Effects of chronic jet lag on the central and peripheral circadian clocks in CBA/N mice.

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.