Progressive hearing loss in mice with a mutated vitamin D receptor gene.
BACKGROUND
Both hypo- and hypervitaminosis D can cause sensorineural hearing loss, and aural symptoms due to vitamin D insufficiency are especially common during gravidity. Hormonal forms of vitamin D regulate transcription by binding with the high-affinity vitamin D receptor (VDR).


OBJECTIVE
To assess the effects of impaired vitamin D action in VDR knockout (KO) mice on hearing, cochlear morphology, and cochlear gene expression.


METHODS
Eighteen young male and female mice (10 VDR KO and 8 wild type, WT, < or =6 months old), 33 adult male and female mice (16 VDR KO and 17 WT, between 7 and 14 months old), and 11 aged male and female mice (5 VDR KO and 6 WT, > or =15 months old) on 129S1 genetic background were studied. Auditory thresholds were evaluated by auditory brain stem response. Morphological changes were analyzed using plastic embedding and light microscopy. The expression of key genes (known to play a role in the regulation of cochlear function), and caspase 3 activity, were assessed using immunofluorescent confocal microscopy.


RESULTS
There was a statistically significant difference between the young and the adult groups, and between the adult and aged groups of WT mice. There was also a statistically significant difference between the adult and aged groups in VDR KO mice, and between the young WT group and the young VDR KO group. Spiral ganglion cell loss was observed in the basal turn of adult VDR KO mice, a phenomenon infrequently found in WT mice. Expression of connexin 26, KCNJ10, and transient receptor potential channel vanilloid subfamily 4/6 was not affected by VDR KO-mediated hearing loss. Caspase 3 activation was detected in the spiral ganglion cell and its satellite cells, stria vascularis, spiral ligament fibrocytes, and the organ of Corti in both genotypes. However, the percentage of positive cells and the staining intensity were lower in the VDR KO (compared to the WT) mice.


CONCLUSIONS
These data suggest that sensorineural hearing loss progressively developed at an earlier age in VDR KO mice. While the fundamental gene expressions in the cochlea were not influenced by VDR mutation, it resulted in decrease of caspase 3 activation, which may be one of the factors underlying accelerating age-related hearing loss observed in VDR KO mice.
Zou
Jing
J
Department of Otolaryngology, School of Medicine, University of Tampere, Tampere, Finland.
Minasyan
Anna
A
Keisala
Tiina
T
Zhang
Ya
Y
Wang
Jing-Huan
JH
Lou
Yan-Ru
YR
Kalueff
Alan
A
Pyykkö
Ilmari
I
Tuohimaa
Pentti
P
D000367:Age Factors; D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D003051:Cochlea / Q000473:pathology; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D011304:Presbycusis / Q000235:genetics* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000235:genetics*; D050916:TRPV Cation Channels / Q000235:genetics
D015220:Calcium Channels; D017630:Connexins; C000607043:Gjb2 protein, mouse; D018167:Receptors, Calcitriol; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C446923:Trpv6 protein, mouse; D000072259:Connexin 26; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002118:Calcium