Circadian disruption accelerates liver carcinogenesis in mice.
BACKGROUND
The circadian timing system rhythmically controls behavior, physiology, cellular proliferation and xenobiotic metabolism over the 24-h period. The suprachiasmatic nuclei in the hypothalamus coordinate the molecular clocks in most mammalian cells through an array of circadian physiological rhythms including rest-activity, body temperature, feeding patterns and hormonal secretions. As a result, shift work that involves circadian disruption is probably carcinogenic in humans. In experimental models, chronic jet-lag (CJL) suppresses rest-activity and body temperature rhythms and accelerates growth of two transplantable tumors in mice. CJL also suppresses or significantly alters the expression rhythms of clock genes in liver and tumors. Circadian clock disruption from CJL downregulates p53 and upregulates c-Myc, thus favoring cellular proliferation. Here, we investigate the role of CJL as a tumor promoter in mice exposed to the hepatic carcinogen, diethylnitrosamine (DEN).


METHODS
In experiment 1 (Exp 1), the dose-dependent carcinogenicity of chronic intraperitoneal (i.p.) administration of DEN was explored in mice. In Exp 2, mice received DEN at 10 mg/kg/day (cumulative dose: 243 mg/kg), then were randomized to remain in a photoperiodic regimen where 12 h of light alternates with 12 h of darkness (LD 12:12) or to be submitted to CJL (8-h advance of light onset every 2 days). Rest-activity and body temperature were monitored. Serum liver enzymes were determined repeatedly. Mice were sacrificed and examined for neoplastic lesions at 10 months.


RESULTS
In Exp 1, DEN produced liver cancers in all the mice receiving 10 mg/kg/day. In Exp 2, mice on CJL had increased mean plasma levels of aspartate aminotransferase and more liver tumors as compared to LD mice at approximately 10 months (p = 0.005 and 0.028, respectively). The mean diameter of the largest liver tumor was twice as large in CJL vs LD mice (8.5 vs 4.4 mm, p = 0.027). In LD, a single histologic tumor type per liver was observed. In CJL, up to four different types were associated in the same liver (hepatocellular- or cholangio-carcinomas, sarcomas or mixed tumors). DEN itself markedly disrupted the circadian rhythms in rest-activity and body temperature in all the mice. DEN-induced disruption was prolonged for >or= 3 months by CJL exposure.


CONCLUSIONS
The association of circadian disruption with chronic DEN exposure suggests that circadian clocks actively control the mechanisms of liver carcinogenesis in mice. Persistent circadian coordination may further be critical for slowing down and/or reverting cancer development after carcinogen exposure.
Filipski
Elisabeth
E
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif F-94807, France.
Subramanian
Perumal
P
Carrière
Jennyfer
J
Guettier
Catherine
C
Barbason
Hervé
H
Lévi
Francis
F
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000473:pathology; D002940:Circadian Rhythm / Q000187:drug effects*; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D009378:Neoplasms, Multiple Primary / Q000139:chemically induced / Q000473:pathology; D012509:Sarcoma / Q000139:chemically induced / Q000473:pathology; D013997:Time Factors
D002273:Carcinogens; D004052:Diethylnitrosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase