The final version of the international harmonized nomenclature for proliferative lesions in rats was issued on June 21, 2000. The recommended nomenclature for proliferative lesions in the liver includes focus of cellular alteration, regenerative hepatocellular hyperplasia, cholangiofibrosis, cholangiofibroma, oval cell hyperplasia, hepatocellular adenoma, hepatocellular carcinoma, bile duct hyperplasia, cholangioma, cholangiocarcinoma, hepatocholangiocellular adenoma, and hepatocholangiocellular carcinoma. Foci of cellular alteration are further classified into the following phenotypes: amphophilic, diffusely basophilic, tigroid basophilic, clear cell, eosinophilic, and mixed (basophilic/eosinophilic). Hepatocellular carcinomas are divided into 3 types based on their growth patterns: acinar, solid, and trabecular. In consideration of this international harmonized nomenclature, the current classification, terminology, and diagnostic criteria for prolifrative lesions in the liver of rats recommended by the Japanese Society of Toxicologic Pathology (JSTP) were reviewed by a Working Group of the JSTP. The hepatic proliferative lesions reviewed by the present Working Group included lesions of hepatocellular, cholangiocellular, mixed hepatocholangiocellular, sinusoidal, and hemangioendothelial origins. Any comments and questions on these lesions were discussed among pathologists in the Working Group and the results of discussions were presented at the 1st seminar on the continuing education program of the JSTP in November 2000.

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The immunostimulatory α-galactosylceramide, KRN 7000 or (2S, 3S, 4R)-1-0-(α-D-galactopyranosyl)-2-(N-hexacosnoylamino)-1,3,4-octadecatrienol, might be anticipated to have antitumor activity in vivo apart from any direct toxicity to cancer cells. We investigated inhibition of mouse bladder carcinogenesis by intravesically instillated KRN 7000. C57BL/6 mice were divided into 4 groups; all first receiving the carcinogen 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in drinking water for 8 weeks. Next, groups 1 and 2, respectively were administered 10 and 0.1 μg/kg of KRN 7000 intravesically once weekly for 17 weeks. Group 3 received only 0.3 ml of saline (vehicle control). Group 4 did not undergo bladder catheterization. By histologic examination at 26 weeks, the incidence of bladder carcinoma of all types tended to be higher in group 1 than in group 3, but without significance. The incidence of bladder carcinoma in group 4, (no catheterization), was similar to that in group 1. Only one precancerous lesion (papillary or nodular dysplasia) was seen in each of groups 3 and 4. Thus vesical instillation of KRN 7000 did not inhibit bladder carcinogenesis in mice, exposed to the carcinogen studied.

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2,6-Dimethylaniline (DMA) is known as a major metabolite of xylazine, α₂-adrenergic agonist used as a tranquilizer for domestic animals, and has been reported to have a carcinogenic potential to the nasal cavity in rats as well as a nasal tumor pomoting effect in rats. In order to examine whether DMA has any tumor modifying effect in the other respiratory organs, transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) that are highly susceptible to genotoxic carcinogens were given diet containing 0 or 3000 ppm DMA for 26 weeks or 0 or 2000 ppm DMA for 53 weeks after initiation with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Their non-transgenic CB6F1 littermates (non-Tg mice) were also treated in the same manner. No significant difference in the incidence/multiplicity of pulmonary proliferative lesions was observed between the groups treated with NNK alone and NNK plus DMA. These results suggest that DMA has no tumor modifying effect in pulmonary proliferative lesions induced in rasH2 and non-Tg mice.

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The relationship between gastric neoplasia and intestinal metaplasia, a process whose incidence increases with age, remains controversial. In the present experiment, we therefore investigated induction of both intestinal metaplasia and gastric cancers in the Senescence-accelerated mouse (SAMP3/Aicc) treated with N-methyl-N-nitrosourea (MNU). Seven-week-old animals of both sexes received the carcinogen in their drinking water at 120 or 60 ppm on alternative weeks for 10 weeks, or continuously at 30 ppm for the same period, then maintained without further treatment until sacrificed at week 50. The incidences of adenocarcinomas in the 120, 60, and 30 ppm MNU treated and control groups were 6/10 (60%), 5/16 (31.3%), 1/17 (5.9%), and 0/6 (0%) in males, and 2/7 (28.6%), 3/13 (23.1%), 1/6 (16.7%), and 0/9 (0%) in females, respectively. All neoplasms were of well-differentiated type, mainly consisting of gastric epithelial type cells. With immuno- and enzyme-histochemistry, intestinal alkaline phosphatase (I-ALP) positive intestinal absorptive cell-like elements were observed in regions of hyperplasia, adenomas, and adenocarcinomas of MNU treated mice, but no phenotypic expression of goblet or Paneth cells was found. In the control mice, gastric mucosa showed no intestinal epithelium phenotype. Since the degree of appearance of I-ALP positive cells in the lesions in SAMP3/Aicc mice was not different from that found for six other strains mice in our previous work, the results suggest that Senescence-acceleration may not influence intestinalization in the gastric mucosa or induction of gastric carcinomas.

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In order to investigate the nasal carcinogenic potential and nasal tumor modifying effects of 2,6-dimethylaniline (DMA), a metabolite of xylazine which is used for food-producing animals, male transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) were given diet containing 0 or 2000 ppm DMA for 51 weeks after initiation with/without 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Their non-transgenic CB6F1 littermates (non-Tg mice) were also treated in the same manner. Histopathologically, in rasH2 mice, the incidences of inflammations, respiratory metaplasias of the olfactory epithelium, and hyperplasias of the respiratory epithelium in the NNK+DMA group significantly increased as compared with those in the NNK alone group. In both rasH2 mice and non-Tg mice, proliferative Bowman’s glands were induced in the NNK alone, DMA alone, and NNK+DMA groups. The value for PCNA-positive index of proliferative Bowman’s glands in the NNK+DMA group of rasH2 mice significantly increased as compared with the NNK alone case. In rasH2 mice, the incidence of adenomas (33%) in the NNK+DMA group that might be derived from proliferative Bowman’s glands was slightly, but not significantly, higher than that in the NNK alone group. These results suggest that DMA promotes the development of nasal proliferative lesions in rasH2 mice.

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The effects of exogenous growth hormone (GH)-treatment on the development and regeneration of CCl₄-induced acute hepatic injury were examined in GH-deficient Mini rats. Alanin aminotransferase (ALT) and asparate aminotransferase (AST) activities increased significantly at 24 and 48 hours (h) after CCl₄-administration in both GH-treated and non treated groups, and they tended to be suppressed by GH-treatment. The expression level of insulin-like growth factor (IGF)-1 mRNA was higher in GH (+) CCl₄ (+) group than in GH (-) CCl₄ (+) group, especially at 72 h, and that of hepatocyte growth factor (HGF) mRNA was also higher in some points in the former group. Histologically, degenerative changes of hepatocytes observed at 24 and 48 h was less severe in GH (+) CCl₄ (+) group than in GH (-) CCl₄ (+) group. At 72 h, depositions of reticular fibers and extracellular matrix materials were less severe and the number of desmin- or α-SMA-positive cells was larger in GH (-) CCl₄ (+) group than in GH (+) CCl₄ (+) group. Proliferating cell nuclear antigen (PCNA)-labeling index of centrilobular hepatocytes increased at 48 h in both GH (+) CCl₄ (+) and GH (-) CCl₄ (+) groups, and it returned to the control level at 72 h in the former group while that in the latter group showed still higher level at 72 h. In this study, it was shown that CCl₄-induced acute liver injury in Mini rats can be restored by exogenous GH-treatment, and upregulation of IGF-1 and HGF mRNAs may be involved in this phenomenon.

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Pregnant Wistar rats on day 13 of gestation were treated with T-2 toxin at a single oral dose of 2 mg/kg. Rats were sacrificed at 24 and 48 hours after treatment (HAT), and the dams, placenta and fetuses were subjected to histopathological examination. In the dams treated with T-2 toxin, single cell necrosis was observed in the thymus, spleen, liver, stomach, intestines, salivary glands and pancreas. In the liver, fatty change was also observed. In one dam at 24 HAT, hemorrhage from the vagina was observed macroscopically, and hemorrhage in the placenta and single cell necrosis of cytotrophoblasts were observed microscopically. In the fetuses, increase of single cell necrosis was observed in the central nervous system at 24 HAT. At 48 HAT, single cell necrosis of hematopoietic cells and hepatocytes was also increased in the liver. These results indicate that T-2 toxin may induce changes with similar histopathological nature in dam’s organs, placentae and fetuses. These results also suggest that changes observed in the fetuses are caused by the direct effect of T-2 toxin.

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A total of 30 male Sprague-Dawley rats were treated orally with thiamphenicol (TAP) at 200 mg/kg/day for up to 4 weeks followed by 10 weeks recovery. At each week of treatment, 5 of them were examined weights of the testis and accessory genital glands, histology, staging analysis, and measurements of serum luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone (TES). At weeks 3 and 10 of recovery, 5 of them were quantified sperm counts and motility in addition to examinations of organ weights and histology. Cell proliferation activity was assessed at week 10 of recovery. Another group of 10 animals was provided as the vehicle control and examined the same parameters as mentioned above at week 4 of treatment or at week 10 of recovery. Weights of the seminal vesicles and prostate were significantly decreased during the treatment but showed a remarkable recovery after cessation of dosing. The testicular weights decreased rather mildly during the treatment but kept decreasing during the recovery period. In histology, damage of germ cells included apoptosis of germ cells, frequent occurrence of giant cells, and vacuolar spaces in the seminiferous tubules. In staging analysis, the first decreased indices were observed in spermatogonia (type B spermatogonia) in stage V and preleptotene spermatocytes in stage VII at week 2 of treatment. During recovery, an intact seminiferous tubule was seen neighboring to the other one showing “Sertoli only syndrome”. Cell proliferation activity was preserved in isolated cells on the basement membrane of “Sertoli only syndrome” seminiferous tubules. Considerable recovery was observed in sperm counts and motility. Serum TES and LH were decreased at week 4 of treatment but no effects on FSH. It is most likely that Sertoli cells are the primary target in TAP toxicity.

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We encountered with a case of spontaneously occurring malignant cystic schwannoma on the intracranial trigeminal nerve in a rat (32-week-old male Crj:Wistar). The tumor was intermixtures of the solid and cystic areas. The solid area was densely cellular, and pleomorphic spindle-shaped cells with elongated bizarre nuclei, and mitoses were present. The cystic area was less cellular, and cells with less cytoplasm were sporadically present in the area. Morphologically and immunohistochemically (staining with S-100), the solid and cystic areas were considered typical Antoni type A and B, respectively. Taken together, the results indicate that the tumor is a spontaneous malignant cystic schwannoma. In this connection, most cells lining the cysts were positive for S-100 and negative for Factor VIII, while HE staining showed that degenerative vessels were absent in the tumor. Therefore, in this case, we assumed that the origin of the cysts was not from the vessel but from the tumor per se.

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In order to investigate the age group which shows constant hepatocellular proliferation rates in normal male Wistar Hannover GALAS juvenile rats, cell proliferation in the left lateral, the right lateral, and the right medial lobes of the liver was evaluated by BrdU labeling index (LI%) at 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of age. LI% was significantly increased from 4 to 7 weeks of age and lower rate values were shown constantly from 8 to 16 weeks of age. In addition, there was no clear interlobular difference in LI% of the liver in rats of any age.

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