Our current studies are using the Armenian hamster because of its unusual susceptibility to hepatic cancer after estrogen administration. In this animal, estrogen by itself initiates carcinogenesis and few animal models are available to study this direct carcinogenic effect of sex hormone. Epidemiological studies have clearly shown that diet influences the incidence of human breast and prostate cancer, and pathogenesis of both of these tumors is dependent on sex hormones. The relative paucity of these tumors in Asian population may be explained by the lack of fat and/or the abundance of soy flour in the Asian diet. Soy is an abundant source for phytoestrogens that react with estrogen receptor and this could result in blocking or partial activation. Accordingly, we are feeding Armenian hamsters various synthetic diets containing soy protein or casein protein and also diets with high fat content. Corn oil or rape seed oil were used to make high fat diets containing 20% fat versus 5% fat in normal diets. There is some epidemiological evidence linking the use of rape seed oil for cooking with the high incidence of intrahepatic cholestasis of pregnancy in women in Chile and Sweden. For the estrogen challenge, we inject Zeranol, resorcylic acid lactone estrogen. It is a natural estrogen produced by Fusarium fungi and is a common contaminant in the human diet because it is produced by the fungi contaminating grains. Also, the growth promoting (anabolic) effects of Zeranol have led to its widespread use as a growth stimulant in meat production. Although Zeranol is known as a weak estrogen, in Armenian hamster it is effective in inducing acute icterus and followed by consistent tumor formation. After administration of Zeranol, the hepatobiliary dysfunction is quantified by measuring hyperbilirubinemia and liver enzymes (SGOT, SGPT) in serial plasma samples.It is clear at this time that the hepatic response to estrogen is definitely influenced by the diet of the hamsters. The standard laboratory chow uses protein from a variety of sources including fishmeal, alfalfa, land various grains. When casein is used exclusively for protein in the diet, the toxic effect of estrogen on the liver is diminished. If the fat content is increased (rapeseed oil or corn oil) the effect of estrogen is further diminished, and the majority of animals actually show no effects (that is, hyperbilirubinemia, increased transaminase levels, etc.) from the estrogen challenge. These studies indicate that diet does indeed play a role in the ability of hepatic estrogen receptor to mediate the effects of estrogen. At this time it is not known if this effect is mediated through expression of modulation of estrogen receptor or some other mechanism before or after estrogen receptor activation. These initial studies have focused on evaluating the dietary influence on acute toxic effects from estrogen. It is probable that diet will also protect these hamsters from hepatic cancer after chronic estrogen treatment, because previous data indicates a direct quantitative relationship between the acute toxic and chronic neoplastic phases. - Hormonal carcinogenesis, hepatocarcinogenesis, hamster, estrogen
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