Shizuoka-shi, Japan
Shizuoka-shi, Japan

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Nakamura R.,Asubio Pharma Co. | Nishimura T.,Asubio Pharma Co. | Ochiai T.,Asubio Pharma Co. | Nakada S.,Daiichi Sankyo | And 2 more authors.
Journal of Toxicologic Pathology | Year: 2013

In rats, it is sometimes difficult to distinguish malignant reticuloses from astrocytomas in routine histopathological assessment. In the present study, four spontaneous brain neoplasms developing in the cerebrum of one Wistar Hannover rat and three Sprague-Dawley rats were immunohistochemically examined using microglia and macrophage markers. Histopathologically, these neoplasms were localized mainly in the cerebral cortex, hypothalamus or piriform lobe, and the portions showing solid growth did not show characteristic cellular arrangement but had an indistinct boundary with the surrounding brain parenchyma. Neoplastic cells had oval or pleomorphic small nuclei with abundant eosinophilic cytoplasm. Two cases showed neoplastic cell infiltration into the meninges and perivascular spaces. Silver staining showed lack of reticulin fiber production in the stroma of the neoplasms. Immunohistochemically, the neoplastic cells were strongly positive for Iba-1 and sporadically positive for CD68 in all four cases. On the basis of these results, all the neoplasms examined here could be distinguished from astrocytomas and diagnosed as malignant reticuloses. Thus, immunohistochemical demonstration of microglia/macrophage characters, such as using Iba-1, is considered to be helpful for differential diagnosis of malignant reticuloses from astrocytomas among spontaneously occurring primary brain neoplasms in rats. ©2013 The Japanese Society of Toxicologic Pathology.


PubMed | Kumiai Chemical Industry Co., Research Center Inc., Toray Industries Inc, Takeda Pharmaceutical and 10 more.
Type: | Journal: Mutation research | Year: 2016

The reproducibility of the in vivo Pig-a gene mutation test system was assessed across 13 different Japanese laboratories. In each laboratory rats were exposed to the same dosing regimen of N-nitroso-N-ethylurea (ENU), and red blood cells (RBCs) and reticulocytes (RETs) were collected for mutant phenotypic analysis using flow cytometry. Mutant frequency dose response data were analysed using the PROAST benchmark dose (BMD) statistical package. Laboratory was used as a covariate during the analysis to allow all dose responses to be analysed at the same time, with conserved shape parameters. This approach has recently been shown to increase the precision of the BMD analysis, as well as providing a measure of equipotency. This measure of equipotency was used here to demonstrate a reasonable level of interlaboratory reproducibility. Increased reproducibility could have been achieved by increasing the number of cells scored, as this would reduce the number of zero values within the mutant frequency data. Overall, the interlaboratory trial was successful, and these findings support the transferability of the in vivo Pig-a gene mutation assay.


Katsumata T.,Research Center Inc. | Ishibashi T.,Nippon Oil Corporation | Kyle D.,Kyle Consulting Services
Toxicology Reports | Year: 2014

Astaxanthin is believed to be beneficial to human health because it possesses strong antioxidant properties. A natural astaxanthin-rich carotenoid extract (ARE) was produced by a well-controlled fermentation of a natural bacteria Paracoccus carotinifaciens, followed by the extraction and enrichment of the final product comprising mixture of carotenoids that is predominantly astaxanthin. The aim of this study was to evaluate the sub-chronic toxicity of the ARE using 6 week old Sprague-Dawley SPF rats [Crl:CD(SD)]. The test article was suspended in olive oil and administered daily to the rats by oral gavage for 13 weeks at doses of 0 (olive oil), 250, 500 or 1000. mg/kg/day. Each group consisted of 10 animals of each sex. No deaths occurred and no treatment-related changes were observed in the detailed clinical observations, manipulative tests, grip strength, motor activity, body weights, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathology. Dark-red feces were observed throughout the administration period in all treated groups due to excretion of the colored test article. Based on these results, it was concluded that the no observed adverse effect level (NOAEL) for ARE was at least 1000. mg/kg/day for male and female rats, respectively. © 2014 The Authors.


PubMed | Kumiai Chemical Industry Co., Research Center Inc., Tokyo Electron, Daiichi Sankyo and 13 more.
Type: | Journal: Mutation research | Year: 2016

The in vivo mutation assay using the X-linked phosphatidylinositol glycan class A gene (Pig-a in rodents, PIG-A in humans) is a promising tool for evaluating the mutagenicity of chemicals. Approaches for measuring Pig-a mutant cells have focused on peripheral red blood cells (RBCs) and reticulocytes (RETs) from rodents. The recently developed PIGRET assay is capable of screening >110


Ikezaki S.,Bozo Research Center Inc | Takagi M.,Bozo Research Center Inc | Tamura K.,Bozo Research Center Inc
Journal of Toxicologic Pathology | Year: 2011

It is important for the assessment of toxicological effects of chemicals to know what kinds of neoplasms naturally occur in the early life of experimental animals. In the present study, we demonstrated spontaneous neoplasms in Sprague-Dawley rats used in 4-, 13- and 26-week toxicity studies conducted at Bozo Research Center in the last decade. The tumors, which were first observed in 19-week-old animals, included anterior adenoma of the pituitary, follicular cell adenocarcinoma and C cell adenoma of the thyroids, nephroblastoma of the kidneys, basal cell tumor of the skin and malignant lymphoma. Thereafter, hemangiosarcoma of the tongue, adenocarcinoma of the submandibular glands, histiocytic sarcoma of the spleen, oligodendroglioma of the brain and adenocarcinoma and fibroadenoma of the mammary glands were detected in 32-week-old animals. The incidences of mammary adenocarcinoma and pituitary anterior adenoma were higher than those of other tumors. The present results showed that the same tumors as reported in aged rats could also develop in younger rats. © 2011 The Japanese Society of Toxicologic Pathology.


Kuroiwa Y.,Research Center Inc. | Ando R.,Research Center Inc. | Kasahara K.,Research Center Inc. | Nagatani M.,Research Center Inc. | And 2 more authors.
Journal of Toxicologic Pathology | Year: 2013

Historical control data of tumor incidence were collected from the control groups (215 animals of each sex) in four recent carcinogenicity studies that were started between 2005 to 2009 (terminally sacrificed between 2007 and 2011) at BoZo Research Center Inc. (Gotemba, Shizuoka, Japan) using Fischer 344 rats (F344/DuCrlCrlj). These data were compared to the previous historical control data (from 1990 to 2004, previously reported) in the same facility. In the results, the incidence of C-cell adenoma in the thyroid tended to increase in both sexes in recent years (30.8% for males and 24.4% for females in 2005-2009) as compared with the previous data (17.4% and 20.1% for males and 11.5% and 11.8% for females in 1990-1999 and 2000-2004, respectively). In addition, the incidences of pancreatic islet cell adenoma in males and uterine adenocarcinoma tended to increase from around 2000 and remained high in recent years (incidences of islet cell adenoma in males of 10.5%, 17.1% and 20.5% in 1990-1999, 2000-2004 and 2005-2009; incidences of uterine adenocarcinoma of 3.3%, 12.0% and 13.5% in 1990-1999, 2000-2004 and 2005-2009, respectively). There was no apparent difference in the incidence of other tumors. ©2013 The Japanese Society of Toxicologic Pathology.


PubMed | Research Center Inc.
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2016

Extraskeletal osteosarcoma is a very rare tumor in humans and animals. This paper describes a case of extraskeletal osteosarcoma observed in the duodenum of a male ICR mouse. Grossly, a solid mass pushing up the tunica serosa was observed in the duodenal wall. Histologically, the tumor was located in the lamina propria mucosae and tela mucosa. Neoplastic cells densely proliferated in these areas, and replaced of the normal tissue components. A small amount of osteoid and a small clump of bone tissue were observed in the area of neoplastic cell proliferation, especially in the lamina propria mucosae. Neoplastic cells consisted of atypical polygonal cells and pleomorphic spindle-shaped cells, and the former were predominant. Mitotic figures were occasionally observed. Neither invasion of vessels in the duodenum nor metastasis to distant organs was observed. There were no skeletal tumors in the body. Immunohistochemically, the neoplastic cells were positive for anti-osteocalcin, osteonectin, vimentin, and S-100 protein. Judging from these results, the present tumor was diagnosed as extraskeletal osteosarcoma. This is the first report of spontaneous extraskeletal osteosarcoma arising from the duodenum of a mouse.


PubMed | Research Center Inc.
Type: | Journal: Mutation research | Year: 2016

As a part of a collaborative study of the Pig-a assay by the Mammalian Mutagenicity Study Group of the Japanese Environmental Mutagen Society, a genotoxicity study on acetaminophen (APAP) was performed using the red blood cell (RBC) Pig-a and PIGRET assays. The dose levels were set at 0 (vehicle, 0.5% methylcellulose solution), 500, 1000, and 2000mg/kg, and APAP was administered once by oral gavage to male Sprague Dawley rats. For the positive control group, N-nitroso-N-ethylurea (ENU, 40mg/kg) was administered in the same way. The RBC Pig-a and PIGRET assays were performed using peripheral blood collected at pre-dosing and 1, 2 and 4 weeks after dosing. In both the RBC Pig-a and PIGRET assays, there were no changes in the Pig-a gene mutant frequency (MF) by the APAP treatment at any time point. The Pig-a MFs as measured by the RBC Pig-a assay for the ENU-treated group increased in a time-dependent manner with the maximum value at week 4; however, those using the PIGRET assay reached comparable values at week 1. Based on the above results, APAP was determined to have no mutagenicity under the conditions of this study, and the PIGRET assay could detect mutagenicity of ENU much earlier than the RBC Pig-a assay.


PubMed | Research Center Inc.
Type: | Journal: Mutation research | Year: 2016

As a part of a collaborative study of the Pig-a assay by the Mammalian Mutagenicity Study Group of the Japanese Environmental Mutagen Society, a genotoxicity study on cisplatin was performed using red blood cell (RBC) Pig-a and PIGRET assays. The dose levels were set at 0 (vehicle, physiological saline), 0.5, 1, and 2 mg/kg, and cisplatin was administered intravenously once to male F344 rats. The RBC Pig-a and PIGRET assays were performed using peripheral blood collected at pre-dosing and 1, 2 and 4 weeks after dosing. In the RBC Pig-a assay, an increase in the Pig-a mutant frequency (MF) was observed at week 4 in the high dose group. Although a significant increase in the Pig-a MF was also observed at week 2 in all cisplatin-treated groups, it was considered that this change was caused by a low MF in the vehicle control group and not to be biologically relevant. In the PIGRET assay, the Pig-a MF was increased at weeks 1, 2 and 4 in the high dose group. In addition, the means of the vehicle control groups Pig-a MFs in the PIGRET assay were lower than those in the RBC Pig-a assay. Based on the above results, cisplatin was determined to have mutagenicity under the conditions of this study, and it was demonstrated that the PIGRET assay was an appropriate tool to evaluate the in vivo mutagenicity much earlier than the RBC Pig-a assay.


PubMed | Bozo Research Center Inc. and Tsumura Research Laboratories
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2016

Keishibukuryogan is a traditional Japanese medicine widely administered to patients with menopausal symptoms. Because humans use it on a long-term basis, we believed that a carcinogenicity study was warranted. We orally administered keishibukuryogan (TJ-25) extract powder to 6-week-old Sprague-Dawley rats [Crl:CD(SD)], which were divided into four dosage groups-0 (water for injection), 100, 500 and 2,500 mg/kg/day for 24 months. We found that TJ-25 did not affect the survival rate of either sex. Furthermore, it did not affect the clinical condition of the rats, number of superficial tumors found by palpation, body weight, food consumption, hematology, or gross pathological findings. The severity of degeneration of muscle fiber in the femoral skeletal muscle increased slightly in males and females in the 2,500 mg/kg/day group, but TJ-25 did not increase the number of tumors found on histopathological examination. In our study, oral administration of TJ-25 extract powder in rats for 24 months was not associated with an increased incidence of tumors.

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