Cochlear homocysteine metabolism and related pathways in the BHMT-/- mouse

Abstract

[Background]: Age-related hearing loss (ARHL) is one of the most common causes of disability in older people, affecting 1/3 of the population over 65-yr. Epidemiological studies have shown correlations among the nutritional condition, increased plasma homocysteine (Hcy) and HL, suggesting that nutritional supplementation may be beneficial. Accordingly, rodent experimental models have provided the molecular basis to understand the observed effects. [Objectives]: Analyze the relevance of BHMT in the cochlea using Bhmt-/- mice, whose dependence on the metabolism of folate for the remetilacion of Hcy is greater, in the development of hearing loss and study of the contribution to gene silencing to damage by noise, and the influence of this genetic background on the effects by noise. [Methods]: Three-month-old Bhmt-/- mice were used to determine hearing loss after exposure to noise. [Results]: We present results showing that: 1) 3 month-old mice with Bhmt gene deleted present higher threshold shift after noise exposure; 2) an increase of plasma Hcy in knockout mice respect to wild type and heterozygous mice, with significant increase in total Hcy levels to 28 days of exposure to noise; 3) Noise exposure induced a significant decrease in MTR levels and a significant increase in the expression of Bhmt2 and Mtr in Bhmt gene deleted as compared to Bhmt null without exposure noise cochleae. In contrast, Bhmt-/- mice showed CBS protein levels similar to those in Bhmt+/+. [Conclusions]: Our results confirm that the lack of BHMT in the cochlea alters cochlear Hcy metabolism. Deletion of BHMT makes the cochlea more sensitive to noise and expression and protein levels suggest changes in the mRNA or protein half-lives at several levels and a need to remethylate Hcy, either because of Hcy accumulation or an increased need of methionine.