Initiation, promotion, and inhibition of carcinogenesis in rainbow trout.
The identification of etiological agents in feral fish neoplasia epizootics has been hampered in part by the lack of suitable fish models, and complicated by the likely existence of environmental agents which can act to stimulate or reduce population responses to genotoxin insult. The response of fish to tumor inhibitors and promoters, and the underlying mechanisms of modulation, have been studied in the rainbow trout model. Dietary treatment of trout with the compounds indole-3-carbinol (I3C), beta-naphthoflavone (BNF), or the polychlorinated biphenyl (PCB) complex Aroclor 1254, before and during exposure to aflatoxin B1 (AFB1), was shown to reduce the final incidence of hepatocellular carcinoma after 12 months, compared to fish receiving AFB1 only. By contrast, treatment of trout with BNF or I3C following AFB1 initiation led to a significant enhancement of ultimate tumor response. Similarly, simultaneous treatment of trout with PCB and the carcinogen N-nitrosodiethylamine led to syncarcinogenic enhancement, rather than inhibition, of tumor response. Mechanisms of inhibition of AFB1 carcinogenesis by PCB, BNF, and I3C were investigated. PCB and BNF, but not I3C, are known to be strong inducers of trout cytochrome P448 and associated activities. Dietary induction by BNF or PCB was shown to be accompanied in isolated hepatocytes by considerably altered AFB1 metabolism, and by significantly reduced rates of DNA adduct formation for all three agents. All agents differentially altered in vivo AFB1 pharmacokinetics, enhanced bile elimination of AFB1 as the aflatoxicol-M1 glucuronide, and significantly reduced peak levels of liver DNA adduct formation. No effects were seen on repair of AFB1-DNA adducts, which was very slow in trout.(ABSTRACT TRUNCATED AT 250 WORDS)
Bailey
G
G
Selivonchick
D
D
Hendricks
J
J
D000818:Animals; D002273:Carcinogens; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D012487:Salmonidae / Q000502:physiology*; D014337:Trout / Q000502:physiology*
D002273:Carcinogens