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.
Laboratoire Rythmes Biologiques et Chronothérapeutique, Institut du Cancer et d'Immunogénétique et Université Paris XI, Villejuif, France.
S
S
van den Heiligenberg
P
P
Deprés-Brummer
H
H
Barbason
B
B
Claustrat
M
M
Reynes
F
F
Lévi
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D002940:Circadian Rhythm / Q000187:drug effects; D004052:Diethylnitrosamine / Q000494:pharmacology; D007813:Laparotomy; D008027:Light; D008099:Liver / Q000473:pathology / Q000601:surgery; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives / Q000652:urine; D009043:Motor Activity / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate
D002273:Carcinogens; C054513:6-sulfatoxymelatonin; D004052:Diethylnitrosamine; D008550:Melatonin; D010634:Phenobarbital