Exposure to diphtheria toxin during the juvenile period impairs both inner and outer hair cells in C57BL/6 mice.
Diphtheria toxin (DT) administration into transgenic mice that express the DT receptor (DTR) under control of specific promoters is often used for cell ablation studies in vivo. Because DTR is not expressed in mice, DT injection has been assumed to be nontoxic to cells in vivo. In this study, we demonstrated that DT application during the juvenile stage leads to hearing loss in wild-type mice. Auditory brainstem response measurement showed severe hearing loss in C57BL/6 mice administered DT during the juvenile period, and the hearing loss persisted into adulthood. However, ototoxicity did not occur when DT was applied on postnatal day 28 or later. Histological studies demonstrated that hearing loss was accompanied by significant degeneration of inner and outer hair cells (HCs), as well as spiral ganglion neurons. Scanning electron microscopy showed quick degeneration of inner HCs within 3days and gradual degeneration of outer HCs within 1week. These results demonstrated that DT has ototoxic action on C57BL/6 mice during the juvenile period, but not thereafter, and the hearing loss was due to degeneration of inner and outer HCs by unknown DT-related mechanisms.
Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: konishi@med.nagoya-u.ac.jp.
Hiroyuki
H
Konishi
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Nutritional Health Science Research Center, Chubu University, Kasugai 487-8501, Japan. Electronic address: nobugami@med.nagoya-u.ac.jp.
Nobutaka
N
Ohgami
Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: aika.mat@hotmail.co.jp.
Aika
A
Matsushita
Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: kondogagigugego@gmail.com.
Yuki
Y
Kondo
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: y.aoyama1007@gmail.com.
Yuki
Y
Aoyama
Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: 4444.forum@gmail.com.
Masaaki
M
Kobayashi
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: t-nagai@med.nagoya-u.ac.jp.
Taku
T
Nagai
Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan. Electronic address: ugawa@med.nagoya-cu.ac.jp.
Shinya
S
Ugawa
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: kyamada@med.nagoya-u.ac.jp.
Kiyofumi
K
Yamada
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: katomasa@med.nagoya-u.ac.jp.
Masashi
M
Kato
Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: kiyama@med.nagoya-u.ac.jp.
Hiroshi
H
Kiyama
D000375:Aging; D000818:Animals; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects* / Q000502:physiology; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects* / Q000473:pathology; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013136:Spiral Ganglion / Q000187:drug effects / Q000473:pathology
D004167:Diphtheria Toxin
cochlea; degeneration; diphtheria toxin; hair cell; hearing loss; ototoxicity