Lung cancer is one of the most common cancers in the world, and the incidence of lung cancer is increasing. Therefore, it is particularly important to detect carcinogenic or tumor promoting substances of lung carcinogenesis in our environment, so that such harmful chemicals can be eliminated from our environment. Furthermore, detection of chemopreventive agents of lung carcinogenesis is also important to reduce our risk of lung cancer. It is necessary to establish reliable in vivo animal models of lung carcinogenesis for that purpose. The A/J mouse is a mouse strain sensitive to lung carcinogens, and also develops spontaneous lung tumors without any chemical treatment. In our department, we have demonstrated that a treatment of 4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone (NNK), a tobacco specific nitrosamine, or 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (MeIQx), a heterocyclic amine, induced lung tumors in the female A/J mouse in 16 and 32 weeks. The lung tumors developed in the A/J mouse are histopathologically classified as adenocarcinomas, adenomas, and alveolar cell hyperplasias. Some of these types of lung cancer are similar to those of human lung cancer. We also investigated the chemopreventive effects of bovine LF (bLF) on different phases of NNK-induced lung tumorigenesis in A/J mice. The A/J mouse is very useful mouse strain as a reliable in vivo model, which can be used for detecting chemopreventive agents of lung carcinogenesis.

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The pigs have been a well-recognized experimental animal in biomedical research for many years. Minipigs particularly have gained in massive importance in biomedical research over the last few years. Pigs are increasingly being used as an alternative non-rodent animal species to the dog or monkey in toxicology because of the morphological and physiological similarities between porcine and human organs, especially the skin, cardiovascular system, gastrointestinal tract, and the urinary system. Accumulating data indicate that the minipig can be used for all routes of administration and is preferable to the dog or monkey in many cases. The advantages of the minipig compared to the domestic pig are its smaller size, even at full maturity, slower growth during studies, ease of handling, and controlled genotype as well as microbiologically obvious characteristics. Minipigs also have an advantage over traditional non-rodent animals because of increasing ethical concerns about the use of them in experiments. Reservoir of information from studies using minipigs is the keystone for the future diffusion of them as a good alternative to the non-rodent animals traditionally used in toxicology.

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The present study investigated the dose-response relationship in testicular toxicology of pubescent (7-) and adult (17-week-old) Sprague-Dawley rats whose dams had been injected (i.g.) with 25 pg, 2.5 ng, 250 ng, or 7.5 μg of 3,3',4,4',5-pentachlorobiphenyl (PCB126)/kg or the vehicle on days 13 to 19 post-conception. Rat at 7 and 17 weeks of age of the 7.5 μg group and at 7 weeks of age of the 250 ng group showed an increase in the percentage of seminiferous tubules at Stages VII-VIII. At 7 and 17 weeks of age, rats of the 7.5 μg group showed a decrease in preleptotene spermatocytes with spermatids at all Stages, while animals of the 250 ng group also showed a decrease in preleptotene spermatocytes, but with round spermatids increasing at Stages VI-VII and elongated spermatids decreasing at Stage VIII. At 7 weeks of age, rats of the 2.5 ng group showed an increase in round spermatids at Stages VI-VII. The formation of spermatogenic cells in rats of the 25 pg group was similar to that seen in the vehicle group. The number of Sertoli cells and cauda epididymal sperms in rats of the PCB126 groups were similar to those of the vehicle group. Prenatal PCB126 exposure induced dose-related defective spermatogenesis. A high dose of PCB126 affected the development of spermatogonia and spermatids in puberty and adulthood, while a low dose affected the conversion of spermatids at puberty, although this was recovered in adulthood. Because the serum testosterone levels were similar in the PCB126 and vehicle group rats in puberty and adulthood, a direct endocrine cause for the observed effects was unlikely.

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The current experiment was conducted to evaluate whether prolongation of infusion time is useful for the amelioration of nedaplatin (NDP)-induced nephrotoxicity. Eight-week-old male rats were treated with 12 mg/kg NDP with the following dosing protocols, bolus injection, 1- or 4-hour continuous infusions (1hIF or 4hIF, respectively), and sacrificed 3 days after dosing. Urinary parameters were monitored on the day of the sacrifice, and the kidneys and femurs were removed for histopathological examination and bone marrow analysis. In the Bolus-NDP group, urine pH and specific gravity were decreased compared with the corresponding control group and glucosuria and occult blood were detected, while no abnormalities were noted in these urine parameters in the 4hIF-NDP group. Histopathological examination revealed slight to moderate renal lesions, such as single cell and/or focal necrosis in the epithelium of cortical tubules and collecting ducts in the renal papilla in the Bolus-NDP group. In the 1hIF- and 4hIF-NDP groups, there were clear reductions in the severity of renal tubular damage compared with the Bolus-NDP group, and the severity of renal tubular damage tended to reduce with increased infusion time. A TUNEL assay revealed that the numbers of TUNEL-positive cells in the 1hIF- and 4hIF-NDP groups were significantly lower than that in the Bolus-NDP group. There was a significant decrease in the number of TUNEL-positive cells in the 4hIF-NDP group compared with that in the 1hIF-NDP group. However, prolongation of the infusion time had no clear effect on the myelotoxicity of NDP. These results provide new evidence that prolongation of the infusion time is effective at minimizing the nephrotoxicity of NDP.

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The present study was performed to investigate the modifying effects of arctiin, a plant lignan isolated from Arctium lappa (burdock) seeds, on uterine carcinogenesis induced by N-ethyl-N-nitrosourea (ENU) initiation in mice. Female ICR mice aged 5 weeks were administered a single intra-uterine injection of ENU at a dose of 50 mg/kg via the vagina. After 1 week, the animals were fed a soybean-free diet containing 0 (control), 0.004, 0.02 and 0.1% of arctiin for 26 weeks. Histopathological examinations revealed the development of uterine proliferative lesions such as adenocarcinoma, atypical hyperplasia, adenomyosis, and endometrial hyperplasia. However, there were no significant differences in the incidences and severities of these lesions among the groups. These results indicate that arctiin showed no definite modifying effects on uterine carcinogenesis under the present experimental conditions.

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We found spontaneous dwarfs in Wistar Hannover GALAS rats, which were caused primarily by hypothyroidism (Doi et al. 2004, J Toxicol Pathol). It is known that juvenile hypothyroidism causes growth arrest, delay of bone age and epiphyseal dysgenesis. In this study, we morphologically investigated the bone, particularly the growth plate using 8- and 45-week-old dwarf (D) rats and compared the results with those from age-matched and younger juvenile (1-, 3-, 4- and 5-week old) normal Wistar Hannover GALAS (N) rats. At necropsy, 8- and 45-week-old D rats showed a small body size, low length of tibia and brachygnathia, which suggested dwarfism resulting from hypothyroidism. Histologically, 8-week-old D rats showed a small epiphysis ossification center, hypertrophy of osteoblasts, and a reduction of the vascular/bone cell invasion in the growth plate. Although the hypertrophied osteoblasts resembled those of 3-week-old N rats, the number of proliferating and hypertrophied chondrocytes in D rats were fewer than those of 3-week-old N rats. At 45 weeks old, the chondrocyte column structure in the growth plate of the D rats remained, suggesting a delay of epiphysial fusion. A small ossification center, hypertrophy of the osteoblasts and a delay of epiphysial fusion in D rats suggested a delay of bone age. Although low thyroid hormone and/or growth hormone might be responsible for these changes in the growth plate, these changes differed from thyroidectomized 6-week-old rats, suggesting a difference in the effect of thyroid hormone and/or growth hormone depending on the age of the animal.

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A large, well-demarcated solitary mass appeared in the chest of an intact female Sprague-Dawley rat. The tumor cells were generally small and round, with scant eosinophilic cytoplasm, and arranged in an alveolar pattern. In some areas, the tumor cells contained fine vacuoles, which were confirmed to be lipid droplets. Immunohistochemistry analysis revealed that most of the tumor cells were strongly positive for vimentin and weakly positive for S100 protein, neuron-specific enolase, and CD34. The cells were negative for desmin, myogenin, α-smooth muscle actin, keratin, CD68, and von Willebrand factor. Electron microscopy revealed that there were no cellular organelles showing specific differentiation, other than mitochondria and rough endoplasmic reticulum. The tumor had no characteristic features for determining the cell of origin and was diagnosed as an undifferentiated mesenchymal tumor and classified as a sarcoma, NOS (not otherwise specified).

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Two cases of focal nodular lesions different from regenerative nodules or preneoplasia were found in rat livers. The lesion in Case No. 1 was found in the medial lobe and showed lobular structures with hypertrophic hepatocytes at the center of the lobular structures and atrophic hepatocytes at the periphery. It contained the portal veins but very few bile ducts and hepatic arteries in the central areas. This nodule was diagnosed as nodular regenerative hyperplasia based on its histopathological similarities to such lesions in human cases. The lesion in Case No. 2 was found in the caudate lobe, and contained a large sclerosing portal vein with preserved normal portal triads accompanied by degenerative cellular and inflammatory changes. Based on its histopathological similarities with such lesions in aged canines, this lesion was diagnosed as nodular hyperplasia. Observed vascular abnormalities in both these cases suggested the presence of previous circulatory disturbance with a close anatomical association to the hyperplastic lesions. We, thus, propose a new histopathological entity of hepatocellular hyperplasia which develops in association with local circulatory disturbance and is distinct from post-necrotic regenerative hyperplasia.

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A smooth muscle hamartoma of the nipple was found in a 9-month-old beagle dog. No abnormalities were observed on necropsy. Histopathologically, there was a solitary lesion measuring 3 × 1 mm in size in the dermis of the nipple. The lesion was unencapsulated but well demarcated and was composed of numerous intersecting fascicles, with the nuclei of the some of the cells being round or oval-shaped, and those of others being fusiform with blunt edges. These fascicles, associated with the nipple smooth muscle, were surrounded by a large amount of mature collagen. There was no evidence of cytologic atypia or mitotic figures. Immunohistochemistry showed positive staining for alpha-smooth muscle actin (αSMA), but negative staining for S-100 protein, cytokeratin and p63, suggesting that the lesion was derived from the smooth muscle of the nipple. Therefore, a diagnosis of smooth muscle hamartoma of the nipple was made.

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The Spontaneously Diabetic Torii (SDT) rat is a novel rat model recently established for type 2 diabetes mellitus. In this report, we describe the unique histopathologic characteristics of the diabetic ocular lesions observed in both sexes in aging SDT rats. The eyes were histopathologically examined at various ages in 23 SDT rats (twelve males 39 - 70 weeks; eleven females 60 - 82 weeks). Diabetic ocular lesions included cataract, rupture of the lens, posterior vitreous detachment, proliferative retinopathy, tractional retinal detachment and iris neovascularization in all of the animals of both sexes at ages over 60 weeks. The onset of diabetes is approximately 6 months later in females than in males, however, the diabetic ocular lesions were similar in females and males at ages over 60 weeks. The impaired glucose tolerance (IGT) noted over a long period of time in females may contribute to the progressive development of the lesions.

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