DIMS Institute of Medical Science Inc.

Ichinomiya, Japan

DIMS Institute of Medical Science Inc.

Ichinomiya, Japan
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Kakehashi A.,Osaka City University | Hagiwara A.,DIMS Institute of Medical Science Inc. | Imai N.,DIMS Institute of Medical Science Inc. | Nagano K.,Nagano Toxicologic Pathology Consulting | And 6 more authors.
Toxicology and Applied Pharmacology | Year: 2013

To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000. mg/kg body weight twice a day by gavage for 1 and 2. weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500. ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans. © 2013 Elsevier Inc.


Hagiwara A.,DIMS Institute of Medical Science Inc. | Doi Y.,DIMS Institute of Medical Science Inc. | Imai N.,DIMS Institute of Medical Science Inc. | Nakashima H.,DIMS Institute of Medical Science Inc. | And 6 more authors.
Toxicology | Year: 2011

The modifying potential of ethyl tertiary-butyl ether (ETBE) on tumor development was investigated in a medium-term multi-organ carcinogenesis bioassay using male F344 rats. Animals were sequentially given 5 carcinogens with different target sites in the first 4 weeks for multi-organ initiation. After one week they received ETBE by gavage at dose levels of 0 (control), 300 or 1000. mg/kg/day until experimental week 28. Further groups were also given ETBE at doses of 0 or 1000. mg/kg/day without prior carcinogen application. Incidences and multiplicities of follicular cell hyperplasias and neoplasms in the thyroid were significantly increased at dose levels of more than 300. mg/kg/day. Combined incidences of squamous cell hyperplasias and papillomas of the forestomach were also significantly increased at 300 and 1000. mg/kg/day. Incidences and multiplicities of adenocarcinomas in the colon were increased at 1000. mg/kg/day. The numbers and areas of glutathione S-transferase placental form (GST-P) positive foci per unit area of the liver sections, and the incidence of hepatocellular adenomas were also significantly increased at 1000. mg/kg/day, along with multiplicities of atypical hyperplasias of renal tubules of the kidney and the incidence of papillomatosis of the urinary bladder. This latter lesion was also seen at low incidence at 1000. mg/kg/day without initiation. Thus, the current results indicate that ETBE has tumor promoting potential for the thyroid and forestomach at dose levels of 300. mg/kg/day and more, and for the colon, liver, kidney and urinary bladder at 1000. mg/kg/day, under the present experimental conditions. © 2011 Elsevier Ireland Ltd.


Hagiwara A.,DIMS Institute of Medical Science Inc. | Imai N.,DIMS Institute of Medical Science Inc. | Nakashima H.,DIMS Institute of Medical Science Inc. | Toda Y.,DIMS Institute of Medical Science Inc. | And 5 more authors.
Food and Chemical Toxicology | Year: 2010

This study was designed to evaluate and characterize any adverse effect of nisin A, when administered to both sexes of F344/DuCrlCrlj rats (10 males and 10 females in each group) at dietary levels of 0%, 0.2%, 1.0% and 5.0% for 90. days. Animals given NaCl at a dietary level of 3.712% (equivalent to the NaCl content in 5.0% nisin A diet) served as a reference material treated group.There were no deaths, and the treatment had no toxicologically significant effects on clinical signs, body weights, food consumption, ophthalmology, hematology, or gross pathology.Statistically significant increases of water consumption, urine volume, and urinary sodium and chlorine, and decreases of urinary potassium and serum sodium, along with increases of absolute and relative kidney weight, and incidences of minimal squamous cell hyperplasia of limiting ridge in the forestomach, were found in nisin A-treated groups. It was considered that these changes were related to NaCl, since they were also noted in rats given diet containing the reference substance.Thus, no toxicologically significant changes were apparent in both sexes of F344/DuCrlCrlj rats fed diet containing 0%, 0.2%, 1.0% and 5.0% nisin A for 90. days. Therefore, the no-observed-adverse-effect level (NOAEL) for nisin A was concluded to be a dietary level of 5.0% (2996. mg/kg/day for males and 3187. mg/kg/day for females). © 2010 Elsevier Ltd.


Furukawa F.,DIMS Institute of Medical Science Inc. | Doi Y.,DIMS Institute of Medical Science Inc. | Suguro M.,DIMS Institute of Medical Science Inc. | Morita O.,Kao Corporation | And 4 more authors.
Food and Chemical Toxicology | Year: 2011

This study was conducted to examine the post-initiation carcinogenic potential of coated and uncoated titanium dioxide nanoparticles (CTDN and UCTDN) using a mouse medium-term skin carcinogenesis bioassay. For this purpose, 5, 10 and 20 mg/animal doses of CTDN or UCTDN were applied to mouse skin in the post-initiation phase (up to 20 weeks) in a two-stage skin carcinogenesis model using 7 week old CD1 (ICR) female mice. 7,12-dimethylbenz[. a]anthracene (DMBA) and 12- o-tetradecanoylphorbol 13-acetate (TPA) were used as the initiator and a positive control promoter, respectively. Pentalan 408 served as a vehicle control. No changes in survival rate, general condition and body weight related to the test materials were observed. On macroscopic observation, 1-2 nodules/group on the skin were observed in each group applied CTDN and UCTDN as well as the control group after DMBA initiation. The nodules were histopathologically diagnosed as squamous cell hyperplasia, sebaceous gland hyperplasia, squamous cell papilloma and keratoacanthoma. CTDN and UCTDN experiments, while enlargement of the mandibular, pancreatic, lumbar region and inguinofemoral lymph nodes, spleen and thymus was observed in mice given 5 and 10 mg but not 20 mg, the lack of dose-dependence suggests no biological significance.In the present study, CTDN and UCTDN applied in post-initiation stages at doses of up to 20 mg/mouse did not increase the development of nodules, and thus it was concluded that titanium dioxide nanoparticles do not possess post-initiation potential for mouse skin carcinogenesis. © 2010 Elsevier Ltd.


PubMed | DIMS Institute of Medical Science Inc. and Osaka City University
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2015

In the present study, in continuation of our previous experiment in order to investigate the mode of action (MOA) of ethyl tertiary-butyl ether (ETBE) hepatotumorigenicity in rats, we aimed to examine alterations in cell proliferation, that are induced by short-term administration of ETBE. F344 rats were administered ETBE at doses of 0, and 1,000 mg/kg body weight twice a day by gavage for 3, 10, 17 and 28 days. It was found that the previously observed significant increase of P450 total content and hydroxyl radical levels after 7 days of ETBE administration, and 8-OHdG formation at day 14, accompanied by accumulation of CYP2B1/2B2, CYP3A1/3A2, CYP2C6, CYP2E1 and CYP1A1 and downregulation of DNA oxoguanine glycosylase 1, was preceded by induction of cell proliferation at day 3. Furthermore, we observed an increase in regenerative cell proliferation as a result of ETBE treatment at day 28, followed by induction of cell cycle arrest and apoptosis by day 14. These results indicated that short-term administration of ETBE led to a significant early increase in cell proliferation activity associated with induction of oxidative stress, and to a regenerative cell proliferation as an adaptive response, which could contribute to the hepatotumorigenicity of ETBE in rats.


Xu J.,Nagoya City University | Futakuchi M.,Nagoya City University | Iigo M.,Nagoya City University | Fukamachi K.,Nagoya City University | And 11 more authors.
Carcinogenesis | Year: 2010

Titanium dioxide (TiO2) is evaluated by World Health Organization/International Agency for Research on Cancer as a Group 2B carcinogen. The present study was conducted to detect carcinogenic activity of nanoscale TiO2 administered by a novel intrapulmonary spraying (IPS)-initiation-promotion protocol in the rat lung. Female human c-Ha-ras proto-oncogene transgenic rat (Hras128) transgenic rats were treated first with N-nitrosobis(2-hydroxypropyl)amine (DHPN) in the drinking water and then with TiO2 (rutile type, mean diameter 20 nm, without coating) by IPS. TiO2 treatment significantly increased the multiplicity of DHPN-induced alveolar cell hyperplasias and adenomas in the lung, and the multiplicity of mammary adenocarcinomas, confirming the effectiveness of the IPS-initiation-promotion protocol. TiO2 aggregates were localized exclusively in alveolar macrophages and had a mean diameter of 107.4 nm. To investigate the underlying mechanism of its carcinogenic effects, TiO2 was administered to wild-type rats by IPS five times over 9 days. TiO2 treatment significantly increased 8-hydroxydeoxy guanosine level, superoxide dismutase activity and macrophage inflammatory protein 1α (MIP1α) expression in the lung. MIP1α, detected in the cytoplasm of TiO2-laden alveolar macrophages in vivo and in the media of rat primary alveolar macrophages treated with TiO2 in vitro, enhanced proliferation of human lung cancer cells. Furthermore, MIP1α, also detected in the sera and mammary adenocarcinomas of TiO2-treated Hras128 rats, enhanced proliferation of rat mammary carcinoma cells. These data indicate that secreted MIP1α from TiO2-laden alveolar macrophages can cause cell proliferation in the alveoli and mammary gland and suggest that TiO2 tumor promotion is mediated by MIP1α acting locally in the alveoli and distantly in the mammary gland after transport via the circulation. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.


Takahashi M.,Japan National Institute of Health Sciences | Kato H.,Japan National Institute of Health Sciences | Doi Y.,DIMS Institute of Medical Science Inc | Hagiwara A.,DIMS Institute of Medical Science Inc | And 5 more authors.
Journal of Toxicological Sciences | Year: 2012

To obtain initial information on the possible repeated-dose oral toxicity of fullerene C60, Crl:CD(SD) rats were administered fullerene C60 by gavage once daily at 0 (vehicle: corn oil), 1, 10, 100, or 1,000 mg/kg/day for 29 days, followed by a 14-day recovery period. No deaths occurred in any groups, and there were no changes from controls in detailed clinical observations, body weights, and food consumption in any treatment groups. Moreover, no treatment-related histopathological changes were found in any organs examined at the end of the administration period and at the end of the recovery period. Blackish feces and black contents of the stomach and large intestine were observed in males and females at 1,000 mg/kg/day in the treatment group. There were no changes from controls in the liver and spleen weights at the end of the administration period, but those weights in males in the 1,000 mg/kg/day group increased at the end of the recovery period. Using liquid chromatography-tandem mass spectrometry, fullerene C60 were not detected in the liver, spleen or kidney at the end of the administration period and also at the end of the recovery period. In conclusion, the present study revealed no toxicological effects of fullerene C60; however, the slight increases in liver and spleen weights after the 14-day recovery period may be because of the influence of fullerene C60 oral administration. In the future, it will be necessary to conduct a long-term examination because the effects of fullerene C60 cannot be ruled out.


Tamano S.,DIMS Institute of Medical Science Inc.
Asian Pacific Journal of Cancer Prevention | Year: 2010

There is a pressing need for medium term models as alternatives for two year testing of environmental compounds for carcinogenicity and toxicity. Optimally these should be of short duration in vivo, readily performed in the laboratory without the need for specialist equipment, be based on a priori reasoning and scientific principles and use effective surrogates for malignancies. The two models developed in DIMS Institute of Medical Science, the medium-term liver carcinogenesis bioassay and the medium-term multi-organ carcinogenesis bioassay, fulfil these criteria and have the massive advantage of already being used for testing of large numbers of agents.


Imai N.,Nagoya City University | Imai N.,DIMS Institute of Medical Science Inc. | Kawabe M.,DIMS Institute of Medical Science Inc. | Hikage T.,Hokkaido University | And 3 more authors.
Systems Biology in Reproductive Medicine | Year: 2011

In recent years concern has arisen whether carrying a cellular phone near the reproductive organs such as the testes may cause dysfunction and particularly decrease in sperm development and production, and thus fertility in men. The present study was performed to investigate the effects of a 1.95GHz electromagnetic field on testicular function in male Sprague-Dawley rats. Five week old animals were divided into 3 groups of 24 each and a 1.95-GHz wide-band code division multiple access (W-CDMA) signal, which is used for the freedom of mobile multimedia access (FOMA), was employed for whole body exposure for 5 hours per day, 7 days a week for 5 weeks (the period from the age of 5 to 10 weeks, corresponding to reproductive maturation in the rat). Whole-body average specific absorption rates (SAR) for individuals were designed to be 0.4 and 0.08 W/kg respectively. The control group received sham exposure. There were no differences in body weight gain or weights of the testis, epididymis, seminal vesicles, and prostate among the groups. The number of sperm in the testis and epididymis were not decreased in the electromagnetic field (EMF) exposed groups, and, in fact, the testicular sperm count was significantly increased with the 0.4 SAR. Abnormalities of sperm motility or morphology and the histological appearance of seminiferous tubules, including the stage of the spermatogenic cycle, were not observed. Thus, under the present exposure conditions, no testicular toxicity was evident. © 2011 Informa Healthcare USA, Inc.


PubMed | DIMS Institute of Medical Science Inc., Nagano Toxicologic Pathology Consulting and Japan Bioassay Research Center
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2015

Tumor-promoting effects of ethyl tertiary-butyl ether (ETBE) were investigated in a 2-stage carcinogenesis bioassay with regard to hepatic and renal carcinogenesis in rats. Male 6-week-old Wistar rats were given drinking water containing N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN), as an initiator, at a dose of 500 ppm for 2 weeks. Starting one week thereafter, the animals were administered ETBE at dose levels of 0 (control), 100, 300, 500 or 1,000 mg/kg/day by gavage for 19 weeks from week 4 to 22. Necropsy of all rats was performed at week 23, and livers and kidneys were examined histopathologically. Incidences of hepatocellular adenomas, and those of combined hepatocellular adenomas and carcinomas were significantly elevated in rats given 1,000 mg/kg/day ETBE, but not 100500 mg/kg/day ETBE, and there was a significant increase in the average numbers of lesions. No significant differences in incidences and average numbers of renal tubule neoplasms were found in rats administered 1001,000 mg/kg/day ETBE. However, the average numbers of atypical tubule hyperplasias, considered to be preneoplastic lesions, were significantly increased in rats given ETBE at 1,000 mg/kg/day, but not in rats given 500 mg/kg/day or lower doses. Thus, these results imply that ETBE has hepatic and renal tumor-promoting activities that affect EHEN-induced carcinogenesis in male rats, and the no-observed-effect level is 500 mg/kg/day under the present experimental conditions.

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