Manganese-mediated acceleration of age-related hearing loss in mice.
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.
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Nutritional Health Science Research Center, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan.|Voluntary Body for International Health Care in Universities, Nagoya, Japan.
Nobutaka
N
Ohgami
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Voluntary Body for International Health Care in Universities, Nagoya, Japan.
Ichiro
I
Yajima
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Machiko
M
Iida
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Xiang
X
Li
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Voluntary Body for International Health Care in Universities, Nagoya, Japan.
Reina
R
Oshino
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Mayuko Y
MY
Kumasaka
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Voluntary Body for International Health Care in Universities, Nagoya, Japan.
Masashi
M
Kato
D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D034381:Hearing Loss / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008345:Manganese / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D013136:Spiral Ganglion / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008345:Manganese; D011392:Proline; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse