Fish Models for Environmental Carcinogenesis: The Rainbow Trout

Abstract

Progress over the past 30 years has revealed many strengths of the rainbow trout as an alternative model for environmental carcinogenesis research. These include low rearing costs, an early life-stage ultrasensitive bioassay, sensitivity to many classes of carcinogen, a well-described tumor pathology, responsiveness to tumor promoters and inhibitors, and a mechanistically informative nonmammalian comparative status. Low-cost husbandry, for example, has permitted statistically challenging tumor study designs with up to 10,000 trout to investigate the quantitative 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, carcinogen response, husbandry requirements, and pathology. The principal known neoplasms occur in liver (mixed hepatocellular/cholangiocellular adenoma and carcinoma, hepatocellular carcinoma), kidney (nephroblastoma), swim bladder (adenopapilloma), and stomach (adenopapilloma). Trout possess a complex but incompletely characterized array of cytochromes P450, transferases, and other enzymic systems for phase I and phase II procarcinogen metabolism. In general, trout exhibit only limited capacity for DNA repair, especially for removal of bulky DNA adducts. This factor, together with a high capacity for P450 bioactivation and negligible glutathione transferase-mediated detoxication of the epoxide, accounts for the exceptional sensitivity of trout to aflatoxin B1 carcinogenesis. At the gene level, all trout tumors except nephroblastoma exhibit variable and often high incidences of oncogenic Ki-ras gene mutations. Mutations in the trout p53 tumor suppressor gene have yet to be described. There are many aspects of the trout model, especially the lack of complete organ homology, that limit its application as a surrogate for human cancer research. Within these limitations, however, it is apparent that trout and other fish models can serve as highly useful adjuncts to conventional rodent models in the study of environmental carcinogenesis and its modulation. For some problems, fish models can provide wholly unique approaches.

Neoplastic and nonneoplastic hepatic changes in lake whitefish (Coregonus clupeaformis) from the St. Lawrence River, Quebec, Canada.

“…Prior to this study and the previous report from our group (13), a single hepatic neoplasm (a cholangiocarcinoma) had been diagnosed in a fish from the genus Coregonus (lake herring, Coregonus artedi; Essex County, NY; RTLA #1426). To our knowledge, the present report is the first description of a series of hepatic neoplasia in a wild population of salmonid fish, although the domesticated rainbow trout is susceptible to a variety of carcinogenic compounds that cause hepatocellular carcinomas (15)(16)(17)(18). In humans and in other mammals, common causes of hepatic neoplasia are chemical carcinogens and viruses (19)(20)(21).…”

Aflatoxins in aquatic species: metabolism, toxicity and perspectives

“…Finally, the higher efficiency of CYP-mediated AFBO production along as with the great amount of AFBO produced directly from AFB 1 and indirectly from AFL 1 might account for the high rate of DNA-adduct formation found in trout. Such results with the low GST-AFBO conjugating activity contribute to explain the extreme trout sensitivity to AFB 1 toxicity and carcinogenicity (Valsta et al 1988;Bailey et al 1996).…”

“…Even though the epoxidation of the terminal furan ring of AFB 1 gives rise to a mixture of stereoisomers epoxides, the AFB-exo-8,9-epoxide and AFB-endo-8,9-epoxide, the most critical product for establishing deleterious adducts with cellular macromolecules and genome damage is the exo-epoxide (Raney et al 1993). Once formed inside the cell, the exo-epoxide is sufficiently stable to migrate from the endoplasmic reticulum to the nucleus where it binds covalently to genetic material, inducing structural modifications and a spectrum of DNA lesions (Bailey et al 1996;Guengerich 2006). The predominant adduct, the 8,9-dihydro-8-(N7-guanyl)-9-hydroxylatioaflatoxin B 1 (AFB 1 -N7-GUA), which derives from a nucleophilic attack of DNA N7 guanine base on C 8 of AFBO, is produced at highest levels in the liver of mammals, trout and coho salmon (Croy et al 1980;Bailey et al 1988;Johnson and Guengerich 1997).…”

The hepatocytes of the brown trout (Salmo trutta f. fario): a stereological study of their number and size during the breeding cycle

“…The interest in knowing how liver structure differs in vertebrates is an old driving force, and the piscine liver in particular has always been a matter of debate and renditions (Elias and Bengelsdorf 1952;Beresford and Henninger 1986;Hinton and Couch 1998). Another point of interest is that fish liver is prone to tumors (Nigrelli and Jakowska 1961); therefore, it is being used as a model in the study of carcinogenesis, namely that related with pollutants (Bailey et al 1996). Structural changes evoked by diets have also been often considered (Caballero et al 1999;Figueiredo-Silva et al 2005).…”