                    <jats:italic>Animalia Chordata Mus musculus<\/jats:italic>\n                    ) were randomly divided into 2 groups (\n                    <jats:italic>n<\/jats:italic>\n                    = 65 each) that were fed folate\u2010deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7\u2010fold decline in serum folate and a 3\u2010fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL\u2010positive\u2010apoptotic cochlear cells. RT\u2010quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase\u2010complex adaptor cytochrome\n                    <jats:italic>b<\/jats:italic>\n                    \u2010245, \u03b1\u2010polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress.\u2014Mart\u00ednez\u2010Vega, R., Garrido, F., Partearroyo, T., Cediel, R., Zeisel, S. H., Mart\u00ednez\u2010\u00c1lvarez, C., Varela\u2010Moreiras, G., Varela\u2010Nieto, I., and Pajares, M. A. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 29, 418\u2010432 (2015).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.14-259283","type":"journal-article","created":{"date-parts":[[2014,11,11]],"date-time":"2014-11-11T01:33:20Z","timestamp":1415669600000},"page":"418-432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism"],"prefix":"10.1096","volume":"29","author":[{"given":"Raquel","family":"Mart\u00ednez\u2010Vega","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Alberto Sols (CSIC\u2010UAM) Madrid Spain"},{"name":"Unidad 761, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Garrido","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Alberto Sols (CSIC\u2010UAM) Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Partearroyo","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Farmac\u00e9uticas y de la Salud, Facultad de Farmacia Universidad CEU San Pablo Boadilla del Monte Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Cediel","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Alberto Sols (CSIC\u2010UAM) Madrid Spain"},{"name":"Unidad 761, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Instituto de Salud Carlos III Madrid Spain"},{"name":"Hospital Cl\u00ednico Veterinario Facultad de Veterinaria Universidad Complutense de Madrid Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Zeisel","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill, Nutrition Research Institute Kannapolis North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concepci\u00f3n","family":"Martinez\u2010Alvarez","sequence":"additional","affiliation":[{"name":"Departamento de Anatom\u00eda y Embriolog\u00eda Humana I, Facultad de Medicina Universidad Complutense de Madrid Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Varela\u2010Moreiras","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Farmac\u00e9uticas y de la Salud, Facultad de Farmacia Universidad CEU San Pablo Boadilla del Monte Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Varela\u2010Nieto","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Alberto Sols (CSIC\u2010UAM) Madrid Spain"},{"name":"Unidad 761, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, Instituto de Salud Carlos III Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda A.","family":"Pajares","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas Alberto Sols (CSIC\u2010UAM) Madrid Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,11,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-011-1597-8"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/geront\/gnr159"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-102108-134135"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2102"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.03.017"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986711797535254"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4103\/1463-1741.104893"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2013.09.028"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000339356"},{"key":"e_1_2_7_11_1","first-page":"243","article-title":"Effect of vitamin B12 deficiency on otoacoustic emissions","volume":"33","author":"Karli R.","year":"2013","journal-title":"Acta Otorhinolaryngol. 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