Folate deficiency alters homocysteine cycle in the cochlea and causes premature hearing loss in mice

Abstract

The methionine/homocysteine cycle is modulated by nutritional factors and its alterations have been associated to several pathologies including deafness (1). We have studied the impact of a dietary-induced folic acid deficiency on cochlear methionine metabolism and in hearing. C57BL/6J mice were fed with normal diet or folate deficient (FD) for 8 weeks. Hearing was evaluated by ABR threshold analyses and cochlear morphology was evaluated by hematoxylin-eosin staining and immunohistochemistry. RT-qPCR and Western blotting were used to determine cochlear levels of the methionine cycle enzymes, peptide mass fingerprint was carried out for protein identification, and plasma Hcy (pHcy) levels were determined by HPLC. The control group showed normal ABR thresholds (8 to 28 kHz, 27-48 dB SPL) whereas the FD group presented moderate to profound hearing loss (8 to 28 kHz, 52-85 dB SPL). Folic acid deficiency caused a reduction in plasma folate levels whilst pHcy levels were increased. All Hcy cycle enzymes studied were expressed in the cochlea. But some of them showed altered mobility in Western blotting as compared to the reference liver mobility patterns, suggesting post-translational modifications in the cochlea. In summary our data indicate that: i) the main enzymes of Hcy metabolism are expressed in the cochlea; ii) alterations in the methionine cycle secondary to folic acid deficit caused hearing loss; and iii) hearing loss correlated with alterations in the expression of Hcy cycle enzymes, and elevations of systemic pHcy.[1] Cohen-Salmon, M. et al. “Connexin30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis”, Proc Natl Acad Sci U S A 104: 6229-6234, 2007.