FISH MODELS FOR ENVIRONMENTAL CARCINOGENESIS - THE RAINBOW-TROUT

Progress over the past 30 years has revealed many strengths of the rai nbow trout as an alternative model for environmental carcinogenesis re search. These include low rearing costs. an early life-stage ultrasens itive bioassay, sensitivity to many classes of carcinogen, a well-desc ribed tumor pathology, responsiveness to tumor promoters and inhibitor s. and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challengi ng tumor study designs with up to 10,000 trout to investigate the quan titative interrelationships among carcinogen dose, anticarcinogen dose . DNA adduct formation. and final tumor outcome. The basic elements of the trout carcinogen bioassay include multiple exposure routes, carci nogen response, husbandry requirements, and pathology. The principal k nown neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblasto ma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trou t possess a complex but incompletely characterized array of cytochrome s P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited ca pacity for DNA repair, especially for removal of bulky DNA adducts. Th is factor, together with a high capacity for P450 bioactivation and ne gligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B-1 ca rcinogenesis. At the gene level. all trout tumors except nephroblastom a exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet t o be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a s urrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly u seful adjuncts to conventional rodent models in the study of environme ntal carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.