The objective of the proposed study is to develop a new animal model for dietary modulation of chemical and viral hepatitis-related primary hepatocellular carcinoma (PHC). Previous work in this laboratory has resulted in establishment of an experimental colony of woodchucks for the study of woodchuck hepatitis virus (WHV), a model for hepatitis B virus and related PHC. Chemically-induced PHC can be promoted in the rat by a lipotrope deficient diet.
The specific aims of this proposal are to determine if woodchucks will develop a hepatopathy in response to lipotrope deficient diets, and to determine if a lipotrope deficient diet will enhance expression of two oncodevelopmental gene products, Alpha-fetoprotein (AFP) and Gamma-Glutamyl transferase (GGT) in woodchucks exposed to aflatoin B1 or experimentally infected with WHV. In Study I, juvenile woodchucks and weanling rats were fed purified diets containing 20% soy protein and 5 or 15% fat with or without supplemental choline, methionine, folic acid, and vitamin B12. After 12 weeks, lipotrope deletion resulted in decreased growth in rats but not in woodchucks. Lipotrope depletion also resulted in elevated serum markers of hepatic injury and hepatic lipid accumulation in rats but not in woodchucks. In a study currently in progress, juvenile woodchucks and rats are being fed similar diets containing 10% or 20% protein, with or without the supplemental lipotropic factors, to determine if hepatopathy can be induced in the woodchuck with a lower level of dietary protein. After 3 weeks, there is no apparent difference in feed intake or weight gain between woodchucks fed supplemented and unsupplemented diets containing 20% protein, but at 10% protein there is an apparent decrease in feed intake and weight gain in the unsupplemented animals. It is anticipated, therefore, tha at 10% dietary protein young woodchucks will continue to grow adequately but will be more sensitive to lipotrope deficiency. In Study II, juvenile woodchucks will be treated with aflatoxin B1 and then fed 10% protein diets with or without the supplemental lipotrope factors. Serum levels of hepatic enzymes and AFP will be determined weekly. After 8 weeks, animals will be sacrificed for histopathological examination. This study will provide information needed to determine if chemically-induced and virus-related PHC respond similarly to post-initiation manipulations.
| Boyd, J N; Sherman, W K; Graham, E S et al. (1986) A comparison of the response of woodchucks and rats to variations in dietary lipotrope and protein content. J Nutr 116:2044-54 |
| Boyd, J N; Graham, E S; Graham, T C et al. (1985) A comparison of the response of woodchucks and rats to variations in dietary lipotrope and lipid content. J Nutr 115:1136-46 |
