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 two sex-hormone related human tumors ,ie breast and prostate cancer. We are feeding Armenian hamsters various synthetic diets containing soy or casein protein and high or low fat content to determine if diet can effect the hepatic response to exogenous estrogen. 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 consistently influenced by the diet of the hamsters. When casein is used exclusively for protein in the diet, the toxic effect of estrogen on the liver is markedly diminished. When the fat content is increased, the effect of estrogen is further diminished, and the majority of animals actually show no effects from estrogen administration. 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. Serum amyloid p component(SAP) and C reactive protein(CRP)belong to a family of proteins called pentraxins and are most noteable because they are acute phase reactants. That is,in response to injury/infection, serum levels are markedly increased and this reponse is thought to help in the protection/repair of the host animal. SAP homologs in hamster, such as female protein(FP),or FP(SAP) are down regulated in an acute phase response. We have been measuring serum levels of SAP in mice and Syrian hamsters, because signs of inflammation have not been found in serum from animals affected with scrapie. However, we have detected increased levels of SAP in mice during clinical signs of scrapie. Also, when female hamsters develop signs of scrapie (after injection with scrapie brain),FP(SAP) levels decrease in females similar to an acute phase response. This SAP response in the first evidence for a systemic acute inflammatory response in scrapie and suggests that a serological change does occur in scrapie and in the TSE diseases. A serological test would be helpful for TSE diagnosis which at present requires a histological examination of affected tissue. We have also found that the female Syrian Hamster is more susceptible to scrapie than the male Syrian Hamster. This enhanced susceptibly may be related to the higher levels of SAP found in the female, because SAP is an integral component of amyloid and the scrapie-PrPRes deposits are amyloidotic in nature. In addition we have found two other mice strains in which SAP is preferentially expressed in females, and these female mice are more susceptible to scrapie than the male mice. There is a possible involvement of SAP in scrapie and the TSE diseases.
| Melby, P C; Chandrasekar, B; Zhao, W et al. (2001) The hamster as a model of human visceral leishmaniasis: progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response. J Immunol 166:1912-20 |
| Coe, J E; Race, R E; Ross, M J (2001) Serological evidence for an inflammatory response in murine scrapie. J Infect Dis 183:185-191 |
