Effects of chronic jet lag on the central and peripheral circadian clocks in CBA/N mice
Effects of chronic jet lag on the central and peripheral circadian clocks in CBA/N mice
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DOI：
10.3109/07420528.2013.837478
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发表时间：
2014-01-01
影响因子：
2.8
通讯作者：
Yasuo, Shinobu
中科院分区：
文献类型：
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作者：
Iwamoto, Ayaka;Kawai, Misato;Yasuo, Shinobu
昼夜周期的频繁变化，如倒班或频繁的时差反应，会扰乱生物钟，增加患包括癌症在内的许多疾病的风险。实验破坏生物钟也会增加小鼠的肿瘤发展，尽管大多数研究使用的是在褪黑激素合成和分泌方面基因受损的菌株。在这里，我们研究了实验性慢性时差对CBA/N小鼠中枢和外周时钟的影响，每2天提前8小时的光暗周期，持续10天。在10天的慢性时差反应后，老鼠被暴露在持续的黑暗中。在视交叉上核（SCN）中，慢性时差改变了大多数时钟基因的时间表达，但不会引起昼夜节律振荡的完全干扰。在肝脏中，Per1、Bmal1和Dbp表达的时间模式发生了相移，Per2的表达因慢性时差反应而显著上调。此外，肝脏细胞周期相关基因c-Myc和p53的表达被慢性时差作息显著激活，且Per2与p53表达呈显著正相关。我们测定了血浆中褪黑激素和皮质酮作为慢性时差反应的候选激素信使的浓度，但它们的总体水平不受慢性时差反应的影响。此外，肝脏中MT1褪黑激素和糖皮质激素受体的表达受到慢性时差反应的抑制。这些数据表明，在CBA/N小鼠中，频繁的明暗周期改变了SCN的中央时钟相位，扰乱了肝脏的外周时钟和凋亡功能，这可能与激素受体的抑制有关。
The disruption of the circadian clock by frequent shifts in the light-dark cycle, such as shift-work or frequent jet lag, increases the risk of many diseases, including cancer. Experimental disruption of the circadian clock also increases tumor development in mice, although most studies used the strains that are genetically impaired in melatonin synthesis and secretion. Here, we examined the effects of experimental chronic jet lag with 8 h advances of the light-dark cycle every 2 days for 10 days on the central and peripheral clocks of CBA/N mice, the strain with normal profiles of melatonin synthesis and secretion. Mice were exposed to constant darkness after the 10 days of chronic jet lag. In the suprachiasmatic nucleus (SCN), chronic jet lag shifted the temporal expression of most clock genes examined without causing total disturbance of circadian oscillations. In the liver, the temporal patterns of Per1, Bmal1, and Dbp expression were phase-shifted, and Per2 expression was significantly upregulated by chronic jet lag. Further, the expression of cell cycle-related genes, c-Myc and p53 in the liver was significantly activated by the chronic jet lag schedule with a significant positive correlation between Per2 and p53 expression. We determined the plasma concentrations of melatonin and corticosterone as candidate hormonal messengers of chronic jet lag, but their overall levels were not affected by chronic jet lag. Moreover, the expression of the MT1 melatonin and glucocorticoid receptors in the liver was suppressed by chronic jet lag. These data suggest that in CBA/N mice, frequent advances of light-dark cycles modify the phases of central clock in the SCN and disturb the peripheral clock in the liver and apoptotic functions, which may be associated with the suppression of hormone receptors.