Publications by authors named "Seigo Hayashi"

34 Publications

Comparison of acute inhalation toxicity of sulfuric acid by the inhalation and intratracheal instillation methods.

J Toxicol Pathol 2021 Jul 24;34(3):269-273. Epub 2021 Apr 24.

Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

Recently, intratracheal instillation has been focused on as a simple, low-cost alternative to the inhalation method. In this study, intratracheal instillation of sulfuric acid, a typical acidic compound, was performed to compare the acute toxicity of acidic compounds that could cause damage to the respiratory system between intratracheal instillation and inhalation. Sulfuric acid was administered to male rats at doses of 0.7, 2, 7, 20, and 60 mg/kg by dividing the total dose into four doses. General condition and body weight were examined up to 14 days after administration, and macropathological and histopathological examinations were performed. The half-lethal dose was then estimated. All animals administered 20 and 60 mg/kg sulfuric acid and one animal administered 2 mg/kg sulfuric acid died within 4 h after administration. No abnormalities were observed in other animals. At 20 and 60 mg/kg, multiple red foci or diffuse red areas were macroscopically observed in the lungs. In these lesions, histopathologically, clefts between the mucosal epithelium and basement membrane and necrosis of the alveolar epithelium were observed. Deaths in these groups may have resulted from lung injury. No notable changes were observed in other animals. Therefore, the half-lethal dose of sulfuric acid by intratracheal instillation was estimated as 7-20 mg/kg. The acute toxicity by intratracheal instillation was evaluated with two-fold sensitivity since the exposure at the half-lethal sulfuric acid concentration in inhalation studies was calculated as 43.2 mg/kg.
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http://dx.doi.org/10.1293/tox.2020-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280304PMC
July 2021

A case report of RccHan: WIST rat with multiple neoplastic and non-neoplastic proliferative lesions.

J Toxicol Pathol 2021 Jul 30;34(3):251-259. Epub 2021 Apr 30.

Toxicology and Environmental Science Department, Biological Research Laboratories, Nissan Chemical Corporation, 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan.

It is extremely rare to have multiple spontaneous proliferative lesions in young adult rats. Here, we report the occurrence of different proliferative lesions in multiple tissues of a 7-week-old female rat in a 1-week repeated toxicity study. Grossly, multiple white patches and nodules in the bilateral kidneys, femoral and subcutaneous masses, and a nodule in the liver were observed. Renal lesions were diagnosed as renal mesenchymal tumors. One of the femoral subcutaneous masses was diagnosed as an adenolipoma consisting of mammary epithelial cells and mature adipocytes. The other femoral and abdominal subcutaneous masses were diagnosed as lipomas consisting of mature adipocytes. The liver nodule was diagnosed as non-regenerative hepatocellular hyperplasia, which was characterized by the proliferation of slightly hypertrophic hepatocytes. In the cauda equina, the growth of enlarged Schwann cells around the axon was observed, and this lesion was diagnosed as a neuroma.
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http://dx.doi.org/10.1293/tox.2021-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280308PMC
July 2021

Databases for technical aspects of immunohistochemistry: 2021 update.

J Toxicol Pathol 2021 Apr 25;34(2):161-180. Epub 2021 Feb 25.

Conference on Experimental Animal Histopathology.

With the aim of sharing information about the technical aspects of immunohistochemistry (IHC) and facilitating the selection of suitable antibodies for histopathological examination, this technical report describes the results of a questionnaire distributed during the period of 2018 to 2019 among members of the Conference on Experimental Animal Histopathology. Additionally, it describes the immunological properties and supplier details (clone, supplier, catalog number, species reactivity, etc.) as well as the IHC staining conditions (fixing solution, fixing time, embedding, antigen retrieval method, antibody dilution, incubation time, incubation temperature, positive control tissue, blocking condition, secondary antibody information, etc.) for a total of 509 primary antibodies (comprising 220 different types). These survey results were an update on the contents reported by CEAH in 2017.
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http://dx.doi.org/10.1293/tox.2021-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100252PMC
April 2021

Effect of sampling time on somatic and germ cell mutations induced by acrylamide in gpt delta mice.

Genes Environ 2021 Feb 17;43(1). Epub 2021 Feb 17.

Division of Genetics and Mutagenesis, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-9501, Japan.

Background: Acrylamide (AA) is a rodent carcinogen and classified by the IARC into Group 2A (probable human carcinogen). AA has been reported to induce mutations in transgenic rodent gene mutation assays (TGR assays), the extent of which is presumed to depend on exposure length and the duration of expression after exposure. In particular, it is not clear in germ cells. To investigate mutagenicity with AA in somatic and germ cells at different sampling times, we conducted TGR assays using gpt delta transgenic mice.

Results: The male gpt delta mice at 8 weeks of age were treated with AA at 7.5, 15 and 30 mg/kg/day by gavage for 28 days. Peripheral blood was sampled on the last day of the treatment for micronucleus tests and tissues were sampled for gene mutation assays at day 31 and day 77, those being 3 and 49 days after the final treatment (28 + 3d and 28 + 49d), respectively. Another group of mice was treated with N-Ethyl-N-nitrosourea (ENU) at 50 mg/kg/day by intraperitoneal administration for 5 consecutive days and tissues were sampled at the day 31 and day 77 (5 + 26d and 5 + 72d). Frequencies of micronucleated erythrocytes in the peripheral blood significantly increased at AA doses of 15 and 30 mg/kg/day. Two- to three-fold increases in gpt mutation frequencies (MFs) compared to vehicle control were observed in the testes and lung treated with 30 mg/kg/day of AA at both sampling time. In the sperm, the gpt MFs and G:C to T:A transversions were significantly increased at 28 + 3d, but not at 28 + 49d. ENU induced gpt mutations in these tissues were examined at both 5 + 26d and 5 + 72d. A higher mutant frequency in the ENU-treated sperm was observed at 5 + 72d than that at 5 + 26d.

Conclusions: The gpt MFs in the testes, sperm and lung of the AA-treated mice were determined and compared between different sampling times (3 days or 49 days following 28 day-treatment). These results suggest that spermatogonial stem cells are less sensitive to AA mutagenicity under the experimental condition. Prolonged expression time after exposure to AA to detect mutagenicity may be effective in somatic cells but not in germ cells.
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http://dx.doi.org/10.1186/s41021-021-00175-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890838PMC
February 2021

The effects of β-naphthoflavone on rat placental development.

J Toxicol Pathol 2019 Oct 20;32(4):275-282. Epub 2019 Aug 20.

Veterinary Clinical Pathology, Faculty of Veterinary Medicine Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime 794-8555, Japan.

The morphological effects of β-naphthoflavone (β-NF) on placental development in pregnant rats were examined. β-NF, administered to pregnant rats intraperitoneally at 15 mg/kg bw from gestation day (GD) 9 to GD 14, had no effect on maternal body weight gain, mortality, or clinical sign. In the β-NF-exposed rats, intrauterine growth retardation (IUGR) rates increased on GDs 17 and 21, although there was no effect on fetal mortality rate, fetal or placental weight, or external fetal abnormality. Histopathologically, β-NF induced apoptosis and inhibition of cell proliferation of the trophoblastic septa in the labyrinth zone, resulting in its poor development. In the basal zone, β-NF induced spongiotrophoblast apoptosis and delayed glycogen islet regression, resulting in their cystic degeneration. β-NF-induced CYP1A1 expression was detected in the endothelial cells of the fetal capillaries in the labyrinth zone and in the endothelial cells of the spiral arteries in the metrial gland, but not in any trophoblasts. This indicates that CYP1A1 is inducible in the endothelial cells of the fetal capillaries in the labyrinth zone, and that these cells have an important role in metabolizing CYP1A1 inducers crossing the placental barrier.
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http://dx.doi.org/10.1293/tox.2019-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831496PMC
October 2019

[Present Status and Problems of Management and Guidance for Visiting Pharmacy Service to In-home Patients by Hospital Pharmacists].

Gan To Kagaku Ryoho 2018 Mar;45(Suppl 1):32-34

Dept. of Pharmacy, Morimachi Hospital.

We conducted a survey of the background of 41 patients who received management and guidance from an in-home visiting pharmacy service and of the contents of support by the pharmacist, using patients' medical records from May 2016 to March 2017. Support comprised delivery of medicine to alleviate a burden to caregiver, suggesting medication, adjusting remaining medicines, and providing support during hospitalization. Out of 285 visits, there were 32 visits for which a medical fee could not be claimed. The main reasons for this were delivery of medicine on the day of visiting medical care, management of prescribed medicine at home, and delivery of temporal medicines. We used SWOT analysis to examine the problems and to consider improvements. The results showed that the different method for calculating medical fees is disadvantage for the hospital pharmacy, compared with the health insurance pharmacy. On the other hand, an advantage for the hospital pharmacist is that he or she can refer to the patient's medical records and support them during hospitalization.
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March 2018

Effect of dibutyltin on placental and fetal toxicity in rat.

J Toxicol Sci 2017 ;42(6):741-753

Courses of Veterinary Laboratory Medicine, School of Veterinary Medicine, Faculty of Agriculture, Tottori University.

In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl-treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl-induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation.
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http://dx.doi.org/10.2131/jts.42.741DOI Listing
March 2018

Histopathology of a wavy medaka.

J Toxicol Pathol 2016 Apr 15;29(2):115-8. Epub 2016 Feb 15.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Shiraoka, Saitama 349-0294, Japan.

Wavy medakas are medakas that exhibit spinal curvature characterized by dorsoventrally curved vertebrae. We found a spontaneous wavy medaka in our experimental stock and subjected it to a histopathological examination. Macroscopically, the wavy medaka's spine formed an M shape, and its vertebrae displayed a dorsoventral curvature that started at the third vertebral bone. Microscopically, the vertebral cavities were filled with fibrous tissue, which was similar to that seen in the central parts of the intervertebral discs of a normal medaka. The vertebral joints were composed of vacuolated notochord cells without intervertebral disc formation. These changes were also observed in the caudal region, which exhibited less curvature. In the normal medaka, the intervertebral discs form via the regression of the notochord that plays a key role in the development of vertebrae and disc formation. We concluded that notochordal subinvolution had induced intervertebral disc dysplasia, leading to lordokyphosis, in the wavy medaka.
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http://dx.doi.org/10.1293/tox.2015-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866008PMC
April 2016

Histomorphological comparison of rat placentas by different timing of chlorpromazine-administration.

Exp Toxicol Pathol 2015 Sep 18;67(9):443-52. Epub 2015 Jul 18.

Courses of Veterinary Laboratory Medicine, School of Veterinary Medicine, Faculty of Agriculture, Tottori University, 4-101 Koyama-cho Minami Tottori 680-8553, Japan.

The effects of chlorpromazine-treatment timing on the development of the placenta in pregnant rats were examined. Chlorpromazine was administered intraperitoneally at 100mg/kg on gestation day (GD) 11 (GD11-treated group), GD 13 (GD13-treated group) or GD 15 (GD15-treated group) into pregnant rats. All treated dams exhibited decreased body weight, prone position, hypothermia, loss or decrease of locomotor activity, etc. The fetal mortality rates were increased up to 42.9% in the GD11- and GD13-treated groups and up to 16.7% in the GD15-treated group. The embryo/fetal weight was on a declining trend from GD 16 onward, and the intrauterine growth retardation (IUGR) rates on GD 21 were increased in all treated groups. The placental weight showed a declining trend from GD 15 onward in all treated groups. Histopathologically, apoptosis was detected 1 or 2 days after treatment, and led to hypoplasia in the labyrinth zone and metrial gland, and cystic degeneration in the basal zone on GD 21 in all treated groups. There was no difference in the histopathological lesions on GD 21 among the treated groups. Thus, it is considered that chlorpromazine-induced placental toxicity is characterized in that there is no obvious specific sensitive period from GD 11 to GD 15. Chlorpromazine induced a non-specific transient development retardation of the placenta by apoptosis independently of the cell proliferation period in each part/zone.
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http://dx.doi.org/10.1016/j.etp.2015.06.001DOI Listing
September 2015

Evaluation of repeated dose micronucleus assays of the liver using N-nitrosopyrrolidine: a report of the collaborative study by CSGMT/JEMS.MMS.

Mutat Res Genet Toxicol Environ Mutagen 2015 Mar;780-781:25-30

The repeated dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens, and can be integrated into a general toxicological study. To assess the performance of the assay, N-nitrosopyrrolidine (NPYR), a genotoxic hepatocarcinogen, was tested in 14- or 28-day RDLMN assays. NPYR was orally administered to rats at a daily dose of 25, 50 or 100 mg/kg. One day after the last administration, a portion of the liver was removed and hepatocyte micronucleus (MN) specimens were prepared by the new method recently established by Narumi et al. In addition, a bone marrow MN assay and a histopathological examination of the liver were conducted. The detection of Phospho-Histone H3 was performed by immunohistochemistry to evaluate the proliferation rate of hepatocytes. The results showed significant increase in the number of micronucleated hepatocytes and Phospho-Histone H3-positive cells from the lowest dose in both 14- and 28-day RDLMN assays. On the other hand, the bone marrow MN assay yielded a negative result, which was in accordance with the existing report of the bone marrow MN assay using mice. Upon histopathological examination, inflammatory lesions and hypertrophy were noted, which may explain the increase in the hepatocyte proliferation and the enhancement of MN induction by NPYR. Our findings indicate that the RDLMN assay could be a useful tool for comprehensive risk assessment of carcinogenicity by providing information on both genotoxicity and histopathology when integrated into a general repeat dosing toxicity assay.
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http://dx.doi.org/10.1016/j.mrgentox.2014.05.007DOI Listing
March 2015

Pancreatic Ductal Adenocarcinoma in a Wistar Hannover GALAS Rat.

J Toxicol Pathol 2014 Jul 29;27(2):147-51. Epub 2013 Dec 29.

Department of Pharmaceutical Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku-ku, Tokyo 169-0073, Japan ; Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan.

There are no reported spontaneous cases of pancreatic ductal adenocarcinoma (PDAC), and there are few reports about chemically-induced PDAC in rats. We encountered a PDAC in a Wistar Hannover GALAS rat that had been subjected to a medium-term multiorgan carcinogenicity bioassay. This article describes the histological and histochemical findings of the tumor. The tumor was located in the pancreatic tissue and had not invaded the liver parenchyma or the mucosal layer of the alimentary tract. The tumor cells were atypical and were mainly arranged in small tubules. In addition, abundant stroma and mucus production were observed in the tumor. In an immunohistochemical examination, the tumor cells were positive for cytokeratin, Sox9 and pancreas duodenum homeobox 1 and negative for amylase 2A and insulin. Therefore, the tumor was diagnosed as a PDAC based on its histological and histochemical findings. We considered that the tumor was caused by the carcinogens administered during the abovementioned bioassay.
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http://dx.doi.org/10.1293/tox.2013-0068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110940PMC
July 2014

Early indicators of delayed adverse effects in female reproductive organs in rats receiving neonatal exposure to 17alpha-ethynylestradiol.

J Toxicol Sci 2014 ;39(5):775-84

Division of Pathology, National Institute of Health Sciences.

We previously reported that neonatal exposure to 17α-ethynylestradiol (EE) led to delayed adverse effects in which age-related anovulation after sexual maturation was accelerated. To identify early indicators of these adverse effects, female Wistar Hannover GALAS rats received a single EE injection (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24 hr of birth. Histopathological changes in ovarian and uterine development were investigated from postnatal day (PND) 14 to 10 weeks of age. Immunohistochemical expression of estrogen receptor alpha (ERα) in the uterus, serum levels of sex-related hormones and gene expression in the hypothalamus were examined. Although neonatal exposure to EE did not affect body growth or ovarian development, serum FSH tended to decrease at doses ≥ 2 μg/kg, and Kiss1 mRNA level in the whole hypothalamus was significantly decreased in all EE-treated groups at PND14.The number of uterine glands at PND21 was suppressed at doses ≥ 20 μg/kg, and ERα expression in the uterine epithelium at estrus stage decreased in a dose-dependent manner at 10 weeks of age. These results demonstrated that the various identified changes that occurred before the appearance of delayed adverse effects could be candidate early indicators.
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http://dx.doi.org/10.2131/jts.39.775DOI Listing
April 2015

Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

J Toxicol Sci 2014 Jun;39(3):437-45

Biological Research Laboratories, Nissan Chemical Industries, Ltd.

Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.
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http://dx.doi.org/10.2131/jts.39.437DOI Listing
June 2014

Effects of pyperonyl butoxide on the female reproductive tract in rats.

J Toxicol Sci 2013 ;38(6):891-902

Division of Pathology, National Institute of Health Sciences.

This study was investigated the effects of piperonyl butoxide (PBO) on the female reproductive tract. Female Crj:Donryu rats were fed a basal diet containing 5,000, 10,000 or 20,000 ppm PBO for 28 days, and compared with food-restricted rats of comparable body weights to those in the PBO 10,000 or 20,000 ppm groups. Although treatment with 20,000 ppm PBO for 28 days depressed body weight gain, the abnormal estrous cyclicity, mainly prolonged diestrus, was also induced by the PBO treatment which was not correlated with body weight change. 20,000 ppm PBO treatment markedly decreased uterine weights and slightly decreased ovarian weights. 10,000 and 20,000 ppm PBO treatment increased liver weights. These cycle and organ weight changes were linked to atrophic uterus and increased atretic follicles in the ovary. In hormone assays, PBO at both doses reduced serum E2 levels, but did not affect corticosterone levels. An anti-uterotrophic assay showed a slight but significant decrease in absolute uterine weight and a reduction of endometrial epithelium height in the 20,000 ppm group. PBO was positive in an ER α antagonist reporter gene assay, although the activity was much weaker than that of 4-hydroxytamoxifen. These results indicate that high-dose PBO treatment directly induces atrophic changes in the female reproductive tract in rats, and these effects are likely the result of a hypoestrogenic state and the anti-estrogenic activity of PBO.
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http://dx.doi.org/10.2131/jts.38.891DOI Listing
September 2014

Effect of chlorpromazine on rat placenta development.

Exp Toxicol Pathol 2014 Jan 16;66(1):41-7. Epub 2013 Oct 16.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Shiraoka-shi, Saitama 349-0294, Japan. Electronic address:

We examined the sequential histopathological changes in the placentas from rats exposed to chlorpromazine. Chlorpromazine was intraperitoneally administered on GD 14 at 50 and 100 mg/kg and the placentas were sampled on GDs 14.5, 15, 17 and 21. The incidence of dams with complete fetal resorption was increased from GD 17 up to 20% at 50 mg/kg and 44.4% at 100 mg/kg. The embryo/fetal weights reduced on GDs 15 and 17 at 50 mg/kg and during GDs 15-21 at 100 mg/kg. The placental weights reduced on GD 17 at 50 mg/kg and during GDs 14.5-21 at 100 mg/kg. Histopathologically, in the labyrinth zone, apoptotic cells were scattered in the trophoblastic septa without inhibition of cell proliferation on GDs 14.5 and 15 at 50 and 100 mg/kg in a dose-dependent manner. A decrease in trophoblasts led to labyrinth zone hypoplasia. In the basal zone, apoptotic cells were scattered on GDs 14.5 and 15 at 100 mg/kg, and most of them appeared to be glycogen cells. A decrease in glycogen cells induced the delayed development of glycogen cell islands and the subsequent remaining glycogen cell islands, and led to the cystic degeneration of glycogen cells. In addition, failure of development of the glycogen cell islands led to the impaired interstitial invasion of the glycogen cells, and then metrial gland hypoplasia occurred.
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http://dx.doi.org/10.1016/j.etp.2013.08.002DOI Listing
January 2014

Background data on developmental parameters during the gestation period in rats.

J Toxicol Pathol 2013 Mar 22;26(1):83-8. Epub 2013 Apr 22.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Shiraoka, Saitama 349-0294, Japan.

Background data during the gestation period were obtained from 128 Wistar Hannover GALAS rats and 26 Crl:CD(SD) pregnant rats in the control groups of our previous toxicity studies. The body weights of dams in the Wistar Hannover GALAS rats were significantly lower throughout the gestation period than those in the Crl:CD(SD) rats. In contrast, the time-dependent change in the body weight gain (%) of dams showed very similar trends in both strains. The mean number of live embryos/fetuses in the Wistar Hannover GALAS rats was 12.0, and was lower than that (14.5) in the Crl:CD(SD) rats. The placental weights gradually increased with pregnancy progression and reached a plateau on gestation day (GD) 19, although the embryo/fetal weights rapidly increased from GD 17 to GD 21. The embryo/fetal weights in the Wistar Hannover GALAS rats were significantly lower on only GD 21 than those in the Crl:CD(SD) rats. It is considered that this fetal weight difference between the strains develops during the fetal period, but not during the organogenesis period. In contrast, there were no differences in the placental weights between the two strains. Microscopically, the thickness of the labyrinth zone in the Wistar Hannover GALAS rats was thicker throughout the gestation period than that in the Crl:CD(SD) rats.
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http://dx.doi.org/10.1293/tox.26.83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620220PMC
March 2013

Delayed effects of neonatal exposure to 17alpha-ethynylestradiol on the estrous cycle and uterine carcinogenesis in Wistar Hannover GALAS rats.

Reprod Toxicol 2013 Sep 22;40:16-23. Epub 2013 May 22.

Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis.
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http://dx.doi.org/10.1016/j.reprotox.2013.05.005DOI Listing
September 2013

Effect of estrogen on rat placental development depending on gestation stage.

Exp Toxicol Pathol 2013 Jul 17;65(5):695-702. Epub 2012 Nov 17.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Saitama 349-0294, Japan.

We examined the sequential histopathological changes in the placenta from rats exposed to estrogen. 17 β-estrogiol-3-benzoate was intraperitoneally administered at 100 μg/animal/day during GD 6 to GD 8 (GD6-8 treated group), GD 9 to GD 11 (GD9-11 treated group) and GD 12 to GD 14 (GD12-14 treated group), and the placentas were sampled on GDs 11, 13, 15, 17, and 21. Fetal mortality rates were increased up to approximately 50% in the GD6-8 and 9-11 treated groups, but there was no change of fetal weight on GD 21. An increase in placental weight and a reduction in fetal/placental weight ratio were detected during GD 17 to GD 21 in the GD6-8 treated group. Histopathologically, hypoplasia of metrial gland was detected with defective development of spiral arteries in the GD6-8 and GD9-11 treated groups. A decrease in the thickness of metrial gland was observed from GD 11 onwards in the GD6-8 treated group and from GD 13 onwards in the GD9-11 treated group. The endovascular trophoblasts invaded into the spiral arteries in the deep part of metrial gland in these treated groups. The number of phospho-histone H3 positive cells was decreased on GD 11 or GD 13 in these groups. In the decidua basalis, transitory necrosis was observed with hemorrhage on GD 13 in the GD6-8 and GD9-11 treated groups. In the labyrinth zone, cystic dilatation of the sinusoid was observed with congestion in the GD6-8 treated group, resulting in an increased placental weight. Therefore, we consider that estrogen inhibits the proliferation of decidualized endometrial stromal cells in the metrial gland, and leads to metrial gland hypoplasia with less development of the spiral arteries. The reduced utero-placental blood flow is supposed to be one of the important factors for poor reproductive performance.
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http://dx.doi.org/10.1016/j.etp.2012.09.002DOI Listing
July 2013

Carcinogen-induced Thyroid Proliferative Lesions in Wistar Hannover GALAS Rats with Thyroid Dysplasia.

J Toxicol Pathol 2012 Mar;25(1):11-7

Incidences and morphological features of thyroid proliferative lesions induced by carcinogens in Wistar Hannover GALAS rats (GALAS rats) showing normal growth with or without thyroid dysplasia were examined. All thyroid tissue samples were obtained from our recently conducted study using male GALAS rats treated with 5 carcinogens according to the medium-term multiorgan carcinogenicity bioassay protocol (called DMBDD treatment). In the DMBDD-treated rats, thyroid dysplasia was found in 9 out of 114 rats. Follicular cell adenomas were found in 5 out of 9 rats with thyroid dysplasia and in 7 out of 105 rats without thyroid dysplasia. The incidence of adenoma was significantly increased in rats with thyroid dysplasia (55.6%) compared with that in rats without thyroid dysplasia (6.7%). Adenomas in rats with thyroid dysplasia were observed as single or multiple nodules, well demarcated and composed of variously sized vacuolated cells or unvacuolated cells. These histopathological features and staining profiles of luminal colloid for PAS and thyroglobulin, together with PCNA-positive cells, were fundamentally similar to those of rats without thyroid dysplasia. On the other hand, the luminal colloid in adenomas of rats with thyroid dysplasia had a tendency to be poorly stained for T(4) compared with that of rats without thyroid dysplasia. From these findings, it appears that dysplastic thyroids of rats showing normal growth are more sensitive to carcinogens than normal thyroids. In addition, the morphological features of carcinogen-induced thyroid proliferative lesions in GALAS rats with thyroid dysplasia were fundamentally similar to those of rats without thyroid dysplasia, except for the vacuoles and T(4) staining profile.
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http://dx.doi.org/10.1293/tox.25.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320152PMC
March 2012

Toxicological pathology in the rat placenta.

J Toxicol Pathol 2011 Jun 30;24(2):95-111. Epub 2011 Jun 30.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan.

The placenta grows rapidly for a short period with high blood flow during pregnancy and has multifaceted functions, such as its barrier function, nutritional transport, drug metabolizing activity and endocrine action. Consequently, the placenta is a highly susceptible target organ for drug- or chemical-induced adverse effects, and many placenta-toxic agents have been reported. However, histopathological examination of the placenta is not generally performed, and the placental toxicity index is only the placental weight change in rat reproductive toxicity studies. The placental cells originate from the trophectoderm of the embryo and the endometrium of the dam, proliferate and differentiate into a variety of tissues with interaction each other according to the development sequence, resulting in formation of a placenta. Therefore, drug- or chemical-induced placental lesions show various histopathological features depending on the toxicants and the exposure period, and the pathogenesis of placental toxicity is complicated. Placental weight assessment appears not to be enough to evaluate placental toxicity, and reproductive toxicity studies should pay more attention to histopathological evaluation of placental tissue. The detailed histopathological approaches to investigation of the pathogenesis of placental toxicity are considered to provide an important tool for understanding the mechanism of teratogenicity and developmental toxicity with embryo lethality, and could benefit reproductive toxicity studies.
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http://dx.doi.org/10.1293/tox.24.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234607PMC
June 2011

Effect of cisplatin on rat placenta development.

Exp Toxicol Pathol 2013 Jan 15;65(1-2):211-7. Epub 2011 Sep 15.

Toxicology & Environmental Science Department, Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan.

We examined the sequential histopathological changes in the placenta from rats exposed to cisplatin. Cisplatin was intraperitoneally administered at 2 mg/kg/day during GDs 11-12 (GD11,12-treated group), or GDs 13-14 (GD13,14-treated group), and the placentas were sampled on GDs 13, 15, 17 and 21. Fetal mortality rates were increased up to approximately 65% from GD 17 onward, and fetal weights were decreased on GD 21 in the GD11,12-treated group. A reduction in placental weights was detected from GD 15 onward, and the placentas on GD 21 were macroscopically small and thin in both treated groups. Histopathologically, in the GD13,14-treated group, an increase in apoptotic cells was detected on GDs 15 and 17 in the labyrinth zone, and on GD 21 in the basal zone, resulting in labyrinth zone hypoplasia. By contrast, in the GD11,12-treated group, an increase in apoptotic cells was detected on GDs 13, 15 and 17 in the labyrinth zone, and during the experimental period in the basal zone. A decrease in Phospho-Histone H3 positive cells was detected on GD 13 in the labyrinth zone and basal zone, resulting in hypoplasia of the labyrinth zone and basal zone. In addition, a marked decrease in glycogen cell-islands in the basal zone was also detected on GDs 15 and 17. There was a reduction in interstitial invasion of glycogen cell-like trophoblasts into the metrial gland on GD 15, resulting in metrial gland hypoplasia. Therefore, we consider that cisplatin administration in pregnant rats induces growth arrest of the labyrinth zone and basal zone, leading to small placenta. It is assumed that metrial gland hypoplasia is secondarily induced by the failure of glycogen cell island development associated with basal zone hypoplasia.
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http://dx.doi.org/10.1016/j.etp.2011.08.008DOI Listing
January 2013

Delayed adverse effects of neonatal exposure to diethylstilbestrol and their dose dependency in female rats.

Toxicol Pathol 2011 Aug 11;39(5):823-34. Epub 2011 Jul 11.

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, Japan.

Neonatal exposure to estrogenic chemicals causes irreversible complex damage to the hypothalamus-pituitary-gonadal axis and reproductive system in females. Some lesions are noted after maturation as delayed adverse effects. We investigated the characteristics and dose dependence of delayed effects using female rats neonatally exposed to diethylstilbestrol (DES). Female Donryu rats were subcutaneously injected with a single dose of DES of 0 (control), 0.15, 1.5, 15, 150, or 1,500 µg/kg bw after birth. All except the lowest dose had estrogenic activity in a uterotrophic assay. All rats at 1500 µg/kg and some at 150 µg/kg showed abnormal morphologies in the genital tract, indicating they were androgenized before maturation. Although no morphological abnormalities were noted at 15 µg/kg or lower, onset of persistent estrus was significantly accelerated in the 1.5, 15, and 150 µg/kg groups with dose dependency, and the latest onset was from seventeen to twenty-one weeks of age at 1.5 µg/kg. The neonatal exposure to DES increased uterine adenocarcinoma development only at 150 µg/kg, although uterine anomalies were detected at 1,500 µg/kg. These results indicate that neonatal exposure to DES, which exerts estrogenic activity in vivo, induces delayed adverse effects in female rats in a dose-dependent manner. Early onset of persistent estrus appears to be the most sensitive parameter.
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http://dx.doi.org/10.1177/0192623311413785DOI Listing
August 2011

The use of an automated hematology analyzer to observe cell growth in the chromosome aberration test using human lymphocytes.

J Toxicol Sci 2010 Dec;35(6):923-7

Human lymphocytes have been frequently used for in vitro chromosome aberration or micronucleus tests on whole-blood culture. However, it is difficult to observe or confirm the cell growth of lymphocytes just before chemical treatment compared with cultured cell lines, such as CHL or CHO cells. In order to overcome this drawback of using whole-blood culture, we investigated a possibility of using an automated hematology analyzer (AHA) (Sysmex XT-2000i, SYSMEX Corp. (Hyogo, Japan)) to measure the growth of lymphocytes applying a manual function of this apparatus. In this study, whole-blood samples were cultured for 4 days, and the growth of lymphocytes was measured once a day using a standard flow cytometer (FCM) with antibody CD3 and DNA staining solution, and by the AHA simultaneously. The results showed that growth curves produced employing the two methods coincided fairly well. Therefore, it can be concluded that the growth of lymphocytes in whole-blood culture can be measured using AHA in a straightforward and rapid way in in vitro chromosome aberration or micronucleus tests.
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http://dx.doi.org/10.2131/jts.35.923DOI Listing
December 2010

The impairment of metrial gland development in tamoxifen exposed rats.

Exp Toxicol Pathol 2012 Jan 6;64(1-2):121-6. Epub 2010 Aug 6.

Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan.

We examined the sequential histopathological changes in the placenta from rats exposed to tamoxifen. Tamoxifen was administered intraperitoneally at doses of 0 and 2 mg/kg/day on gestation days (GDs) 8, 9 and 10, and the placentas were sampled on GDs 11, 13, 15, 17, and 21. The fetal mortality rates in the tamoxifen group were increased up to 56%. However, there were no effects on the weights of live embryos/fetuses and their placentas. Histopathologically, the size of metrial gland in the tamoxifen group was reduced on all sampling times. The spiral arteries appeared less well developed in the hypoplastic metrial gland. A decrease in uterine natural killer (uNK) cells and mitotic uNK cells around the spiral arteries in the metrial gland was detected from GD 13 onward and on GDs 11 and 13, respectively. There were no obvious changes in the labyrinth zone or basal zone. We consider that the anti-estrogen effect of tamoxifen inhibits the proliferation of decidualized endometrial stromal cells in the metrial gland and leads to inhibition of the proliferative activity of uNK cells, followed by defective development of spiral arteries, and metrial gland hypoplasia. It is assumed that the metrial gland hypoplasia might be involved in the tamoxifen-induced embryo/fetus-toxicity.
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http://dx.doi.org/10.1016/j.etp.2010.07.004DOI Listing
January 2012

The relationship between fetal growth restriction and small placenta in 6-mercaptopurine exposed rat.

Exp Toxicol Pathol 2011 Jan 18;63(1-2):89-95. Epub 2009 Nov 18.

Toxicology & Environmental Science Department, Biological Research Laboratories, Nissan Chemical Industries, Ltd., 1470 Shiraoka, Minamisaitama, Saitama 349-0294, Japan.

In order to investigate the effect of placental size on fetal intrauterine growth retardation (IURG), we examined the morphology and alterations in the expression of glucose transporter in the placentas of rats exposed to 6-mercaptopurine (6-MP). 6-MP was administered orally at 0 and 60 mg/kg/day on gestation day (GD) 9, 11, 13 or 15, and the placentas were sampled on GDs 17 and 21. The main findings in the treated groups were small placenta caused by mitotic inhibition and apoptosis, fetal resorption and IUGR with or without some malformations. The most sensitive period to 6-MP-induced fetal mortality was found to be in the GD9-treated group, and the small placenta and fetal abnormalities in the GD11-treated group, respectively. However, the litters in a quarter of the dams with the treatment on GD 11 had no fetotoxicity despite 25% decline in the placental weight. Histopathologically, the expression of glucose transporter GLUT3 was increased in the trophoblastic septa in all treated groups, particularly remarkable with proliferation of trophoblasts in the above litters, where the fetal-placental weight ratio was increased. Thus, we consider that the normal fetal growth and development can be maintained caused by adaptive change, even if the placental weight decreased by approximately 25% in 6-MP exposed rats.
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http://dx.doi.org/10.1016/j.etp.2009.10.001DOI Listing
January 2011

Multi-endpoint genotoxic assay using L5178Y (Tk(+/-) -3.7.2c) cells.

J Toxicol Sci 2009 Oct;34(5):547-53

When the mouse lymphoma Tk assay (MLA) provides a positive result, its cause can be roughly estimated by examining colony sizes. An increase in the number of large colonies means that the compound tested has point mutational potential, while an increase in small colonies indicates the potential for chromosome aberration. However, it was found to be difficult to clearly judge this in the case of caffeine known as a clastogen lacking the potential of point mutation. In our study, caffeine significantly increased the thymidine kinase (Tk) mutation frequencies derived from large colonies as well as those from small colonies in the standard protocol, although the frequencies derived from a small colony were higher than those from large colonies at higher doses. Therefore, we prolonged the expression period from 2 days, a standard period, to 6 days after treatment and then examined the Tk and Hprt mutations simultaneously. The result showed that caffeine gave a completely negative result on a mutation test for both Tk and Hprt. On the other hand, ethyl methanesulfonate (EMS), a genotoxic carcinogen, showed a positive result for both. Moreover, caffeine and EMS significantly increased the frequencies of micronucleated cells. In conclusion, when MLA gives a positive result and the cause is ambiguous, in order to identify the exact cause of the positive response, it is helpful to perform a confirmatory test investigating the potential of Tk and Hprt gene mutation simultaneously after 6-day expression and to perform an in vitro micronucleus assay during the expression period.
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http://dx.doi.org/10.2131/jts.34.547DOI Listing
October 2009

Histopathological effect of ketoconazole on rat placenta.

J Vet Med Sci 2008 Nov;70(11):1179-84

Biological Research Laboratories, Nissan Chemical Industries, Ltd., Saitama, Japan.

In order to investigate the morphological effects of ketoconazole on hypertrophied placentas, we examined the sequential histopathological changes in the placenta from rats exposed to ketoconazole. Ketoconazole was administered orally at 0 and 25 mg/kg/day during gestation days (GDs) 12 to 14, and the placentas were sampled on GDs 15, 17 and 21. All dams showed neither effect on body weight nor any abnormal clinical signs during the experimental period. In the treated group, the placentas appeared more hypertrophic with increases in the weight, diameter and thickness on GD 21. Histopathologically, increased thickness was noted in the labyrinth zone and basal zone on GDs 17 and 21, while on GD 15 the change had been already evident in the former zone. In the labyrinth zone, the mitotic figures of the trophoblasts were significantly elevated on GD 15. A multiple cystic dilatation of maternal sinusoids was observed in some placentas on GDs 15, 17 and 21. In the basal zone, an increase in spongiotrophoblasts and clusters of glycogen cells were detected on GDs 17 and 21. In the decidua basalis, there were no significant changes in either histology or thickness between the control and treated group during GDs 15 to 21. In conclusion, ketoconazole increased the population of composed cells in the labyrinth and basal zone, leading to placental hypertrophy in pregnant rats.
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http://dx.doi.org/10.1292/jvms.70.1179DOI Listing
November 2008

Myostatin preferentially down-regulates the expression of fast 2x myosin heavy chain in cattle.

Proc Jpn Acad Ser B Phys Biol Sci 2008 ;84(8):354-62

Laboratory of Functional Morphology, Department of Animal Biology, Graduate School of Agricultural Science, Tohoku University, Miyagi, Japan.

Myostatin is involved in an inhibitor of muscular growth and differentiation. Myoblasts derived from double-muscled Japanese shorthorn cattle (DM myoblasts) with absence of functional myostatin had higher abilities to proliferate and differentiate than myoblasts derived from normal-muscled cattle (NM myoblasts). In DM myoblasts, mRNA expressions of fetal myosin heavy chain (MyHC) in growth medium and of fast 2a and 2x MyHC in fusion medium were significantly greater than that in NM myoblasts. No significant difference existed in expressions of embryonic and slow MyHC mRNA between DM and NM myoblasts. The expression of MyoD mRNA was suppressed in myoblasts by administration of myostatin. Two cloned DM myoblast strains (DMc) were established. Addition of myostatin for DMc resulted in less myotube formation and suppression of mRNA expression of fast 2x MyHC. These findings suggest that the endogenous myostatin preferentially down-regulates the expression of the fast 2x MyHC and participates in differentiation of myofiber types during early bovine myogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722022PMC
http://dx.doi.org/10.2183/pjab.84.354DOI Listing
November 2008

Effect of 6-mercaptopurine on rat placenta.

J Vet Med Sci 2008 Jun;70(6):551-6

Biological Research Laboratories, Nissan Chemical Industries, Ltd., Saitama, Japan.

In order to investigate the toxic effects of 6-mercaptopurine (6-MP) on placental development, we examined sequential morphology in the placentas from rats exposed to 6-MP. 6-MP was intraperitoneally administered at 60 mg/kg during gestation days (GDs) 11 to 12, and the placentas were sampled on GD 13, 15 or 21. In the 6-MP-treated group, maternal body weight suppression, increased death embryo/fetus ratio and some malformations were observed. The placenta weights were decreased on GDs 15 and 21. Macroscopically, placentas on GD 21 were small, brittle and thin with a white peripheral rim. Histopathologically, in the labyrinth zone, 6-MP treatment mainly evoked decreased mitosis on GDs 13 and 15, increased apoptotic cell on GDs 13, 15 and 21 and thinning on GDs 15 and 21. In the basal zone, 6-MP evoked decreased mitosis on GDs 13, and PAS-positive material in the spongiotrophoblasts was still detected on GD 15. Thickening of the basal zone was observed with cytolysis of glycogen cells, apoptosis and an increased number of composed cells on GD 21. In conclusion, 6-MP administration in pregnant rats induced growth arrest of the labyrinth zone and developmental delay in the basal zone, leading to small placentas. The fetotoxicity of 6-MP may be responsible for its direct anti-proliferative effects and resulting placental dysfunction.
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http://dx.doi.org/10.1292/jvms.70.551DOI Listing
June 2008

Carcinogenic risk of copper gluconate evaluated by a rat medium-term liver carcinogenicity bioassay protocol.

Arch Toxicol 2008 Aug 19;82(8):563-71. Epub 2008 Mar 19.

Toxicology and Environmental Science Department, Biological Research Laboratories, Nissan Chemical Industries Limited, Saitama, Japan.

Carcinogenic risk and molecular mechanisms underlying the liver tumor-promoting activity of copper gluconate, an additive of functional foods, were investigated using a rat medium-term liver carcinogenicity bioassay protocol (Ito test) and a 2-week short-term administration experiment. In the medium-term liver bioassay, Fischer 344 male rats were given a single i.p. injection of N-nitrosodiethylamine at a dose of 200 mg/kg b.w. as a carcinogenic initiator. Starting 2 weeks thereafter, rats received 0, 10, 300 or 6,000 ppm of copper gluconate in diet for 6 weeks. All rats underwent 2/3 partial hepatectomy at the end of week 3, and all surviving rats were killed at the end of week 8. In the short-term experiment, rats were given 0, 10, 300 or 6,000 ppm of copper gluconate for 2 weeks. Numbers of glutathione S-transferase placental form (GST-P) positive lesions, single GST-P-positive hepatocytes and 8-oxoguanine-positive hepatocytes, and levels of cell proliferation and apoptosis in the liver were significantly increased by 6,000 ppm of copper gluconate in the medium-term liver bioassay. Furthermore, hepatic mRNA expression of genes relating to the metal metabolism, inflammation and apoptosis were elevated by 6,000 ppm of copper gluconate both in the medium-term liver bioassay and the short-term experiments. These results indicate that copper gluconate possesses carcinogenic risk toward the liver at the high dose level, and that oxidative stress and inflammatory and pro-apoptotic signaling statuses may participate in its underlying mechanisms.
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http://dx.doi.org/10.1007/s00204-008-0294-xDOI Listing
August 2008
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