RRC ID 36986
Author Mutai H, Miya F, Fujii M, Tsunoda T, Matsunaga T.
Title Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4.
Journal PLoS ONE
Abstract Various factors that are important for proper hearing have been identified, including serum levels of zinc. Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltransferase and histone deacetylase (Hdac) in the postnatal as well as adult mouse auditory epithelium. DBA/2J mice, which are a model for progressive hearing loss, were injected subcutaneously with one or a combination of the following reagents: L-methionine as a methyl donor, valproic acid as a pan-Hdac inhibitor, and folic acid and vitamin B12 as putative factors involved in age-related hearing loss. The mice were treated from ages 4 to 12 weeks (N ≥ 5), and auditory brainstem response (ABR) thresholds were measured at 8, 16, and 32 kHz. Treatment of the mice with a combination of L-methionine and valproic acid (M+V) significantly reduced the increase in the ABR threshold at 32 kHz. Treatment with any of these reagents individually produced no such effect. Microarray analyses detected 299 gene probes that were significantly up- or down-regulated in the cochleae of mice treated with M+V compared with the control vehicle-treated mice. Quantitative RT-PCR confirmed significant up-regulation of a zinc importer gene, Zip4, in the cochleae of mice treated with M+V. Immunohistochemistry demonstrated an intense Zip4 signal in cochlear tissues such as the lateral wall, organ of Corti, and spiral ganglion. Finally, mice treated with the Zip4 inducer (-)-epigallocatechin-3-O-gallate showed a significant reduction in the increase of the ABR threshold at 32 kHz and up-regulation of Zip4 expression in the cochlea. This study suggests that epigenetic regulatory pathways can modify auditory function and that zinc intake in the cochlea via Zip4 mediates maintenance of mammalian hearing.
Volume 10(4)
Pages e0124301
Published 2015
DOI 10.1371/journal.pone.0124301
PII PONE-D-15-00344
PMID 25875282
PMC PMC4397065
MeSH Animals Catechin / analogs & derivatives Catechin / pharmacology Cation Transport Proteins / genetics* Cation Transport Proteins / metabolism Cochlea / drug effects Cochlea / metabolism Down-Regulation / drug effects Epigenesis, Genetic* Evoked Potentials, Auditory, Brain Stem / drug effects Hearing Loss / chemically induced Hearing Loss / metabolism Hearing Loss / pathology* Immunohistochemistry Methionine / toxicity* Mice Mice, Inbred DBA Microscopy, Fluorescence Oligonucleotide Array Sequence Analysis Organ of Corti / metabolism Real-Time Polymerase Chain Reaction Spiral Ganglion / metabolism Up-Regulation / drug effects* Valproic Acid / toxicity*
IF 2.776
Times Cited 8
Human and Animal Cells Hepa1-6(RCB1638)