Zou Jing, Minasyan Anna, Keisala Tiina, Zhang Ya, Wang Jing-Huan, Lou Yan-Ru, Kalueff Alan, Pyykkö Ilmari, Tuohimaa Pentti
Department of Otolaryngology, School of Medicine, University of Tampere, Tampere, Finland.
Audiol Neurootol. 2008;13(4):219-30. doi: 10.1159/000115431. Epub 2008 Feb 7.
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).
To assess the effects of impaired vitamin D action in VDR knockout (KO) mice on hearing, cochlear morphology, and cochlear gene expression.
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.
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.
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.
维生素D缺乏和过量均可导致感音神经性听力损失，孕期维生素D不足引起的耳部症状尤为常见。维生素D的激素形式通过与高亲和力维生素D受体（VDR）结合来调节转录。
评估VDR基因敲除（KO）小鼠维生素D作用受损对听力、耳蜗形态及耳蜗基因表达的影响。
研究了129S1遗传背景下的18只年轻雌雄小鼠（10只VDR KO小鼠和8只野生型（WT）小鼠，年龄≤6个月）、33只成年雌雄小鼠（16只VDR KO小鼠和17只WT小鼠，年龄在7至14个月之间）以及11只老年雌雄小鼠（5只VDR KO小鼠和6只WT小鼠，年龄≥15个月）。通过听性脑干反应评估听觉阈值。采用塑料包埋和光学显微镜分析形态学变化。使用免疫荧光共聚焦显微镜评估关键基因（已知在耳蜗功能调节中起作用）的表达及半胱天冬酶3活性。
WT小鼠的年轻组与成年组之间、成年组与老年组之间存在统计学显著差异。VDR KO小鼠的成年组与老年组之间以及年轻WT组与年轻VDR KO组之间也存在统计学显著差异。在成年VDR KO小鼠的蜗底观察到螺旋神经节细胞丢失，这在WT小鼠中很少见。连接蛋白26、KCNJ10和瞬时受体电位香草酸亚家族4/6的表达不受VDR KO介导的听力损失影响。在两种基因型的螺旋神经节细胞及其卫星细胞、血管纹、螺旋韧带纤维细胞和柯蒂氏器中均检测到半胱天冬酶3激活。然而，VDR KO小鼠（与WT小鼠相比）阳性细胞百分比和染色强度较低。
这些数据表明，VDR KO小鼠在较早年龄就逐渐出现感音神经性听力损失。虽然耳蜗中的基本基因表达不受VDR突变影响，但它导致半胱天冬酶3激活减少，这可能是VDR KO小鼠中加速年龄相关性听力损失的因素之一。
