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Synergistic Hepatocarcinogenic Effect of Hepadnaviral Infection and Dietary Aflatoxin B₁ in Woodchucks

Abteilung Cytopathologie [P. B., N. I. K., H. J. H., S. R., I. T.], Zentrales Tierlabor [M. M., U. Z.], Abteilung Biostatistik [A. K-S.], and Abteilung Onkologische Diagnostik und Therapie [U. H.], Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, and Institut für Virologie der Universität Essen, 45147 Essen [M. E., T. T., M. R.], Germany

Interactive hepadnaviral and chemical hepatocarcinogenesis was studied in woodchucks inoculated as newborns with woodchuck hepatitis virus (WHV), which is closely related to the human hepatitis B virus. When the woodchucks reached 12 months of age, aflatoxin B₁ (AFB₁) was administered in the diet at dose levels of 40 µg/kg body weight/day for 4 months and subsequently 20 µg/kg body weight/day (5 days/week) for lifetime. WHV DNA was demonstrated by Southern blot hybridization in the serum and by PCR in the serum and/or liver tissue. The histo- and cytomorphology of the liver were investigated by light and electron microscopy. WHV carriers with and without AFB₁ treatment developed a high incidence of preneoplastic foci of altered hepatocytes, hepatocellular adenomas, and hepatocellular carcinomas that appeared 6–26 months after the beginning of the combination experiment. Administration of AFB₁ to WHV carriers resulted in a significantly earlier appearance of hepatocellular neoplasms and a higher incidence of hepatocellular carcinomas compared to WHV carriers not treated with AFB₁. Neither hepatocellular adenomas nor carcinomas (but preneoplastic foci of altered hepatocytes) were detected in woodchucks receiving AFB₁ alone, and no preneoplastic or neoplastic lesions were found in untreated controls. These results provide conclusive evidence of a synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary AFB₁. Except for the frequent presence of ground glass cells containing surface antigen filaments in the infected woodchucks, the phenotype of preneoplastic foci of altered hepatocytes was similar in WHV carriers with and without exposure to AFB₁ and in animals treated with AFB₁ alone. Clear cell foci excessively storing glycogen and/or fat, amphophilic cell foci crowded with mitochondria and peroxisomes, and mixed cell foci composed of various cell types including basophilic cells rich in ribosomes predominated. The cellular phenotype in neoplastic lesions varied from clear, amphophilic, and mixed cell populations in highly differentiated adenomas and carcinomas to basophilic cell populations prevailing in poorly differentiated carcinomas. The striking similarities in altered cellular phenotypes of preneoplastic hepatic foci emerging after both hepadnaviral infection and exposure to AFB₁ suggest closely related underlying molecular mechanisms that may be mainly responsible for the synergistic hepatocarcinogenic effect of these oncogenic agents.

¹ To whom requests for reprints should be addressed, at Abteilung für Cytopathologie (0310), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

Received 4/17/95. Accepted 6/14/95.

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