In this comparative review, histomorphological features of common nonneoplastic and neoplastic hepatocyte lesions of rats and humans are examined using H&E-stained slides. The morphological similarities and differences of both neoplastic (hepatocellular carcinoma and hepatocellular adenoma) and presumptive preneoplastic lesions (large and small cell change in humans and foci of cellular alteration in rats) are presented and discussed. There are major similarities in the diagnostic features, growth patterns and behavior of both rat and human hepatocellular proliferative lesions and in the process of hepatocarcinogenesis. Further study of presumptive preneoplastic lesions in humans and rats should help to further define their role in progression to hepatocellular neoplasia in both species.

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A short-term 5-day nose-only cigarette smoke exposure study was conducted in Fisher 344 rats to identify smoke-induced tracheal protein changes. Groups of 10 male and female 5 week old rats were assigned to 1 of 4 exposure groups. Animals received filtered air, or 75, 200 or 400 mg total particulate matter (TPM)/m³ of diluted 3R4F Kentucky reference cigarette mainstream smoke. Exposures were conducted for 3 hrs/day, for 5 consecutive days. Tracheas from half the rats were processed for pathology, and tracheas from the other half of the rats frozen immediately for proteomics. We hypothesized that smoke will activate tracheal inflammatory, apoptotic, proliferative, and stress-induced pathways. Mucosal epithelial toxicity from the inhaled material was evidenced by cilia shortening and loss of tracheal mucosal epithelium in smoke-exposed animals. Mucosal thinning occurred in all smoke-exposed groups with hyperplastic reparative responses in the 200 and 400 mg TPM/m³ groups. Tracheal lysates from control vs. treated animals were screened for 800 proteins using antibody-based microarray technology and subsequently the most changed proteins evaluated by Western blot. Tracheal proteins expressed at high levels that were markedly increased or decreased by smoke exposure depended on dose and gender and included caspase 5, ERK 1/2 and p38. Signaling pathways common between the morphologic and protein changes were stress, apoptosis, cell cycle control, cell proliferation and survival. Changes in identified proteins affected by smoke exposure were associated with tracheal mucosal pathology, may induce functional tracheal changes, and could serve as early indicators of tracheal damage and associated disease.

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The purposes of the present study were to evaluate the hepatocarcinogenicity of concurrent treatment of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and diethylnitrosamine (DEN) in rats and to determine whether no effect levels of combinations of these two different structural categories of genotoxic hepatocarcinogens exist. Two 16-week rat hepatocarcinogenesis assays were performed using a total of 790 male F344 rats. In experiment 1, we evaluated the effects of concurrent treatment of a subcarcinogenic dose of DEN on rat hepatocarcinogenesis induced by various doses of MeIQx. In experiment 2, we determined hepatocarcinogenicities of combinations of MeIQx and DEN at subcarcinogenic doses, low carcinogenic doses and high carcinogenic doses. Quantitative analyses of glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, revealed that concurrent treatment with subcarcinogenic doses of DEN did not enhance MeIQx-induced rat hepatocarcinogenicity. We also found that concurrent treatment with combinations of subcarcinogenic doses of DEN and MeIQx was not hepatocarcinogenic, indicating that the combined effects of subcarcinogenic doses of DEN and MeIQx were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic effects. Synergetic effects were observed only in rats coadministered high carcinogenic doses of the 2 carcinogens. These results demonstrate the existence of no effect levels of combinations of these 2 genotoxic hepatocarcinogens, and provide new evidence supporting our idea that there is a threshold, at least a practical threshold, that should be considered when evaluating the risk of genotoxic carcinogens.

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Morphological and immunohistochemical examinations were carried out on the pancreas of a hyperglycemic 5-year-old male cynomolgus monkey. Body weight gradually decreased from 6 months before termination, accompanying a slight reduction in food consumption and anorexia for the last 2 days. The blood glucose level was markedly elevated when examined at termination. Histopathologically, in the exocrine pancreas, diffuse hyperplasia of centroacinar and intercalated duct cells and diffuse atrophy of acinar cells with sporadic apoptosis were observed, although most centroacinar and intercalated duct cells were proliferating cell nuclear antigen (PCNA)-positive in both the present case and age-matched control animals. In the endocrine pancreas, the islets tended to be hypertrophic, with an increase in insulin-positive cells in comparison with the age-matched control animals. PCNA-positive cells also tended to increase in the islets, although positive cells for phospho-histone H3, a marker for mitotic cells, were not detected in the endocrine and exocrine pancreas. Moreover, neither inflammation nor amyloidosis was noted in the islets. In conclusion, the present case probably suffered from early-stage type 2 diabetes mellitus, and it provides fundamental information concerning pancreatic histopathology under insulin-related derangement in monkeys.

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Spontaneous mammary adenocarcinoma was observed in a 12-week-old female SD rat. A movable mass in the right cervical region was found at 11 weeks of age, and the rat was sacrificed the following week. The mass was located in the vicinity of the right salivary gland and measured 38 mm × 26 mm × 16 mm in gross size. It was a firm whitish mass, with a cut surface that was also whitish in appearance. Histopathologically, neoplastic cells formed glandular structures that contained secreted eosinophilic material. Ultrastructurally, similar secreted material and lipid droplets were in the cytoplasm of the neoplastic cells. Immunohistochemically, the neoplastic cells were positive for cytokeratin 8, cytokeratin 18 and estrogen receptor α. Based on these findings, the tumor was diagnosed as a mammary gland adenocarcinoma, and we therefore conclude that this tumor type can occur spontaneously in female SD rats as young as 12 weeks of age.

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Lysophosphatidic acid (LPA) acts as a simple phospholipid that interacts with G protein-coupled transmembrane LPA receptors. Recently, it has been reported that each LPA receptor plays different biological roles in acquisition of the malignant property of tumor cells. In this study, to assess the involvement of LPA receptor-3 (LPA₃) in cell survival after treatment with anticancer drugs, we generated Lpar3-expressing FM3A-a3A9 cells from mouse mammary tumor FM3A cells and examined the cell survival rate after treatment with anticancer drugs compared with Lpar3-unexpressing cells. Cells were treated with 0.005 to 10 μM of cisplatin (CDDP) or doxorubicin (DOX) for 3 days. For the CDDP and DOX treatments, the cell survival rate of FM3A-a3A9 cells was significantly higher than that of Lpar3-unexpressing cells. The expression level of the Mdr1a gene in FM3A-a3A9 cells was higher than that of Lpar3-unexpressing cells, whereas no significant difference in multidrug resistance 1b (Mdr1b) and glutathione S-transferase mu1 (Gstm1) expressions was found. These results suggest that LPA₃ may enhance the cell survival rate after treatment with anticancer drugs in mouse mammary tumor cells, correlating with increased expression of the Mdr1 gene.

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Maxillary gingivae from male and female Crl:CD(SD) rats at 12, 16, 21, and 34 weeks of age were examined histologically. The incidence of gingivitis was approximately 40%, with no age or sex predilection, and was most frequent between the first and second molar. Lesions were characterized by acute focal neutrophilic infiltration into the gingival mucosa, occasionally with inflammatory exudate. In severe cases, inflammation extended to the periodontal ligament with abscess formation, and adjacent alveolar bone destruction/resorption. The most characteristic finding was the presence of hair shafts associated with the lesion, which was observed in approximately 80% of the rats with gingivitis. These findings suggest that molar gingivitis occurs in rats from an early age and persists thereafter, and that the main cause of gingivitis in rats is hair penetration into the gingiva. It would be prudent to keep these background lesions in mind as potential modifiers in toxicity studies.

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