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.
van den Heiligenberg
S
S
Laboratoire Rythmes Biologiques et Chronothérapeutique, Institut du Cancer et d'Immunogénétique et Université Paris XI, Villejuif, France.
Deprés-Brummer
P
P
Barbason
H
H
Claustrat
B
B
Reynes
M
M
Lévi
F
F
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