The rapid induction of hyperplastic foci and adenomas of the Harderian gland by treatment with N-ethyl-N-nitrosourea (ENU) followed by administration of urethane (UR) was studied in male B₆C₃F₁ mice. The mice were initiated intraperitoneally with ENU (40, 60, or 90 mg/kg body wt) once a week for 3 weeks, and given drinking water containing UR (600 ppm) from 1 week after the last exposure to ENU. Light microscopic examination of the Harderian gland was conducted 20, 25, and 30 weeks after the first treatment of ENU to examine sequential changes induced by ENU and/or UR. In mice treated with 40 mg/kg body wt of ENU alone, hyperplastic foci and adenomas were found from week 25, but there were no significant differences in the development of these lesions compared with the vehicle control group until week 30. UR significantly increased the development of ENU (40 mg/kg)-induced hyperplastic foci and adenomas at weeks 25 and 30, respectively, compared with the ENU(40 mg/kg)-alone and UR-alone groups. Magnitudes of initiation by 60 and 90 mg/kg body wt of ENU were too strong to assess the promoting effect of UR. The present results indicate the usefulness of a two-stage system comprising ENU initiation as an in vivo short-term test for carcinogenetic modulators of the mouse Harderian gland.

View full abstract

Lymphoid neoplasms occurring in three different (C3H/He, C57BL/6, and B6C3F₁) strains of female mice after injection of the bone-seeking and alpha-emitting radionuclide, ²³⁹Pu citrate were compared by immunohistochemistry with those from the alkylating agent, N-methyl-N-nitrosourea (MNU)-injected mice. There was a variety of phenotypes from either T-cell to B-cell or histiocytic lineages in lymphoid neoplasms of the control, saline-injected mice. While strain differences were noted in the incidence and proportion, lymphoid neoplasms occurring early after ²³⁹Pu-injection were, however, characterized by B220⁺ phenotypes but negative for both T-cell-specific markers (Thy 1, CD3) and B-cell markers (CD5, CD19, CD79b) to be classified into pre-B-cell lymphomas derived from progenitor B-cells. In contrast, almost all the MNU-induced lymphomas were shown to be CD3⁺ or rarely Thy 1⁺ but B220 ^- T-lymphoblastic lymphomas. These results indicate differences in immunophenotypic expression but also might reflect different carcinogenic processes between chemical- and radiation-induced murine lymphomas.

View full abstract

We investigated the role of platelet aggregation on 2-bromoethylamine hydrobromide-induced renal papillary necrosis by using the rats treated with antiplatelet drug. Ten male Sprague-Dawley rats were orally administered with ticlopidine hydrochloride at 300 mg/kg/day for 5 successive days. Ten control rats were orally administered with the vehicle. Five rats in each group were injected intraperitoneally with 2-bromoethylamine hydrobromide at 100 mg/kg at 1 hr after the 3rd administration of ticlopidine or the vehicle and the remaining five rats in each group received saline in the same manner. On the last day of the treatment, blood was collected and ADP-induced platelet aggregation was measured. The kidneys were examined microscopically and the area of total renal papillary necrosis was measured. Platelet aggregation was significantly inhibited in ticlopidine-treated rats. However, renal papillary necrosis was observed in all rats injected with 2-bromoethylamine hydrobromide and there was no difference in the area of renal papillary necrosis between ticlopidine and vehicle-treated groups. These data showed that platelet aggregation did not contribute to the development of 2-bromoethylamine hydrobromide-induced renal papillary necrosis in rats.

View full abstract

Endometrial polyps from an 11-year-old female nulliparous mongrel cat are described. Pedunclated polypoid masses consisting mainly of endometrial glands and stroma protruded into the lumen of the uterus. The endometrial glands were distributed in a haphazard low density pattern, while the stromal cells were distributed with various consistency. Throughout the polyps, mild to moderate proliferation of the connective tissue with admixed small blood vessels was observed, with some of these blood vessels exhibiting thickened walls. The perivascular stromal element was also observed in polyps, as an incidental microscopic finding. It was characterized by multiple perivascular whorl-like arrangements of spindle shaped cells. They were immunohistochemically positive for alpha-smooth muscle actin, desmin, and S-100. These elements appear to originate from the endometrial stromal cells through smooth muscle metaplasia.

View full abstract

Osteosarcomas were found in the lung of a 62-week-old ICR female mouse having malignant systemic lymphoma. Macroscopically, the firm white nodules were located in all lobes of the lungs. Microscopically, the multiple nodules were mainly composed of irregularly shaped bone/osteoid tissues and pleomorphic or spindle-shaped osteoblast-like cells. Most of the tumors were well-differentiated and bone/osteoid tissues were abundant in the middle of the tumors, while at the tumor periphery and in a few nodules tumor cells were dominant with thin trabeculae of osteoid. These cells had hypochromatic, irregularly oval nuclei with a few small nucleoli, and, furthermore, anisokaryosis and mitosis were observed. The tumor cells were also present in the blood vessels and bronchial tubes. Immunohistochemically, the cells were positive for proliferating cell nuclear antigen (PCNA) and vimentin, but negative for cytokeratin and S-100 protein. Ultrastructurally, the cells had prominent nucleoli and dilated rough endoplasmic reticula, and collagen fibers with high electron density particles (hydroxy apatite) were observed around the cells. These findings suggest that the present tumors were malignant osteogenic neoplasms, and we diagnosed these tumors as osteosarcomas. Based on the multifocal growth pattern and presence in the blood vessels, in spite of the primary site being unknown, the tumors were considered to be metastatic.

View full abstract

A palpable abdominal mass was found in a 4-year-old female cynomolgus monkey (Macaca fascicularis) with chronic anorexia. Grossly, there were numerous coalescing firm nodular lesions, 1 to 5 cm, scattered in the omentum and mesentery. Histologically, there was prominent infiltrative growth of fibroblastic cells with a large amount of collagen fibers in the nodular lesions involving the intestinal tract. The morphological features of the lesion were similar to those of retroperitoneal fibromatosis (RF) in SRV-2-infected macaques, and also closely resembled those of peritoneal desmoid tumor in human. This macaque case is possibly the first reported case of RF in Japan.

View full abstract

The pathogenesis of sperm granulomas is very complicated, and leakage of spermatozoa into extraluminal tissues is regarded as a crucial event. We previously reported that sperm granulomas were frequently induced in the epididymides of pubertal rats by excessive dose of L-cysteine (L-Cys). Here, we compared the incidence of sperm granulomas between L-Cys-treated pubertal (6-week-old) and adult (11-week-old) rats by intraperitoneally injecting daily with L-Cys (800 mg/kg body weight) for 4 weeks. L-Cys-induced sperm granulomas were seen in 6 rats of 10 L-Cys-treated pubertal rats, whereas only one rat in 40 L-Cys-treated adult rats developed a sperm granuloma, indicating age-dependent decrease in the frequency. In L-Cys-treated pubertal rats, additionally, small ducts (indicative of immaturity), dilated ducts, and interstitial edema were frequently seen, but such findings were rarely present in L-Cys-treated adult rats. The accumulation of spermatozoa in epididymal ducts was often observed both in L-Cys-treated pubertal and adult rats. These findings indicated that the administration with a large amount of L-Cys might have disturbed the luminal microenvironments, with greater influence on pubertal rats than adult rats. Particularly, the findings, that the incidences of small ducts and sperm granulomas were high in L-Cys-treated pubertal rats and low in L-Cys-treated adult rats, suggested that the prerequisite for sperm granuloma formation might be associated mainly with the delayed maturation of epididymal ducts seen exclusively in pubertal rats due to excessive dose of L-Cys.

View full abstract

The prevalence of eosinophilic granulomatous pneumonia (EGP) is well known in Brown Norway (BN) rats. In this study, age-related changes in the incidence and severity of EGP in 4 to 20 weeks old BN rats were examined under two different housing conditions (isolator cages without woodchips and common cages with woodchips for bedding) in a SPF animal room in Charles River Japan Inc. A routine microbiological survey gave negative results to any specific pathogens tested. As a result of histopathological examination, there were no lung lesions observed at the age of 4 weeks. EGP developed at and after the age of 7 weeks, but the incidence and severity of EGP showed no age-related changes under both housing conditions. These findings suggest that EGP in BN rats may be a hypersensitivity response of strain-specific nature as reported by Albers and Clifford.

View full abstract