Japan Bioassay Research Center

Kawasaki, Japan

Japan Bioassay Research Center

Kawasaki, Japan
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Matsumoto M.,Japan Bioassay Research Center | Kano H.,Japan Bioassay Research Center | Suzuki M.,Japan Bioassay Research Center | Katagiri T.,Japan Bioassay Research Center | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2016

The carcinogenicity and chronic toxicity of hydrazine monohydrate was examined by administrating hydrazine monohydrate in drinking water to groups of 50 F344/DuCrj rats and 50 Crj:BDF1 mice of both sexes for two years. The drinking water concentration of hydrazine monohydrate was 0, 20, 40 or 80 ppm (wt/wt) for male and female rats and male mice; and 0, 40, 80 or 160 ppm for female mice. Survival rates of each group of males and females rats and mice were similar to the respective controls, except female rats administered 80 ppm. Two-year administration of hydrazine monohydrate produced an increase in the incidences of hepatocellular adenomas and carcinomas in rats of both sexes along with hepatic foci. In mice, the incidences of hepatocellular adenomas and carcinomas were increased in females, and significantly increased incidences of hepatocellular adenomas in females administered 160 ppm were observed. Thus, hydrazine monohydrate is carcinogenic in two species, rats and mice. Additionally, non-neoplastic renal lesions in rats and mice and non-neoplastic nasal lesions in mice were observed. © 2016 Elsevier Inc.


Ema M.,Japan National Institute of Advanced Industrial Science and Technology | Okuda H.,Japan Bioassay Research Center | Gamo M.,Japan National Institute of Advanced Industrial Science and Technology | Honda K.,Japan National Institute of Advanced Industrial Science and Technology
Reproductive Toxicology | Year: 2017

We summarized significant effects reported in the literature on the reproductive and developmental toxicity of silver nanoparticles (AgNPs) in laboratory animals. AgNPs showed testicular/sperm toxicity in males and ovarian and embryonic toxicity in females. Maternal injection of AgNPs delayed physical development and impaired cognitive behavior in offspring. Ag was accumulated in the testes after administration of AgNPs. AgNPs were identified in the visceral yolk sac after administration during early gestation in mice. Radiolabeled AgNPs were detected in placenta, breast milk, and pre- and postnatal offspring after injection during late gestation in rats. Ag in the ionic form, and possibly also particles, was suggested to be bioavailable. Although this review provides initial information on the potential reproductive and developmental toxicity of AgNPs, data is still very limited. Further studies using state-of-the-art methodologies and the relevant routes and doses for human exposure are required. © 2017 Elsevier Inc.


Kakehashi A.,Osaka City University | Tago Y.,Osaka City University | Yoshida M.,Japan National Institute of Health Sciences | Sokuza Y.,Osaka City University | And 4 more authors.
Toxicological Sciences | Year: 2012

Our research is focused on modifying effects of an isoflavone aglycones (IAs)-rich extract at a hormonally active dose of 150 mg/kg body weight/day on mammary and endometrial carcinogenesis in female Donryu rats. IA administered for 2 weeks in a phytoestrogen-low diet exerted estrogenic activity and induced cell proliferation in the uterus of ovariectomized rats. Furthermore, administration for 4 weeks resulted in elevation of cell proliferation in the mammary glands of 7,12-dimethylbenz[a]anthracene (DMBA)-treated animals. Forty weeks of postpubertal administration of IA to 5-week-old rats after initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) caused significant increase of incidence and multiplicity of mammary adenocarcinoma, multiplicities of endometrial atypical hyperplasia, adenomatous polyps, and an increased trend of uterine adenocarcinomas. Liquid chromatography with tandem mass spectrometry and immunohistochemical analyses revealed significant elevation of tumorigenesis-related proteins such as S100 calcium-binding protein A8, kininogen 1, and annexins 1 and 2 in mammary adenocarcinomas and cadherin EGF LAG seven-pass G-type receptor 2, DEAD box polypeptide 1, and cysteine- and glycine-rich protein 1 in uterine proliferative lesions of IA-treated animals. Those changes are likely to be related to modulation of estrogen receptor (ER), AP1, nuclear factor-kappa B, and actin signaling pathways. Our results indicate that the postpubertal exposure of Donryu rats to IA at an estrogenic dose results in promotion of mammary and uterine carcinogenesis induced by DMBA and ENNG, which might be related to the activation of ER-dependent signaling and alteration of the molecular tumor environment in the mammary gland and endometrium. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Kakehashi A.,Osaka City University | Ishii N.,Osaka City University | Shibata T.,K.K. AB Sciex | Wei M.,Osaka City University | And 5 more authors.
Toxicological Sciences | Year: 2011

In the present study, protein lysates from microdissected glutathione S-transferase placental-form-positive (GST-P +) foci and hepatocellular carcinomas from livers of rats treated with N-diethylnitrosamine followed by phenobarbital at doses of 0 and 500 ppm in the diet for 10 and 33 weeks were analyzed using QSTAR Elite liquid chromatography with tandem mass spectrometry and iTRAQ technology. Among 75 proteins, a total of 27 and 50 proteins displaying significant quantitative changes comparing with adjacent normal-appearing liver tissue were identified in GST-P + foci of initiation control and promotion groups, respectively, which are related to transcription, protein folding, cytoskeleton filaments reorganization, cell cycle control, nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated oxidative stress responses, lipid metabolism, glutathione metabolism, oxidative phosphorylation, and signal transduction. Furthermore, Ingenuity Pathway and bioinformatic analyses revealed that expression changes of genes encoding proteins with altered expression detected in GST-P + foci are likely to be controlled by c-myc, NRF2, aryl hydrocarbon receptor, nuclear factor kappa B, and hepatocyte nuclear factor 4 transcriptional factors. Coordinated overexpression of mitochondrial chaperons prohibitin (PHB) and prohibitin 2 (PHB2), septin 9 (SEPT9), neurabin 1, and other cytoskeletal and functional proteins in areas of GST-P + foci during initiation and/or promotion stages of rat hepatocarcinogenesis was associated with induction of cell proliferation and might be responsible for the neoplastic transformation of rat liver preneoplastic lesions. Newly discovered elevation of PHB, PHB2, and SEPT9 in GST-P + foci and tumors, imply that they might play important role in the onset of liver cancer and be of potential values in the studies of hepatocarcinogenesis. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Kanno J.,Japan Bioassay Research Center
The Journal of toxicological sciences | Year: 2016

Silent Spring by Rachel Carson (1962) established a role for environmental chemicals in cancer and Our Stolen Future by Theo Colbone, Dianne Dumanoski and John Peterson Myers (1996) coined the concept of "Endocrine Disrupting Chemicals (EDCs)" with its mechanistic plausibility for all the living organisms. For basic biologists, seeing a non-monotonic dose-response curve was a matter of course. In contrast, for the toxicologists at that time, the dose-response curves should be monotonic. It took some time for toxicologists to accept the plausibility that animals and humans are subject to the effects of EDCs act in a way that is explained by the new paradigm of receptor-mediated toxicity or in other words "signal toxicity." In classical toxicology, a toxic substance reaches a cellular target and induces malfunction. The target molecules are proteins including enzymes, lipid membranes, DNA, and other components of the cell which are damaged by the toxic substances. On the other hand, in the case of signal toxicity, a chemical binds to a specific receptor - after that, the chemical itself is not important. The signal from the receptor initiates a cascade of molecular events that leads to various changes in the cells and organs. When the signal is abnormal for a cell or an organ in terms of quality, intensity and timing, then the signal will induce adverse effects to the target. An extreme example of signal toxicity is the 1981 Nobel Prize in Physiology or Medicine work by Drs. Hubel and Wiesel. They blocked the signal of sharp images from the retina to the brain and found that the visual cortex needed this signal at the correct time for its proper development. In humans, such signal disruption is well known to induce "form-deprivation amblyopia" in infants. The concept of signal toxicity widens the range of systems vulnerable to EDCs and facilitates the understanding of their biological characteristics. For example, compared with intrinsic ligands, xenobiotic chemicals usually act as weak agonists and/or weak antagonists of receptor systems; the dose-response characteristics and the dose range will depend on the signaling system of concern. If the signal is used for organogenesis and functional maturation, there would be a critical period in the development during which the disturbance of such signals may cause irreversible changes. Since recepter-based signaling mechanisms are usually an amplification systems, it is hard to set a threshold in its dose response, and the outcome of signal toxicity is often stochastic at low doses. This review attempts to explain the benefits of incorporating the concept of signal toxicology for widening the range of toxicology for the better protection of human and environmental health in modern civilized life, where chemicals are designed to be less toxic in terms of traditional toxicity but not yet in "signal toxicity."


Tsukamoto T.,Mie University | Toyoda T.,Japan National Institute of Health Sciences | Mizoshita T.,Nagoya City University | Tatematsu M.,Japan Bioassay Research Center
Seminars in Immunopathology | Year: 2013

Helicobacter pylori infection is an important factor for gastric carcinogenesis in human. In carcinogen-treated Mongolian gerbils, H. pylori infection enhances stomach carcinogenesis, while infection alone induced severe hyperplasia called heterotopic proliferative glands. A high-salt diet or early acquisition of the bacteria exacerbates inflammation and carcinogenesis. Oxygen radical scavengers or anti-inflammatory chemicals as well as eradication of H. pylori are effective to prevent carcinogenesis. H. pylori-associated inflammation induces intestinal metaplasia and intestinalization of stomach cancers independently. It is necessary to control cancer development not only in H. pylori-positive cases but also in H. pylori-negative metaplastic gastritis. © 2012 Springer-Verlag Berlin Heidelberg.


Niwa T.,National Cancer Center Research Institute | Toyoda T.,Japan National Institute of Health Sciences | Tsukamoto T.,Aichi University | Mori A.,National Cancer Center Research Institute | And 2 more authors.
Cancer Prevention Research | Year: 2013

Suppression of aberrant DNA methylation is a novel approach to cancer prevention, but, so far, the efficacy of the strategy has not been evaluated in cancers associated with chronic inflammation. Gastric cancers induced by Helicobacter pylori infection are known to involve aberrant DNA methylation and associated with severe chronic inflammation in their early stages. Here, we aimed to clarify whether suppression of aberrant DNA methylation can prevent H. pylori-induced gastric cancers using a Mongolian gerbil model. Administration of a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), to gerbils (0.125 mg/kg for 50-55 weeks) decreased the incidence of gastric cancers induced by H. pylori infection and N-methyl-N-nitrosourea (MNU) treatment from 55.2% to 23.3% (P < 0.05). In gastric epithelial cells, DNA methylation levels of six CpG islands (HE6, HG2, SB1, SB5, SF12, and SH6) decreased to 46% to 68% (P < 0.05) of gerbils without 5-aza-dC treatment. Also, the global DNA methylation level decreased from 83.0% ± 4.5% to 80.3% ± 4.4% (mean ± SD) by 5-aza-dC treatment (P < 0.05). By 5-aza-dC treatment, Il1b and Nos2 were downregulated (42% and 58% of gerbils without, respectively) but Tnfwas upregulated (187%), suggesting that 5-aza-dC treatment induced dysregulation of inflammatory responses. No obvious adverse effect of 5-aza-dC treatment was observed, besides testicular atrophy. These results showed that 5-aza-dC treatment can prevent H. pylori-induced gastric cancers and suggested that removal of induced DNA methylation and/or suppression of DNA methylation induction can become a target for prevention of chronic inflammation-associated cancers. © 2013 AACR.


Tsukamoto T.,Aichi University | Tatematsu M.,Japan Bioassay Research Center
Current Infectious Disease Reports | Year: 2014

Helicobacter pylori infection is one of the most important factors in gastric carcinogenesis in humans. Epidemiological studies have revealed that H. pylori-infected patients develop significantly more gastric cancers than uninfected individuals. In rodent models, H. pylori inoculation causes strong promoting effects in carcinogen-treated animals, whereas the bacterial infection alone causes only hyperplasic, atrophic, and/or metaplastic lesions. In both human and rodent models, eradication of H. pylori helps inhibit gastric carcinogenesis, especially when there is only mild gastric inflammation and no evidence of severe atrophy or intestinal metaplasia. Chemoprevention studies in humans have been reported and have shown the effectiveness of several medications including a cyclooxygenase-2 inhibitor. Candidate chemicals used in rodent models could hopefully be used in humans in the future. © Springer Science+Business Media 2014.


Fukushima S.,Japan Bioassay Research Center
Asian Pacific Journal of Cancer Prevention | Year: 2010

While it has been generally accepted that genotoxic carcinogens have no dose threshold for their carcinogenic potential, there is increasing evidence that very low doses in fact are incapable of inducing tumours or preneoplastic lesions. Thus not only so-called epigenetic 'non-genotoxic' compounds like phenobarbital and benzene hexachloride, but also unequivocally genotoxic carcinogens like the heterocyclic amines, 2-amino-3,8- dimethyl-imidazo[4,5-f]quinoxaline and amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and the nitrosamines diethylnitrosamine, and dimethylnitrosamine, may exhibit a practical dose threshold below which they do not induce histopathologically assessable lesions. Some form of physiological adaptation may thus be expected to occur in response to low doses of all types of DNA-damaging agents. With 'non-genotoxic' agents there may even be hormesis or paradoxical protection at very low dose.


Yamasaki K.,Chemicals Evaluation and Research Institute | Okuda H.,Japan Bioassay Research Center
Toxicology Letters | Year: 2012

The purpose of this study was to compare endocrine-mediated effects of bisphenol A related compounds, 2,2-bis(4-cyanatophyenyl)propane and 4,4'-cyclohexylidenebisphenol with reference to OECD Test Guideline No. 407. Rats were orally gavaged with 0, 4, 20, and 100. mg/kg/day of 2,2-bis(4-cyanatophyenyl)propane, and 0, 30, 100, and 300. mg/kg/day of 4,4'-cyclohexylidenebisphenol for at least 28 days beginning at 8 weeks of age. Endocrine-mediated effects were not observed in rats given 2,2-bis(4-cyanatophyenyl)propane. Male accessory sex organ weights decreased in the 4,4'-cyclohexylidenebisphenol 300. mg/kg group and serum T4 values increased in all male groups treated with this compound. Our results suggest that endocrine-mediated changes caused by the present bisphenol related compound can be divided into estrogenic or thyroid hormonal effects, and estrogenic effects observed in the repeated-dose study were related to their estrogenic potency confirmed by uterotrophic assay. © 2011 Elsevier Ireland Ltd.

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