The tumor promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats

The hypothesis that light-induced circadian clock suppression exerts a promoting effect on liver carcinogenesis was investigated in rats. Sixty-five male Wistar rats were given diethylnitrosamine (DEN, 10 mg/kg/day p.o.) for 6 weeks and were randomized into 3 groups. Rats from group 1 (N=20) received DEN only. Rats from group 2 (N=22) also received phenobarbital (pheno, 30 mg/rat/day p.o.) for 4 weeks as a promoting agent and rats from group 3 (N=23) were exposed to continuous light. Three months after starting DEN treatment, urinary 6-sulfatoxymelatonin (alphaMT6s) excretion, a marker of circadian clock function, had lost its circadian rhythmicity in the LL group, with a 4-fold lower 24 h mean than that found in the LDpheno and LD groups (8.0 +/- 3.2 ng/ml, 33.6 +/- 3.1 ng/ml and 34.3 +/- 2.4 ng/ml respectively; p from ANOVA <0.001). Laparotomy was then performed. The proportion of rats with macroscopic nodules on liver surface was 72% (LD group), 89% (LDpheno group) and 95% (LL group) (p from chi2 = 0.1). Nodules were more numerous and larger both in the LL group and in the LDpheno one as compared to the LD group (p from chi2 <0.05). All the rats died with hepatocellular carcinomas, with a median survival of 5 months, similar in all 3 groups. Light-induced circadian clock suppression exerted a promoting effect similar to that caused by phenobarbital in this model, yet through different effects on circadian system function.