Page 583 - The Toxicology of Fishes

Chemical Carcinogenesis in Fishes 563

modulation by factors including steroid hormones, anti- or prooxidants, plant extracts, and environmen-
tally persistent xenobiotics (Bailey et al., 1987b). This is followed, admittedly at some distance, by the
medaka. The Oregon State University group (Bailey, Hendricks, and colleagues) has pioneered these
efforts, demonstrating a progression of emphasis from in vivo bioassays to chemical biodistribution,
metabolism, and DNA adduct formation and quantitation to effects on eventual tumor incidence. Their
latest work has extended to DNA arrays of resultant tumors and of livers exposed to promotional agents.

Enhancement of Chemical Carcinogenesis: Focus on Trout
The terms enhancement and its opposite, inhibition, blur the distinction between initiation, promotion,
and progression; however, as we shall see it is often difficult to characterize one factor or modulatory
compound as having a single effect on the carcinogenetic or tumorigenetic process.

Alteration in Xenobiotic Transport
Pretreatment with selected organochlorines has been found to affect the transport of a carcinogenic PAH
in vivo (Donohoe et al., 1998). In one investigation, prefeeding with chlordecone or dieldrin was followed
by determination of levels of tritiated DMBA (from an aqueous exposure) in stomach and liver. Chlor-
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decone pretreatment did not influence [ H]-DMBA hepatic concentrations, hepatic [ H]-DMBA DNA
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binding, or hepatic and stomach tumor incidence. It did, however, elevate bile [ C]-CD and [ H]-DMBA
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concentrations. Dieldrin pretreatment did not influence stomach [ H]-DMBA equivalents or stomach
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tumor incidence; however it resulted in an elevation in biliary and hepatic concentrations of [ H]-DMBA
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equivalents. [ H]-DMBA binding to liver DNA was significantly increased and hepatic tumor incidence
was elevated by dieldrin pretreatment. This study illustrates enhancement by influence of xenobiotic
transport. It is important to note that one organochlorine (dieldrin but not chlordecone) had this effect.
Induced Metabolic Change Resulting in a More Potent Carcinogen
When newly hatched sac-fry were injected with trans-7,8-dihydrobenzo(a)pyrene-7,8-dioll, hepatic
tumors resulted. Marked enhancement was seen with co-injection of BNF or carbon tetrachloride (Kelly
et al., 1993a). Perhaps cyp-dependent and lipid-peroxidation-dependent pathways could be involved in
bioactivation of this compound through epoxidation at the 9,10-position, producing a more potent
carcinogen, the (–) enantiomer of BP-7,8-DHD (Kelly et al., 1993a). Prior treatment of trout with BNF
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increased O -ethylguanine formation by subsequent DEN exposure, enhancing the initiation phase of
carcinogenesis (Fong et al., 1988). Another example of increased DNA adduct formation and enhanced
tumorigenesis was provided in MNNG studies (Kelly et al., 1993b). Dietary hydrogen peroxide enhanced
levels of the mutagenic DNA adduct 8-hydroxy-2′-deoxyguanosine (8-oxo-dG) and tumor formation.

Synergistic or Cocarcinogenic Enhancement
Both cyclopropenoid fatty acids (CPFAs) and aflatoxin are complete carcinogens in the trout model.
Simultaneous exposure to cyclopropenoid fatty acids and to aflatoxin (Lee et al., 1968) revealed a
synergistic effect (cocarcinogenesis) on liver tumor formation in rainbow trout; however, subsequent
work by Bailey and colleagues (1982) suggested that dietary CPFAs repress cyp activities and depress
DNA damage by AFB in vitro. Thus, two factors may be at work in chronic exposures: depression of
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initial AFB -induced DNA damage but highly efficient promotion of transformation from the remaining
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lesions, resulting in a synergistic effect. Bailey’s group (1987b) also provided another example of
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cocarcinogenesis by simultaneous treatment of trout with PCB (Arochlor 1254) and DEN. Co-admin-
istration led to synergism of the tumor response.

Promoters of Tumorigenesis
When trout are exposed to BNF or indole-3-carbinol (I3C) from cruciferous vegetables after AFB 1
initiation, a significant enhancement of tumor response occurs (Bailey et al., 1982). These compounds
do not induce tumor formation when given alone; therefore, they are promoters of tumorigenesis. As