Folic acid deficiency impairs homocysteine metabolism in the inner ear inducing premature hearing loss in C57BL/6J mice

[Background]: Alterations in homocysteine (Hcy) levels and betaine homocysteine methyltransferase (BHMT) expression have been reported in genetic mouse models of human deafness. BHMT is one of the enzymes responsible for Hcy remethylation leading to methionine synthesis. Alterations in BHMT function and/or expression are one of the causes of changes in Hcy levels and indirectly in the production of glutathione. Hcy metabolism is modulated by nutritional factors, among them vitamins, and hence we have studied the impact of a dietary-induced folic acid deficiency on the cochlear methionine metabolism and in hearing. [Methods]: The hearing capacity from the control and folate deficient diet groups was assessed by ABR threshold analyses after 8 weeks of treatment. RT-PCR and western blot were used to determine the cochlear levels of methionine metabolism enzymes, whereas pHcy was determined by HPLC. Cochlear morphology was evaluated by hematoxylin-eosin staining and immunohistochemistry techniques. [Results]: Normal ABR thresholds (8 to 28 KHz, 27- 48 dB SPL) were found in the control group, whereas moderate to severe hearing loss (8 to 28 KHz, 52-85 dB SPL) was detected in the folate-deficient animals. Folate deficiency caused significant changes in protein and mRNA levels of enzymes involved in methionine metabolism and oxidative stress biomarkers together with hyperhomocysteinemia. Control and folate-deficient mice showed normal cytoarchitecture and signs of severe sensorineural hearing loss, respectively. [Conclusions]: Folate deficiency causes increased pHcy levels and alterations in the cochlear methionine cycle, which is concomitant with molecular and cellular alterations in this organ and premature hearing loss in the C57BL/6J mouse. ACKNOWLEDGMENTS: RMV holds a CSIC predoctoral JAE fellowship. This work was supported by grants from Ministerio de Economía y Competitividad (SAF2011-24391, BFU2009-08977), AFHELO (FP7 European Union) and PULEVA.