Manganese-mediated acceleration of age-related hearing loss in mice.

Nobutaka Ohgami,Masashi Kato,Mayuko Y Kumasaka,Reina Oshino,Xiang Li,Ichiro Yajima,Machiko Iida

doi:10.1038/srep36306

Nobutaka Ohgami, Masashi Kato + Show 5 more

Open Access

https://doi.org/10.1038/srep36306

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Journal: Scientific reports	Publication Date: Nov 8, 2016
Citations: 20	License type: CC BY 4.0

Affiliation: Nagoya University, Chubu University

Abstract

Despite the fact that manganese (Mn) is known to be a neurotoxic element relevant to age-related disorders, the risk of oral exposure to Mn for age-related hearing loss remains unclear. In this study, we orally exposed wild-type young adult mice to Mn (Mn-exposed WT-mice) at 1.65 and 16.50 mg/L for 4 weeks. Mn-exposed WT-mice showed acceleration of age-related hearing loss. Mn-exposed WT-mice had neurodegeneration of spiral ganglion neurons (SGNs) with increased number of lipofuscin granules. Mn-exposed WT-mice also had increased hypoxia-inducible factor-1 alpha (Hif-1α) protein with less hydroxylation at proline 564 and decreased c-Ret protein in SGNs. Mn-mediated acceleration of age-related hearing loss involving neurodegeneration of SGNs was rescued in RET-transgenic mice carrying constitutively activated RET. Thus, oral exposure to Mn accelerates age-related hearing loss in mice with Ret-mediated neurodegeneration of SGNs.

Highlights

We performed an experimental study with wild-type young adult C57BL/6J mice (WT mice) at 1 month of age exposed to Mn at 1.65 and 16.50 mg/L for 4 weeks
WT mice exposed to Mn at 1.65 mg/L showed an increased threshold of auditory brainstem response (ABR) at 32 kHz compared with that in the non-exposure group (Fig. 1B,C)
WT mice exposed to Mn at 16.50 mg/L for 2 weeks and 4 weeks showed severe hearing loss at 1–32 kHz compared to the hearing level in the non-exposure group (Fig. 1B,C)

Summary

Introduction

A previous study showed that age-related hearing loss is associated to HIF-1αprotein in SGNs27. A previous in vitro study showed that stabilization of HIF-1αprotein is required for decrease of RET protein in neural cells exposed to cobalt[30]. The results of previous studies raise the possibility that exposure to Mn affects the onset of age-related hearing loss caused by impairment of c-Ret via HIF-1αin SGNs, though it remains unknown whether there is a correlation between HIF-1αprotein and c-Ret in SGNs. We performed an experimental study to examine the correlation between Mn and age-related hearing level in humans and to clarify the mechanism of age-related hearing loss in mice exposed to Mn at possible levels ingested from drinking water

Methods

Results

Conclusion