Department of Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA, USA.
Hear Res. 2011 Jul;277(1-2):211-26. doi: 10.1016/j.heares.2010.12.014. Epub 2010 Dec 25.
The molecular mechanisms underlying the vast differences between individuals in their susceptibility to noise-induced hearing loss (NIHL) are unknown. The present study demonstrated that the effects of noise over-exposure on the expression of molecules likely to be important in the development of NIHL differ among inbred mouse strains having distinct susceptibilities to NIHL including B6 (B6.CAST) and 129 (129X1/SvJ and 129S1/SvImJ) mice. The noise-exposure protocol produced a loss of 40 dB in hearing sensitivity in susceptible B6 mice, but no loss for the two resistant 129 substrains. Analysis of gene expression in the membranous labyrinth 6 h following noise exposure revealed upregulation of transcription factors in both the susceptible and resistant strains. However, a significant induction of genes involved in cell-survival pathways such as the heat shock proteins HSP70 and HSP40, growth arrest and DNA-damage-inducible protein 45β (GADD45β), and CDK-interacting protein 1 (p21(Cip1)) was detected only in the resistant mice. Moreover, in 129 mice significant upregulation of HSP70, GADD45β, and p21(Cip1) was confirmed at the protein level. Since the functions of these proteins include roles in potent anti-apoptotic cellular pathways, their upregulation may contribute to protection from NIHL in the resistant 129 mice.
个体对噪声性听力损失（NIHL）易感性差异的潜在分子机制尚不清楚。本研究表明，噪声过度暴露对可能对 NIHL 发展重要的分子表达的影响在对 NIHL 具有不同易感性的近交系小鼠中存在差异，包括 B6（B6.CAST）和 129（129X1/SvJ 和 129S1/SvImJ）小鼠。噪声暴露方案导致易感 B6 小鼠的听力敏感性损失 40 dB，但两种抗性 129 亚系没有损失。噪声暴露后 6 小时对膜迷路的基因表达分析显示，易感和抗性品系中的转录因子均上调。然而，仅在抗性小鼠中检测到细胞存活途径相关基因的显著诱导，如热休克蛋白 HSP70 和 HSP40、生长停滞和 DNA 损伤诱导蛋白 45β（GADD45β）和细胞周期蛋白依赖性激酶相互作用蛋白 1（p21(Cip1))。此外，在 129 小鼠中，HSP70、GADD45β 和 p21(Cip1) 的显著上调在蛋白质水平上得到了证实。由于这些蛋白质的功能包括在有效的抗细胞凋亡途径中的作用，因此它们的上调可能有助于保护抗性 129 小鼠免受 NIHL。
