It has been demonstrated that the Donryu rat is a high incidence strain for spontaneous development of endometrial adenocarcinomas, associated with a hormonal imbalance. This provides a good model for endometrial adenocarcinoma development in women. An elevated sensitivity to induction of such tumors in this rat strain by a single intra-uterine administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) has also been shown. Endometrial adenocarcinomas can similarly be induced in CD-1 mice by an intra-uterine administration of N-ethyl-N-nitrosourea (ENU) and subcutaneous implantation of 17β-estradiol pellets. These animal systems have allowed two-stage uterine carcinogenicity studies in rodents. In this paper, spontaneous occurrence of uterine tumors, uterine carcinogenesis by chemicals and/or hormones and the influence of several factors on occurrence of uterine tumors in rodents are reviewed and discussed, with the main focus on our own present data.

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Spontaneous invasive pituitary carcinoma of F344 rats used in a 2-year carcinogenicity study were examined histopathologically and immunohistochemically. A modified trimming procedure was devised to increase the detection rate of invasive tumors. The pituitary was dissected together with the sphenoid bone and surrounding tissues, and sagittal or transverse sections were made. The incidence of invasive pituitary tumors was 8.4% for males and 14.8% for females under these preparation methods. The neoplastic cells invaded the capsule, sphenoid bone, surrounding veins, pars intermedia and pars nervosa, peripheral nerve, meninges, and brain. In most of the cases, neoplastic cells infiltrated into the posterior portion of the pituitary capsule. From these observations, the tumor was diagnosed as carcinoma. The incidence of carcinoma invasion into the sphenoid bone was higher in males than in females. Similarly, the proliferating cell nuclear antigen (PCNA) labeling index of carcinomas in males was significantly higher than in females. Almost all carcinomas showed positive cytoplasmic reaction for prolactin (PRL) by immunohistochemical examination. Extra-cranial metastases were not found in these carcinomas. The present study demonstrates that histopathological examination of the pituitary tumor section including the surrounding tissues is crucial for making an actual diagnosis of neoplasm, and that spontaneous pituitary carcinomas in the rat resemble invasive pituitary tumor in humans.

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We investigated the possible renal protective effect of KW-3902 (8-(noradamantan-3-yl)-1 ,3-dipropyl-xanthine), a novel adenosine A₁-receptor antagonist, against the nephropathy induced by repeated administration of cisplatin (2.5 mg/kg, i.v., once weekly for 6 weeks) in rats. Repeated administration of cisplatin increased serum creatinine (S-CRE) and urea nitrogen (S-UN), and decreased creatinine clearance (CL.CRE) for 1 to 6 weeks. Administration of KW-3902 (0.01 and 0.1 mg/kg, i.v. once weekly for 6 weeks) 5 minutes before each cisplatin treatment significantly improved these changes. On the 5^th day after the final administration of cisplatin, KW-3902 significantly improved the increase in kidney weight and the decrease in reabsorption rate of water and sodium. Moreover, on the 5th day after the final administration of cisplatin, tubular lesions, such as tubular necrosis and cystic dilatation of tubules were diffusely observed in the renal cortex in the cisplatin administered group. KW-3902 tended to improve these lesions. This study suggests that pretreatment of KW-3902 could protect against renal lesions caused by repeated administration of cisplatin, which is similar to clinical therapy schedule.

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Groups of 12 male Sprague-Dawley rats received oral treatment with thiamphenicol (TAP) at a dose of 0, 100, or 200 mg/kg/day for 4 weeks and, then, 4 of each group were left untreated for further 13 weeks. After termination of treatment, they were mated with intact females to assess reproducitve potential, collected blood samples for measurement of serum hormones [luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone (TES)], necropsied, weighed the brain, pituitary, adrenals, testes, and accessory genital organs, and carried out histological examinations on the testis and epididymis including stage analysis of the seminiferous tubules. After the withdrawal period, histological observations on these organs were also conducted in all survivors. Retarded weight gain and decreases in weight of organs (organ /brain weight ratio) except adrenals were remarkably evident in rats at 200 mg/kg/day. Reproductive performance was successful in all treated groups except 2 males at 200 mg/kg/day which showed abnormal sperms in their morphology and distribution in the cauda epididymidis. Histological observations in rats at 200 mg/kg/day disclosed a variety of regressive changes of spermatocytes and spermatids including apoptosis, dissociation of cell arrangement, and frequent giant cell formation, suggesting that the primary target of TAP is those germ cells or Sertoli cells. Stage analysis of the seminiferous tubules of the testis showed decreased indices of all types of germ cells in rats at 100 mg/kg/day which manifested no particular changes in routine histological observations, indicating significance and high sensitivity of this analysis in assessment of testicular toxicity by chemicals. Serum levels of LH and TES were decreased in rats at 200 mg/kg/day but not changed at 100 mg/kg/day. After the withdrawal period, all testes from rats at 200 mg/kg/day showed so called “Sertoli only syndrome”. The present results may suggest that the role of Sertoli cells should be more highlighted in the consideration of mechanism of testicular toxicity of TAP.

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Male Sprague-Dawley rats were orally dosed with 10 mg 7, 12-dimethylbenz(a)anthracene 3 or 5 times at 14-day intervals starting from 28 days of age. The male rats were treated with various hormonal treatments such as castration and/or injections (3 times/week) of various doses of 17β-estradiol or progesterone, 14 days after the last administration of 7, 12-dimethylbenz(a)anthracene. Extreme secretion in the wide lumina of the acini of the mammary glands was observed in rats given injections at high doses (0.1 mg and 1 mg) of 17β-estradiol. However, there was little lumina of acini without secretion in developed mammary glands in rats given injections of progesterone. This feature of the mammary glands suggests increased levels of progesterone and estrogens in rats given injections of progesterone because of the conversion of progesterone to estrogen. Number of rats with carcinoma and number of carcinoma per rat increased extremely and slightly in rats given injections of 0.01 mg 17β-estradiol or injections of 4 mg progesterone and in rats given injections of high doses (0.1 mg and 1 mg) of 17β-estradiol, respectively. These results indicate that suitable doses of estrogen, particularly 0.01 mg 17β-estradiol promote the progression of male mammary carcinogenesis. In rats given injections of high doses (0.1 mg and 1 mg) of 17β-estradiol, the number of carcinomas with squamous metaplasia increased significantly, and the number of estrogen receptor-positive carcinomas decreased extremely when cells with nuclei stained by immunohistochemical methods were interpreted as positive cells, and a tumor with 20% of positive cells was considered estrogen receptor-positive.

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Seven-week-old male specific pathogen-free Mongolian gerbils (MGS/Sea) were orally inoculated with 2 × 10⁸ colony-forming units per animal of a broth culture of Helicobacter pylori (H. pylori) ATCC 43504. Histopathological examination of their stomachs after 6 weeks of post inoculation revealed gastritis with hemorrhage, inflammatory cell infiltration, superficial erosion, mucosal thickening, and lymph follicles, in the pyloric mucosa and the fundic mucosa near the transitional zone. In addition, loss of fundic glands and appearance of hyperplastic epithelium with pseudopyloric glands containing paradoxical concanavalin A reactive mucins were evident in the fundic mucosa near the transitional zone. H. pylori bacteria were detected in the surface mucous gel layer lining inflamed mucosa or in the foveolar pits of the same regions. Galactose oxidase-cold thionine Schiff reactive mucins in the surface mucous cells were decreased. BrdU-labeled mucosal epithelial cells were markedly increased, and the generative cell zone was expanded. These features resemble human gastritis associated with H. pylori.

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