Abstract.Hepatoblastomas from B6C3F1 and BALB/c mice were examined by light and electron microscopy and by immunohistochemical reactions for alpha-fetoprotein, keratin, and vimentin. Tumors occurred in one group of a chronic bioassay for the interaction of diet, genetic strain, and the carcinogen, 2-acetylaminofluorene. Tumors had several populations (including epithelial and mesenchymal cells) in various stages of differentiation. Neoplastic epithelial cells had features of embryonal hepatocytes, such as sparse cytoplasmic organelles, absence of glycogen, abundant free ribosomes, occasional bile canaliculi, and peroxisome-like dense bodies. Embryonal fibroblast-like cells had pleomorphic and folded nuclei with prominent perinuclear chromatin and dispersed cytoplasmic organelles. Fibroblast-like cells were surrounded by bundles of collagen fibrils. Intermediate or transitional types of cells were seen. No tumor cells were immunoreactive for mouse alpha-fetoprotein (AFP) antibody, unlike those in hepatocellular adenomas or carcinomas. Epithelial and mesenchymal tumor cells contained intermediate filaments throughout the cytoplasm; some of these cells stained for keratin but not for vimentin. These findings suggest that mouse hepatoblastomas are derived from bipotential liver blastema cells and are composed of a mixture of several cell populations.Hepatoblastomas occur spontaneously and have been induced by chemical treatment in several strains of Distinctive histological features of these tumors, described by Turusov and colleagues in 1 973,42 included tumors diagnosed previously as hepatoblast~mas,~O poorly differentiated cholangiocarcinomas,29 cholangi~ma,~~ and an unusual tumor.4 We are not aware ofreports of hepatoblastomas in mice since 1973, except a case with squamous differentiati~n~~ and N-nitrosodiethylamine-induced hepatobla~tomas.~~ The existence of mouse hepatoblastoma in aged animals is still controversial, and its cell of origin is obs~u r e .~,~~The present study defines the detailed morphologic characteristics of this tumor by histological and ultrastructural observations together with immunohistochemistry for alpha-fetoprotein (AFT), keratin, and vimentin. Materials and Methods AnimalsMice used were part of a study conducted at the National Center for Toxicological Research (NCTR) to compare incStCrlfC3H/Nctr), raised at the NCTR. Diets were NIH-07 and AIN-76A, fed ad libitum. The carcinogen was 2-acetylaminofluorene (2-AAF) incorporated in the diets (Table 1). The study included 96 mice of each sex and strain at each dose group. Design for the AIN diet-and the NIH diet-fed groups were identical (Table 1). Animals were lulled after 24 months or when they became moribund by exsanguination under ether anesthesia.

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Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.