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Effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss in mice.
Experimental Gerontology ( IF 3.3 ) Pub Date : 2020-02-07 , DOI: 10.1016/j.exger.2020.110872
Hyo-Jin Park 1 , Mi-Jung Kim 1 , Chul Han 1 , Karessa White 1 , Dalian Ding 2 , Kevin Boyd 1 , Richard Salvi 2 , Shinichi Someya 1
Affiliation  

The glutathione transferase (GST) detoxification system converts exogenous and endogenous toxins into a less toxic form by conjugating the toxic compound to reduced glutathione (GSH) by a variety of GST enzymes. Of the ~20 GST isoforms, GSTA4 exhibits high catalytic efficiency toward 4-hydroxynonenal (4-HNE), one of the most abundant end products of lipid peroxidation that contributes to neurodegenerative diseases and age-related disorders. Conjugation to GSH by GSTA4 is thought to be a major route of 4-HNE elimination. In the current study, we investigated the effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss using young (3-5 months old) and old (24-25 months old) Gsta4+/+ and Gsta4-/- mice that were backcrossed onto the CBA/CaJ mouse strain, a well-established model of age-related hearing loss (AHL). At 3-5 months of age, loss of Gsta4 resulted in decreased total GSTA activity toward 4-HNE in the inner ears of young mice. However, there were no differences in the levels of 4-HNE in the inner ears between Gsta4+/+ and Gsta4-/- mice at 3-5 or 24-25 months of age. No histological abnormalities were observed in the cochlea and no hearing impairments were observed in young Gsta4-/- mice. At 24-25 months of age, both Gsta4+/+ and Gsta4-/- mice showed elevated ABR thresholds compared to 3-month-old mice, but there were no differences in ABR thresholds, cochlear spiral ganglion neuron densities, or stria vascularis thickness between Gsta4+/+ and Gsta4-/- mice. Together, these results suggest that under normal physiological conditions or during normal aging, GSTA4 is not essential for removal of 4-HNE in mouse inner ears.

中文翻译:

Gsta4 缺乏对小鼠年龄相关耳蜗病理学和听力损失的影响。

谷胱甘肽转移酶 (GST) 解毒系统通过多种 GST 酶将有毒化合物与还原型谷胱甘肽 (GSH) 结合,将外源性和内源性毒素转化为毒性较低的形式。在约 20 种 GST 同种型中,GSTA4 对 4-羟基壬烯醛 (4-HNE) 表现出高催化效率,4-HNE 是导致神经退行性疾病和年龄相关疾病的最丰富的脂质过氧化终产物之一。GSTA4 与 GSH 的结合被认为是 4-HNE 消除的主要途径。在目前的研究中,我们使用年轻(3-5 个月大)和老年(24-25 个月大)Gsta4+/+ 和 Gsta4-/- 小鼠研究了 Gsta4 缺乏对与年龄相关的耳蜗病理学和听力损失的影响,这些小鼠是回交到 CBA/CaJ 小鼠品系上,这是一种成熟的年龄相关性听力损失 (AHL) 模型。在 3-5 个月大时,Gsta4 的缺失导致年轻小鼠内耳中对 4-HNE 的总 GSTA 活性降低。然而,在 3-5 月龄或 24-25 月龄时,Gsta4+/+ 和 Gsta4-/- 小鼠的内耳中 4-HNE 水平没有差异。在耳蜗中未观察到组织学异常,在年轻的 Gsta4-/- 小鼠中未观察到听力障碍。在 24-25 个月大时,与 3 个月大的小鼠相比,Gsta4+/+ 和 Gsta4-/- 小鼠的 ABR 阈值均升高,但 ABR 阈值、耳蜗螺旋神经节神经元密度或血管纹厚度没有差异在 Gsta4+/+ 和 Gsta4-/- 小鼠之间。总之,这些结果表明,在正常生理条件下或正常衰老过程中,GSTA4 对于去除小鼠内耳中的 4-HNE 不是必需的。Gsta4 的缺失导致年轻小鼠内耳中对 4-HNE 的总 GSTA 活性降低。然而,在 3-5 月龄或 24-25 月龄时,Gsta4+/+ 和 Gsta4-/- 小鼠的内耳中 4-HNE 水平没有差异。在耳蜗中未观察到组织学异常,在年轻的 Gsta4-/- 小鼠中未观察到听力障碍。在 24-25 个月大时,与 3 个月大的小鼠相比,Gsta4+/+ 和 Gsta4-/- 小鼠的 ABR 阈值均升高,但 ABR 阈值、耳蜗螺旋神经节神经元密度或血管纹厚度没有差异在 Gsta4+/+ 和 Gsta4-/- 小鼠之间。总之,这些结果表明,在正常生理条件下或正常衰老过程中,GSTA4 对于去除小鼠内耳中的 4-HNE 不是必需的。Gsta4 的缺失导致年轻小鼠内耳中对 4-HNE 的总 GSTA 活性降低。然而,在 3-5 月龄或 24-25 月龄时,Gsta4+/+ 和 Gsta4-/- 小鼠的内耳中 4-HNE 水平没有差异。在耳蜗中未观察到组织学异常,在年轻的 Gsta4-/- 小鼠中未观察到听力障碍。在 24-25 个月大时,与 3 个月大的小鼠相比,Gsta4+/+ 和 Gsta4-/- 小鼠的 ABR 阈值均升高,但 ABR 阈值、耳蜗螺旋神经节神经元密度或血管纹厚度没有差异在 Gsta4+/+ 和 Gsta4-/- 小鼠之间。总之,这些结果表明,在正常生理条件下或正常衰老过程中,GSTA4 对于去除小鼠内耳中的 4-HNE 不是必需的。
更新日期:2020-02-07
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