Initiation, Promotion, and Inhibition of Carcinogenesis in Rainbow Trout

Abstract

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 (13C), ,8-naphthofiavone (BNF), or the polychlorinated biphenyl (PCB) complex Aroclor 1254, before and during exposure to afiatoxin 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 13C 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-Ml 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. Detailed studies demonstrated that glutatione detoxication of the AFB1.2,3-oxide is not a significant pathway in trout fed control or inhibitor diets. The precise means by which 13C reduces adduct formation are presently unclear.

Fish models for environmental carcinogenesis: the rainbow trout.

“…Use of the trout tumor model to study modulation of carcinogenesis has been reviewed elsewhere (158)(159)(160). The historically low spontaneous liver tumor incidence (0.1%) is a significant advantage in the statistical design of multidose tumor inhibition and promotion experiments.…”

Vacuolation, proliferation and neoplasia in the liver of Boston Harbor winter flounder (Pseudopleuronectes americanus)

“…Essentially, there is evidence that, not surrisingly, proto-oncogenes exist in fish, and presumably they can be activated by similar changes to those found in mamals. In contrast, the study of promoters in fish (Bailey et al 1987a(Bailey et al , 1987b(Bailey et al , 1988) is limited to a demonstration of the promotional effects of the PCB formulation…”

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells

“…I3C possesses anti-carcinogenic e ects in experimental animals depending on the time of I3C exposure (Bailey et al, 1987;Dashwood, 1998;Dashwood et al, 1989;Grubbs et al, 1995). Exposure of I3C prior to carcinogenic insult had clearly shown to have protective e ect (Guo et al, 1995;Xu et al, 1996), and that I3C has been shown to inhibit the growth of human cancer cells (Katdare et al, 1998;Tiwari et al, 1994).…”