The latent infection of canine herpes virus was investigated in laboratory beagles with no clinical abnormalities. In eight of twenty-three male dogs which were purchased from the same breeder at the age of six months, the pathogen was confirmed at the age of one year by immunological, histopathological or electron-microscopical examinations. The infected beagles seemed to be healthy in several clinical examinations including blood- and serum-biochemical analyses. The neutralizing titer of the canine herpes virus antibody test ranged from 64 to 128, compared to the undetectable titer in animals obtained from a different breeder and housed in the same conditions. Histopathological examinations revealed eosinophilic inclusion bodies in the cytoplasm of swollen or damaged epithelium of renal papillary ducts, papilla, and/or pelvis accompanied by chronic pelvic inflammation. The inclusion bodies showed positive reaction against anti-human herpes simplex virus antigen. Electronmicroscopically, these inclusion bodies consisted of numerous intracytoplasmic aggregates of virion. The virion particles were round to hexagonal, the envelope or capsid about 140 nm in diameter and arranged in a fine crystalline array. This evidence strongly suggests that the virions were excreted from the body by urination. Although these animals were housed in our laboratory for about half a year, the other beagles housed in separate cages in the same room were not infected by the virus. The results show the importance of preventative measures against latent canine herpes virus infection and maintenance of laboratory conditions to avoid this problem.

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To assess the morphological changes of the lacrimal gland after cholinergic suppression, we performed light- and transmission-electron microscopic examinations on the exorbital lacrimal glands in rats after intragastric intubation of atropine, a nonselective antimuscarinic compound with a high affinity for M3 muscarinic subtype receptors. In addition, areas of acinar cells were measured by an image processor. The weights of the lacrimal gland were decreased at hours 36 and 48 after atropine single administration at 250 mg/kg. Areas of acinar cells, measured by an image processor, were also decreased. Electron-microscopic examination demonstrated decreased number of secretory granules in the apical cytoplasm of acinar cells in all rats on days 7 and 28 of repeated atropine treatment. No changes were evident in other cytoplasmic organelles. Four- and even thirteen-week repeated administration studies revealed no progression in lacrimal acinar cell atrophy. The present findings demonstrate that an antimuscarinic compound that has high affinity for M3 muscarinic subtype receptors induces lacrimal gland acinar cell atrophy caused by a decrease in secretory granules, and that the repeated administration is not associated with any progression or any other changes.

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To assess the risk evaluation of endocrine disrupting chemicals with weak estrogenic or anti-estrogenic effects in mammals, the suitability of 28-day repeated dosing test and the strain difference were investigated in adult female rats. In the study, 60 and 250 (150) mg/kg/day of nonylphenol and 5 and 50 mg/kg/day of atrazine were dosed to female SD, F344, and Donryu rats for 28 days. Abnormal estrous cyclicity was observed in both groups of SD rats given nonylphenol, in the high-dose nonylphenol and atrazine F344 rats, and in both groups of Donryu rats receiving the test compounds. A slight tendency for increase in numbers of uterine BrdU-positive cells was observed in F344 rats given high-dose nonylphenol, and elevation was noted in one animal each which showed persistent estrus in the groups of Donryu rats given atrazine. Organ weight, necropsy and histopathological findings did not point to any effects of these chemicals on the endocrine or reproductive systems except for ovarian atrophy in the atrazine treated Donryu rats with persistent estrus. These results indicate that severe morphological effects might not be induced in female reproductive organs of adult rats by short-term exposure to these chemicals, unless very high doses are given. Vaginal smear may be the most sensitive parameter for detection of estrogenic or anti-estrogenic effects of chemicals, when normal cycling animals are used for the study.

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Rabit mutants with hypotrichosis were found in a colony of Japanese White strain (JW-NIBS) and descendants of the mutants have been successively produced. By genetic analyses, the hypotrichotic condition was inherited by a single autosomal recessive gene, symbolized as htr. The trunk of the htr rabbit did not grow hairs and was covered with a few, fine, soft and short hairs throughout life with the exception of wavy hairs around the nose and extremities. Histologic examination of the skin from htr rabbits revealed thickening of the epidermis, hyperplasia of the sebaceous gland, and dysplastic development of the large guard and small wool hairs. When immunostained with anti AE1 and AE3 antibodies, there were no significant differences in the keratin constituents of the skin between the htr rabbits and age-matched controls. While proliferating cell nuclear antigen (PCNA)-positive cells were numerous in the basal layer of epidermis, external root sheaths, and hair bulbs, apoptotic cells were also increased in the hair bulbs of htr rabbits. There were no significant differences in the number of T and B lymphocytes in the mesenteric lymph nodes between htr and control rabbits.

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The effect of a synthetic steroidal antiandrogen, chlormadinone acetate (CMA), on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Male beagle dogs (5-8 years old) were divided into four experimental groups. Group 1 consisted of untreated controls. Groups 2 to 4 received CMA 0.03, 0.1, and 0.3 mg/kg/day, p.o., respectively, for 6 months. In group 1, glandular hyperplasia of the prostate was clearly detected. The glandular epithelial cells showed uniformly intense nuclear staining for androgen receptor (AR). AR was also localized in the nuclei of the fibro-muscular stromal cells. Immunoreactivity of 5 alpha-reductase type I was positive in most glandular epithelial cells. The staining was positive in the cytoplasm but not in the nuclei. No fibro-muscular stromal cells were stained. In the glandular epithelial cells, the secretory granules were lined up along the apical plasma membrane, and exocytosis was frequently seen. In groups 2 to 4, CMA produced marked atrophy of the glandular epithelium. The interacinar fibro-muscular stroma was prominent. The intensity of the nuclear staining for AR in both epithelial and stromal cells was negative or very weak. Furthermore, the immunoreaction for 5 alpha-reductase type I in most glandular epithelial cells was negative or very weak. Ultrastructurally, the cytoplasm of the glandular epithelial cells was electron-lucent and contained relatively few, poorly developed organelles. In addition, the secretory granules were markedly decreased in both number and size. Furthermore, mitochondrial alterations such as swollen or disappeared mitochondrial cristae or decreased electron density of the matrix were frequently seen in the smooth muscle cells. These results indicate that the uptake of testosterone and/or its androgenic effect on the prostate may be suppressed by CMA. The decreased AR-immunostaining may be explained by the decrease in the number of AR and/or antibody binding sites for AR. The atrophy after treatment with CMA may be due to shrinkage of both glandular and stromal compartments in the prostate tissue.

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β-naphthoflavone (BNF) is a non-genotoxic, strong inducer of cytochrome P450 (CYP) 1A but not CYP 2B. In order to determine its liver tumor promotion potential, groups of male F344 rats were initiated with a single intraperitoneal injection of 200 mg/kg of diethylnitrosamine (DEN) and starting two weeks later, given 1% BNF (n=12) or non-supplemented diet (n=13) for 26 weeks. All animals were subjected to two-thirds partial hepatectomy at week 3. At sacrifice, absolute and relative liver weights in the DEN + BNF group showed statistically significant increase as compared to the DEN-alone group. The incidence of hepatocellular adenomas and numbers of such tumors and altered hepatocellular foci, positive for glutathione S-transferase placental form (GST-P), were also elevated. However, five animals given BNF alone without DEN initiation exhibited no focal hepatocellular lesions including GST-P positive foci. The numbers and areas of connexin 32 (Cx32)-positive spots per hepatocyte in centrilobular areas, and within altered hepatocellular foci and hepatocellular adenomas of the DEN + BNF group were significantly lower than those of the DEN-alone group. Immunohistochemically, CYP 1A1/2 was stained diffusely in the livers of the DEN + BNF group, but hepatocellular adenomas and some altered hepatocellular foci were generally negative. Proliferating cell nuclear antigen (PCNA) labeling indices of surrounding hepatocytes in the DEN + BNF group was about twice that of DEN-alone group, but the difference did not achive statistical significance. In the altered hepatocellular foci and adenomas of DEN + BNF group, the PCNA labeling indices were significantly higher than those of surrounding hepatocytes. These results indicate that BNF, a strong CYP 1A but not CYP 2B inducer, promote hepatocarcinogenesis initiated by DEN.

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A 10-month-old male beagle dog had a renal mesenchymal tumor. The tumor tissue invaded into the adjacent renal tissue in an open-finger-like pattern, and entangled normal glomeruli and tubules. In most parts, the tumor mass showed a myxoid pattern around blood vessels, and in other small parts, a fascicular pattern. The tumor cells were spindle or oval in shape and had a densely basophilic nucleus and scant pale cytoplasm. Immunohistologically, the tumor cells were mostly positive for S-100 and myoglobin, and partially positive for Factor VIII reactions. These findings suggest that the tumor cells have an ability to differentiate into several kinds of mesenchymal cells.

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A mucinous adenocarcinoma was found in the jejunum of an untreated male F344 rat of 126 weeks old. The neoplasm was primarily composed of cuboidal to columnar goblet cells that were arranged in a glandular form. Alcian blue-PAS staining revealed mucin in neoplastic cells and in the lumen. Paneth cells were found scattered among the goblet cells together with metaplastic cartilage and bone formation in the interstitium.

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A small intestinal mucin-secreting adenocarcinoma was found in a 78-week-old male Crj: CD (SD) IGS rat. The neoplasm was present in a portion of the ileum as a white soft mass. Histologically, it consisted of pleomorphic mucin-producing glands, multiple cysts of various sizes, and a well-developed dense fibrous tissue stroma. Chronic inflammatory reaction and osseous metaplasia were observed in the stroma. Ultrastructurally, the microvilli of the epithelium at the luminal surface contained core filaments, and often appeared more stubby and sparse than usual.

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