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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054526-03
Application #
3199085
Study Section
Special Emphasis Panel (SRC (40))
Project Start
1991-06-01
Project End
1995-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Yin, L; Lynch, D; Sell, S (1999) Participation of different cell types in the restitutive response of the rat liver to periportal injury induced by allyl alcohol. J Hepatol 31:497-507
Yin, L; Ghebranious, N; Chakraborty, S et al. (1998) Control of mouse hepatocyte proliferation and ploidy by p53 and p53ser246 mutation in vivo. Hepatology 27:73-80
Ghebranious, N; Sell, S (1998) Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice. Hepatology 27:383-91
Ghebranious, N; Sell, S (1998) The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice. Hepatology 27:967-73
Lee, J H; Rim, H J; Sell, S (1997) Heterogeneity of the ""oval-cell"" response in the hamster liver during cholangiocarcinogenesis following Clonorchis sinensis infection and dimethylnitrosamine treatment. J Hepatol 26:1313-23
Sell, S (1997) Electron microscopic identification of putative liver stem cells and intermediate hepatocytes following periportal necrosis induced in rats by allyl alcohol. Stem Cells 15:378-85
Yavorkovsky, L; Lai, E; Ilic, Z et al. (1995) Participation of small intraportal stem cells in the restitutive response of the liver to periportal necrosis induced by allyl alcohol. Hepatology 21:1702-12
Ghebranious, N; Knoll, B J; Wu, H et al. (1995) Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. Mol Carcinog 13:104-11