The construction of transgenic mice carrying integrated hepatitis B DNA encoding the entire open reading frame for the outer membrane polypeptides of the hepatitis B virus (HBV) provides an experimental animal model in which the hypothesis that aflatoxin exposure and hepatitis B virus infection act synergistically to cause primary hepatocellular carcinoma (PHC) may be tested. PHC, while relatively rare in North America, is one of the most common cancers in some parts of the world. The marked geographic differences in the incidence of PHC have suggested that the most important risk factors for PHC are previous HBV infection and dietary exposure to aflatoxin. The present proposal will test the possible synergy between human HBV infection and dietary carcinogens by exposing transgenic mice expressing different levels of HBV to a known carcinogen (DEN) and to aflatoxin. In the first specific aim the relationship between the level of expression of HBV and carcinogen exposure will be tested in three transgenic mouse lines expressing different-levels of HBsAg polypeptide: 45-2, 45-3 and 50-4, each of which contains the HBsAg genome but which express low, intermediate and high intracellular levels of HBV polypeptide and different degrees of liver cell damage respectively. In the second specific aim, the relationship between the time of exposure and the expression will be tested using a transgenic mouse lineage in which the HBV gene is controlled by the metallothionine gene promoter. Backcrossing of transgenic males with non-transgenic females produces Fls, half of which carry the transgene and half which do not, thus providing non-transgenic littermate controls for each experimental group. Understanding the nature of the possible synergy of HBV infection and aflatoxin exposure in causing PHC could lead to ways to reduce one of the most prevalent and deadly cancers of mankind.
