Iwamoto Ayaka, Kawai Misato, Furuse Mitsuhiro, Yasuo Shinobu
Laboratory of Regulation in Metabolism and Behavior, Faculty of Agriculture, Kyushu University , Fukuoka , Japan.
Chronobiol Int. 2014 Mar;31(2):189-98. doi: 10.3109/07420528.2013.837478. Epub 2013 Oct 22.
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.
频繁的昼夜循环变化，如轮班工作或频繁的时差反应，会扰乱生物钟，增加包括癌症在内的多种疾病的风险。实验性地扰乱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褪黑素合成和分泌存在基因缺陷的品系。在这里，我们研究了每2天将昼夜循环提前8小时，持续10天的实验性慢性时差反应对CBA/N小鼠中枢和外周生物钟的影响，该品系具有正常的褪黑素合成和分泌模式。在10天的慢性时差反应后，小鼠被置于持续黑暗环境中。在视交叉上核（SCN）中，慢性时差反应改变了所检测的大多数生物钟基因的时间表达，但并未导致昼夜节律振荡的完全紊乱。在肝脏中，Per1、Bmal1和Dbp表达的时间模式发生了相位改变，慢性时差反应使Per2表达显著上调。此外，肝脏中细胞周期相关基因c-Myc和p53的表达在慢性时差反应时间表的作用下显著激活，且Per2与p53表达之间存在显著正相关。我们测定了褪黑素和皮质酮的血浆浓度，作为慢性时差反应的候选激素信使，但它们的总体水平不受慢性时差反应的影响。此外，慢性时差反应抑制了肝脏中MT1褪黑素和糖皮质激素受体的表达。这些数据表明，在CBA/N小鼠中，频繁的昼夜循环提前会改变SCN中中枢生物钟的相位，扰乱肝脏中的外周生物钟和凋亡功能，这可能与激素受体的抑制有关。
