The long-term goal of this project is to understand the molecular mechanisms by which AFB leads to human hepatocellular carcinoma (HCC). Aflatoxin B1 (AFB) is an environmental toxin implicated in human liver cancer. Because species vary in their sensitivity to AFB-induced liver cancer, the ideal system in which to study human AFB hepatocarcinogenesis would utilize human hepatocytes. A transgenic mouse system has been developed in which it is possible to replace the original transgenic mouse liver with exogenour liver cells, including xenogeneic (rat) liver cells. The first objective of this proposal is to generate mice whose livers have been reconstituted with human hepatocytes. Deriving mice containing human hepatocytes would provide an unprecedented opportunity to study human hepatocellular biology in vivo, including AFB carcinogenesis. This objective will be accomplished by transplanting human liver cells into immunotolerant transgenic mice. The second objective of the proposal is to determine if AFB is sufficient to cause human HCC. Although there is epidemiological evidence to support a role for AFB in human HCC, it is not clear if AFB alone can cause HCC. To determine this, mice reconstituted with human liver cells will be exposed to AFB and their livers analyzed for the development of HCC. Accomplishment of these objectives will provide a model for a detailed examination of the molecular events involved in AFB hepatocarcinogenesis and a well-characterized experimental system in which to develop strategies aimed at preventing or reversing the development of AFB- induced cancer in human beings. In future studies the model will be employed to examine AFB's putative interaction with human hepatitis B virus in causing HCC.
