The long range goals of this proposal are to understand the significance to human health of epizootics of neoplasia in feral fish populations, and to expand our basic knowledge of the comparative aspects of neoplasia in fish and mammals. Although suspect etiologic agents such as benzo(a)pyrene (BP), dibenz(a,h)anthracene (DBA), and carbazole (CA) have been identified in some epizootic locales, causal relationships have not been established. Definitive associations will require not only direct demonstration of carcinogenic potencies in fish, but also an understanding of the impact on tumor response of confounding variables including: water quality and temperature, nutritional status and growth rate, life stage at risk, genetic variation, population age structure, migration habits, and presence of tumor modulators as well as genotoxins. Further lacking is an understanding of the basic molecular biology of carcinogenesis in fish compared to mammals. Although rainbow trout seldom inhabit polluted environments where fish tumor epizootics occur, they have received over 20 years of study as a tumor model and thus are among the few laboratory fish tumor models with sufficient development to address many of these needs. We propose to use this model with the following specific aims: 1) conduct tumor studies to establish or confirm the carcinogenicities of BP, DBA, CA, and the model carcinogen 7,12-dibenzanthracene (DMBA) in trout by selected exposure routes; 2) determine the impact on tumor response of potential modulating variables including temperature, nutritional status, selected dietary cofactors (DDT, CA, pthalates, Aroclor 1254) and maternally accumulated embryonic Aroclor 1254; 3) conduct mechanism studies on procarcinogen pharmacokinetics, cellular metabolism, DNA adduct formation and repair, and the influence of the above modulating influences on these processes; 4) further characterize fundamental aspects of tumor progression in trout, including development and progression of preneoplastic foci in liver and the transplantability of various tumor types into syngenic hosts; and 5) investigate the possible involvement of oncogenes and tumor transforming genes in trout neoplasia, through the isolation and characterization of selected c-onc genes, determination of their expression and multiplicity in normal and tumor tissue, and development of cell culture systems for oncogenic transfection assay.
| Fong, A T; Dashwood, R H; Cheng, R et al. (1993) Carcinogenicity, metabolism and Ki-ras proto-oncogene activation by 7,12-dimethylbenz[a]anthracene in rainbow trout embryos. Carcinogenesis 14:629-35 |
| Chang, Y J; Mathews, C; Mangold, K et al. (1991) Analysis of ras gene mutations in rainbow trout liver tumors initiated by aflatoxin B1. Mol Carcinog 4:112-9 |
| Mangold, K; Chang, Y J; Mathews, C et al. (1991) Expression of ras genes in rainbow trout liver. Mol Carcinog 4:97-102 |
| Nunez, O; Hendricks, J D; Duimstra, J R (1991) Ultrastructure of hepatocellular neoplasms in aflatoxin B1 (AFB1)-initiated rainbow trout (Oncorhynchus mykiss). Toxicol Pathol 19:11-23 |
