There now is substantial epidemiologic evidence supporting the hypothesis that hepatitis B virus (HBV) is a critical factor in the etiopathogenesis of primary hepatocellular carcinoma (PHC). The oncogenic mechanism is not completely understood, and it has been suggested that HBV may either act independently as a primary carcinogen or as a co-carcinogen with environmental and/or dietary factors such as aflatoxin. It has been difficult to investigate possible interactions between HBV and aflatoxin because of the lack of suitable experimental animal models. The recent observation that woodchucks with chronic active hepatitis and PHC are infected with a virus closely resembling HBV, the woodchuck hepatitis virus (WHV), suggests this animal may be valuable for investigation of these interactions. In the proposed studies, the acute and chronic effects of aflatoxin would be determined to establish if this class of compounds can act as primary hepatocarcinogens in woodchucks. Simultaneously, it is planned to determine the effects of aflatoxin administration and WHV infection on the rates of chronic hepatitis and primary hepatocellular carcinoma and to compare these rates with those of control woodchucks and woodchucks either infected with WHV virus or given aflatoxin separately. A two-by-two experimental design will be employed to examine virus-aflatoxin interactions. Woodchucks will be experimentally infected with WHV at 8 weeks of age. Aflatoxin B1 will be administered at 1 ppm in agar gel diet for 4 months. Time course and response to acute infection and the time to tumor development will be determined by WHV serology, serum chemistry, serum Alpha-fetoprotein, by histochemical evaluation of biopsy tissue for preneoplastic, gamma glutamyl transferase positive foci, and by histological examination of tumor and non-tumorous hepatic tissue. Animals with clinical evidence of tumor that become ill or moribund will be euthanized, otherwise, surviving animals will be followed for 2 years before euthanasia. Complete necropsy examinations will be performed, and hepatic tissue examined for evidence of WHV markers. The primary objective of the investigation is to determine if a synergistic interaction can be demonstrated between WHV and aflatoxin and, by analogy, to test the hypothesis that aflatoxin may enhance development of PHC in individuals with chronic HBV infection.
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| Liu, R H; Jacob, J R; Tennant, B C et al. (1992) Nitrite and nitrosamine synthesis by hepatocytes isolated from normal woodchucks (Marmota monax) and woodchucks chronically infected with woodchuck hepatitis virus. Cancer Res 52:4139-43 |
| Liu, R H; Baldwin, B; Tennant, B C et al. (1991) Elevated formation of nitrate and N-nitrosodimethylamine in woodchucks (Marmota monax) associated with chronic woodchuck hepatitis virus infection. Cancer Res 51:3925-9 |
