Journal Articles

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

November 10, 2014

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolismFASEB J. 2014 Nov 10, Martínez-Vega R1, Garrido F2, Partearroyo T3, Cediel R4, Zeisel SH5, Martínez-Álvarez C6, Varela-Moreiras G3, Varela-Nieto I7, Pajares MA8.

  • 1Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain;
  • 2Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain;
  • 3Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain;
  • 4Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain; Hospital Clínico Veterinario, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain;
  • 5University of North Carolina at Chapel Hill, Nutrition Research Institute, Kannapolis, North Carolina, USA;
  • 6Departamento de Anatomía y Embriología Humana I, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; and.
  • 7Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Unidad 761, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria La Paz, Madrid, Spain ivarela@iib.uam.es.
  • 8Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz, Madrid, Spain.

Abstract

Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma totalhomocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-relatedhearing 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-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative 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-complex adaptor cytochrome b-245, α-polypeptide (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. -Martínez-Vega, R., Garrido, F., Partearroyo, T., Cediel, R., Zeisel, S. H., Martínez-Álvarez, C., Varela-Moreiras, G., Varela-Nieto, I., and Pajares, M. A. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stressand impairment of homocysteine metabolism.

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