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

Abstract

Nutritional imbalance is emerging as a causative factor of hearing loss. 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-related 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-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.

Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss on CBA/Ca Mice

“…This fact was described in previous studies analyzing low intakes of folate or vitamin B 12 for extended periods of time (Cox et al, 1961; Bills et al, 1992), but was not evident in C57BL/6J mice after 2 months of diet (Martinez-Vega et al, 2015a). Altogether, our data support the role of folate deficiency in premature development of hearing loss, although new experiments aimed to analyze its impact in strains with delayed onset of this sensory impairment should consider beginning nutritional interventions at later stages of animal development.…”

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles

“…Oxidative stress may impair betaine‐homocysteine methyltransferase, resulting in accumulation of circulating choline and betaine 38. Second, high plasma concentrations of choline and betaine have been associated with elevated concentrations of trimethylamine N‐oxide 39.…”

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

“…In aged rats, memory and also oxidative stress status, assessed as the activity of SOD and catalase, the glutathione concentration as well as MDA, significantly improved in folic acid supplemented animals [304]. In another study, folate deficiency in mice was associated with hearing loss and significantly increased homocysteine concentrations [305]. Vitamin B 12 (cobalamin) functions as a cofactor for both the methylmalonyl CoA mutase and the methionine synthase which is involved in homocysteine re-methylation and folate cycle [306].…”