P11: Megalocytic nodules in P53 heterozygous and wild-type mice exposed to Fumonisin B1

Abstract

This project was undertaken in order to validate the p53+/- mouse model as an alternative to the 2 year carcinogenicity test. Groups of 10 male mice, either heterozygote (Taconic, P53N5-T) or wild type (Taconic, P53N5-W), were fed AIN-76A diet containing the non-genotoxic carcinogen fumonisin B1 (FB1) at levels of 0, 5, 50 or 150 ppm for 6 months. At necropsy the livers of all mice showed a characteristic nodular appearance. Microscopic studies revealed more or less defined nodules of variable diameters consisting of megalocytic hepatocytes. These distinct cells occupied portions of single lobules and in various places extended into adjacent lobules. The megalocytes had large nuclei that were hyperchromatic. Their cytoplasm was intensely eosinophilic. Nodules were separated by dense, cellular regions composed of small, vacuolated hepatocytes with micronuclei. They were accompanied by numerous apoptotic bodies and oval cells. There was minimal fibrosis and stromal condensation. Minor Kupffer cell hyperplasia and modest, multifocal oncotic necrosis completed the picture. In the liver of high dose groups there were increased apoptotic and oncotic necrosis and increased numbers of altered foci and tumors (adenomas, cholangiomas) relative to the 0 ppm group. The megalocytic liver nodules were an unusual and unexpected result. These megalocytic cells are thought to be mitotically inhibited. The effects of FB1 were dose- but not strain-dependent and therefore unrelated to the status of the p53 gene.