研究業績

研究業績
論文等

一般毒性学
A Study for Collecting Background Data on Wistar Hannover [Crl:WI(Han)] Rats inGeneral Toxicity Studies - Comparative Data to Sprague Dawley Rats Kazuhiro HAYAKAWA1，Yuichi MIMURA2，Shigehiro TACHIBANA，Mami FURUYA, Terutaka KODAMA3，Toyohiko AOKI4，Satoru HOSOKAWA4，Motoko FUKUI2，Seiji SHIBATA2，Masanao YOSHIDA3，Takeshi
MASUYAMA3，Takahiro NARITA3，Makiko KUWAGATA，Shigeru HISADA2, Eiji MAKI5
The Journal of Toxicological Sciences, 2013 ; 38 ( 6 ): 855 - 873
The purpose of the present study was to collect background data from repeated dose toxicity
studies in Wistar Hannover [Crl:WI(Han)] (hereafter Wistar Han) rats with dosing periods of 4 , 13and 26 weeks from four safety research facilities of pharmaceutical companies and contract researchorganizations participating in the International Genetic Standardization (IGS) rat forum supported
by Charles River Laboratories Japan, Inc. The data from Wistar Han rats were compared with thosefrom Sprague Dawley Crl:CD(SD) rats. In addition, the effects of restricted feeding of SD rats werealso investigated by one facility. As a result, body weights and food consumption in Wistar Han rats
were lower than those of SD rats. White blood cell (WBC), neutrophil, lymphocyte, monocyte andeosinophil counts were almost half of those noted for SD rats and platelet counts were almost 20 %less than those in SD rats. Minimal strain differences were noted in several biochemical parameters
including aspartate aminotransferase (AST), alanine aminotransferase, total cholesterol, triglycerideand phospholipids, and in thymus, ovary and testis weights. Ophthalmologic or histopathologic
examinations revealed a higher incidence of corneal opacities or corneal mineralization in WistarHan rats. Restricted feeding of SD rats resulted in intermediate values for body weights and foodconsumption between the ad libitum fed SD and Wistar Han rats, and WBC and AST were lower
than those in the ad libitum fed SD rats. Based on these results, some strain differences might beascribable to reduced food consumption and associated body weight changes in Wistar Han rats.
1Kawashima Drug Safety, Global Drug Safety, Biopharmaceutical Assessment Core Function

Unit, Eisai Co., Ltd.; 2 Developmental Research Center, Aska Pharmaceutical Co., Ltd.;
3Toxicology & Pathology, Development Research Laboratories, Research Center, Ajinomoto

Pharmaceuticals Co., Ltd.; 4 Tsukuba Drug Safety, Global Drug Safety, Biopharmaceutical
Assessments Core Function Unit, Eisai Co., Ltd.; 5 Consultant on Drug Safety Assessment

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秦野研究所年報 Vol. 37. 2014

生殖・発生毒性学
An antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery inrats: A 28-day repeated dose test and reproduction/developmental toxicity test
Mariko MATSUMOTO1,3, Makiko YAMAGUCHI2, Yuka YOSHIDA, Mika SENUMA, Hiromasa TAKASHIMA,Tomoko KAWAMURA1, Hina KATO1, Mika TAKAHASHI1, Mutsuko HIRATA-KOIZUMI1, Atsushi ONO1,Kazuhito YOKOYAMA3, Akihiko HIROSE1
Food and Chemical Toxicology, 2013 ; 56: 290 - 296
A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N'-diphenylp-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats
were dosed with DPPD by gavage for 28 days at 0 , 100 , 300 , or 1000 mg/kg bw/day or for a totalof 42 – 46 days at 0 , 8 , 50 , or 300 mg/kg bw/day. No signiﬁcant adverse effects were observed in
the repeated dose toxicity study up to 1 , 000 mg/kg bw/day in both sexes. In the reproduction/
developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one
died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another femaledelivered only three live pups at 300 mg/kg bw/day. A signiﬁcantly prolonged gestation period wasobserved at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/
developmental toxicity were considered to be 1 , 000 and 8 mg/kg bw/day, respectively.
1Division of Risk Assessment, Biological Safety Center, National Institute of Health Sciences;2

Research Institute for Animal Science in Biochemistry & Toxicology; 3 Department ofEpidemiology and Environmental Health, Juntendo University Faculty of Medicine
Developmental effects of oral exposure to diethylstilbestrol on mouse placenta
Tetsuji NAGAO1, Nao KAGAWA2, Yoshiaki SAITO, Munekazu KOMADA3
Journal of Applied Toxicology, 2013 ; 33 ( 11 ): 1213 - 1221
Placental growth and function are of biological significance in that placental tissue promotesprenatal life and the maintenance of pregnancy. Exposure to synthetic estrogens causes embryonicmortality and placental growth restriction in mice. The aim of the present study was to examine
the effects of diethylstilbestrol (DES) on placenta in mice. DES at 1 , 5 , 10 or 15 µg/kg/day, or 17
β -estradiol (E 2 ) at 50 µg/kg/day, was administered orally to ICR mice on days 4 through to 8 ofgestation. Expression of ERα , ERβ , ERRβ or ERRγ mRNA in the junctional or labyrinth zone of theplacentas on day 13 was assessed using RT-PCR, as well as the embryonic mortality, embryonic andplacental weight, histological changes of labyrinth and ultrastructural changes of the trophoblast
giant cells (TGCs). Embryo mortalities in the DES 10 and 15 µg/kg/day groups were markedly
increased. No significant changes in embryonic and placental weight were observed in any DESor E 2 -exposed groups. Expression of ERα mRNA in the junctional zone with male embryos in the5 µg/kg/day group was significantly higher than that in the control, whereas expression was notdetermined in the 15 µg/kg/day group. Histological observation revealed that the placentas exposed
to DES at 10 µg/kg/day lacked the developing labyrinth. Ultrastructural observation of the TGCs
showed poor rough-surfaced endoplasmic reticulum in the DES 10 µg/kg/day group. The present
data suggest that developmental changes induced by DES may be related to interference with
the nutrition and oxygen exchange between mother and embryo or decreased protein synthesis,
resulting in a high frequency of embryo mortality.

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研究業績
1

Laboratory of Developmental Biology, Department of Life Science, Kinki University;

2Laboratory of Animal Genetics, Department of Life Science, Kinki University; 3 Division of Cell

Biology and Neuroscience, Faculty of Medical Sciences, University of Fukui
A Study for Collecting Background Data on Wistar Hannover [Crl:WI(Han)] Rats inEmbryo-fetal Development Studies - Comparative Data to Sprague Dawley Rats Ken-ichi N ORITAKE 1 , Takashi I KEDA 2 , Keiichi I TO 3 , Yoji M IWA 4 , Mika S ENUMA , Hiromasa
TAKASHIMA5, Taishi TATEISHI6, Shigeru HISADA2, Eiji MAKI7
The Journal of Toxicological Sciences, 2013 ; 38 ( 6 ): 847 - 854
The purpose of the present study was to collect the background data on Wistar Hannover [Crl:WI(Han)](hereafter Wistar Han) rats in embryo-fetal development studies from the 6 safety research facilitiesof pharmaceutical companies and contract research organizations. In each facility, 20 or 22 female
rats were dosed with vehicle solution during the organogenesis period. As a result, no abnormalities inclinical signs and necropsy ﬁndings in dams were found. Body weights and food consumption in dams
were lower than those in Sprague Dawley (SD) rats. The number of corpora lutea (13.3 vs. 16.0 in SD)
and implantations (11.8 vs. 14.7) were fewer, and fetal body weights (3.66 vs. 3.70) and placental
weights (0.42 vs. 0.45) tended to be lower than those in SD rats. Regarding the fetal abnormalities, theincidence of several ﬁndings such as the persistent left umbilical artery (10.4% vs. 1.1 %) and cervical(5.2% vs. 0.4%), full (7.4% vs. 0.9%) or short supernumerary (64.5% vs. 9.9%) and wavy ribs (6.6%vs. 0.3%) was higher than that in SD rats. Our present study showed that they maintained a sufﬁcientnumber of live fetuses and the difference in the fetal sex ratio was not observed. In conclusion, Wistar
Han rats were considered to be a suitable strain for embryo-fetal development toxicity study. Since theincidence of several abnormalities was higher than that in SD rats, it may be said that to accumulate
background control data is important to evaluate the embryo-fetal development toxicity study using
Wistar Han rats.
1Medical Safety Research Laboratories, Daiichi Sankyo Co., Ltd.; 2 Safety Research Department,ASKA Pharmaceutical Co., Ltd.; 3 Biosafety Research Center, Foods, Drugs and Pesticides;
4Nihon Bioresearch Inc.; 5 Ina Research Inc.; 6 Shin Nippon Biomedical Laboratories, Ltd.;

7Consultant on Drug Safety Assessment

細胞毒性学
Studies on mechanism of wear in micro-beads, and food-safety of fine particles caused bywear in a micro-beads millHarumi MATSUZAKI1, Yutaka WAKO1, Mika WATANABE
Powder Technology, 2013 ; 240: 74 - 78
The characteristics of wear in micro-beads were studied by focusing on projections on the surfacesof the micro-beads. Food safety associated with the presence of ﬁne wear particles was studied bycytotoxicity tests reusing micro-beads with the projections worn away. It was shown that the smaller
projections on the micro-beads surface were removed in a shorter time than the larger one and that
if the beads diameter was less than about 60 µm, the size of the projections reached the submicronlevel. Also, it was shown that ﬁne particles formed by wear in micro-beads made of yttrium partiallystabilized zirconia did not show cytotoxicity.
1

Graduate School of Mechanical, Bio-chemical Engineering, Hachinohe Institute of Technology33秦野37.indb 33

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秦野研究所年報 Vol. 37. 2014

食品衛生学
微生物検査の外部精度管理鈴木達也
食品機械装置 , 2014 ; 51 ( 3 ): 57 - 60
ダイズおよびトウモロコシ抽出 DNA の精製度の検討
笠間菊子 , 小熊恭代 , 穐山浩 1 , 鈴木達也 , 渡辺卓穂 , 小島幸一

日本食品化学学会誌 , 2013 ; 20 ( 3 ): 203 - 208
The quality and yield of DNA extracted from soybean and maize samples were compared using
two commercial DNA extraction kits, the DNeasy Plant Mini kit (Mini kit) and the GM quicker kit.
Subsequent quantiﬁcation of the extracted DNA samples by UV spectrophotometry and ﬂuorometry
revealed that the yields of soybean DNA extracted using the Mini kit were approximately threetimes higher when determined by UV spectrophotometry than when they were determined byfluorometry. Conversely, the yields of soybean DNA extracted using the GM quicker kit were
only slightly higher when determined by UV spectrophotometry than when they were determinedby fluorometry. However, the relative DNA yields of maize DNA samples estimated by UV
spectrophotometry and fluorometry were 1 . 77 with the Mini kit and 1 . 52 with the GM quicker
kit. To validate the soybean DNA yields obtained using both extraction kits, DNA samples wereanalyzed by agarose gel electrophoresis and real-time PCR of a reference gene. These analyses
indicated that the Mini kit yields estimated by UV spectrometry were overestimated, due to more
low-intensity bands and fewer gene copies being observed, compared to DNA extracted with the GM
quicker kit. Conversely, the maize DNA yields obtained using the Mini and GM quicker kits showed
only slight differences between the real-time PCR and agarose gel electrophoresis analyses. Theextracted DNA samples were then analyzed by size-exclusion chromatography. The results showedthat the soybean DNA extracted using the Mini kit contained more low-molecular weight impurities
than the DNA extracted using the GM quicker kit and maize extracts obtained with both extraction
kits. Therefore, it appears that the presence of low-molecular weight impurities in soybean DNA
extracted with the Mini kit interferes with the UV quantiﬁcation of DNA.
1

国立医薬品食品衛生研究所

食品分析の信頼性を確保するための外部精度管理について
渡辺卓穂
計測標準と計量管理 , 2014 ; 63 ( 4 ): 6- 11
食品添加物検査の外部精度管理調査について
渡辺卓穂
食品衛生学雑誌 , 2014 ; 55 ( 1 ): J10-J 1434

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研究業績医療機器
第 6 章：非臨床安全性試験・臨床試験における評価【第 1 節】
非臨床試験の評価[ 1 ] 非臨床試験で実施される安全性試験の概要

小島幸一
再生医療における臨床研究と製品開発 , 技術情報協会 , 東京
（2013）, pp. 367 - 374
第 13 章 研究 , 試験に関わる規制・ガイドラインの最新トピックと今後の動向 第 5 節 医療機器 GLP
小島幸一
実験者/試験検査員の誤ったデータの取扱い・試験誤操作防止策, 技術情報協会, 東京（2014）, pp. 505-511

発達神経毒性学
Chapter 5 Sexual Dimorphism in Monoamine Metabolism in BrdU-Treated Rats Showing
Behavioral Dopamine Hypersensitivity: An Animal Model of SchizophreniaKatsumasa MUNEOKA1, Makiko KUWAGATA
Sexual Dimorphism, InTech, (2013 ), pp. 81 - 96
1

Department of Anatomy, Showa University, School of Medicine

薬効薬理Tranexamic acid induces kaolin intake stimulating a pathway involving tachykinin
neurokinin 1 receptors in rats
Hitoshi KAKIUCHI1, Asako KAWARAI-SHIMAMURA2, Makiko KUWAGATA, Kensuke ORITO1
European Journal of Pharmacology, 2014 ; 723 : 1 - 6
Tranexamic acid suppresses post-partum haemorrhage and idiopathic menorrhagia through its
anti-fibrinolytic action. Although it is clinically useful, it is associated with high risks of side effects
such as emesis. Understanding the mechanisms underlying tranexamic acid-induced emesis is very
important to explore appropriate anti-emetic drugs for the prevention and/or suppression of emesis. In
this study, we examined the receptors involved in tranexamic acid-induced kaolin intake in rats, whichreflects the drug's clinical emetogenic potential in humans. Further, we examined the brain regions
activated by administration of tranexamic acid and elucidated pivotal pathways of tranexamic acidinduced kaolin intake. We examined the effects of ondansetron, a 5 -hydroxytryptamine 3 receptor
antagonist, domperidone, a dopamine 2 receptor antagonist, and aprepitant, a tachykinin neurokinin 1(NK1) receptor antagonist, on tranexamic acid-induced kaolin intake in rats. Then, we determined thebrain regions that showed increased numbers of c-Fos immunoreactive cells. Finally, we examined theeffects of an antagonist(s) that reduced tranexamic acid-induced kaolin intake on the increase in c-Fos
immunoreactive cells. Aprepitant signiﬁcantly decreased tranexamic acid-induced kaolin intake. However,neither ondansetron nor domperidone decreased kaolin intake. Tranexamic acid signiﬁcantly increased c-Fos
immunoreactive cells by approximately 5.5-fold and 22-fold in the area postrema and nucleus of solitary
tract, respectively. Aprepitant decreased the number of c-Fos immunoreactive cells in both areas. Tranexamic
acid induced kaolin intake possibly via stimulation of tachykinin NK1 receptors in rats. The tachykinin
NK1 receptor could be targeted to prevent and/or suppress emesis in patients receiving tranexamic acid.
1

Laboratory of Physiology II, Department of Veterinary Medicine, School of VeterinaryMedicine, Azabu University, 2 Corporate Planning Department, Anicom Holdings, Inc.

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秦野研究所年報 Vol. 37. 2014

その他
フロアからの発言
小野宏

日本薬理学雑誌 , 142 ( 5 ) (2013 ), pp. 207 - 208
学会発表等

免疫毒性学
粒子径の異なるナノ白金の LLNA 試験
森村智美 , 関剛幸 , 高岡裕 , 青木聡子 , 又吉

健 , 西垣嘉人 , 吉岡靖男 1 , 堤康央 1 , 桑形麻樹子

第 40 回日本毒性学会学術年会 2013 . 6 . 17～6 . 19（千葉）
同会講演要旨集 , pp. S 3341大阪大学大学院薬学研究科毒性学分野

In vitro 皮膚感作性試験代替法 :KeratinoSens assay の JaCVAM 第三者評価委員会における検証状況
金澤由基子 1 , 安達玲子 2 , 小島幸一 , 筒井尚久 3 , 佐藤一博 4 , 森本隆史 5 , 武吉正博 6 , 牧栄二 7 , 小島肇2

第 20 回日本免疫毒性学会学術大会 2013 . 9 . 12～9 . 13
（東京）
同会講演要旨集 , p. 49
1

独立行政法人 医薬品医療機器総合機構 ; 2 国立医薬品食品衛生研究所 ; 3 田辺三菱製薬株式会社 ;4福井大学 ; 5 住友化学株式会社 ; 6 一般財団法人 化学物質評価研究機構 ; 7 安全性試験コンサルタント

In vitro 皮膚感作性試験代替法 :Direct Peptide Reactivity Assay（DPRA）の JaCVAM 第三者評価委員会における検証状況
武吉正博 1 , 佐藤一博 2 , 森本隆史 3 , 筒井尚久 4 , 安達玲子 5 , 金澤由基子 6 , 小島幸一 , 牧栄二 7 , 小島肇5

第 20 回日本免疫毒性学会学術大会 2013 . 9 . 12～9 . 13
（東京）
同会講演要旨集 , pp. 50 - 51
1

一般財団法人 化学物質評価研究機構 ; 2 福井大学 ; 3 住友化学株式会社 ; 4 田辺三菱製薬株式会社 ;5

国立医薬品食品衛生研究所 ; 6 独立行政法人 医薬品医療機器総合機構 ; 7 安全性試験コンサルタント

36

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研究業績

毒性病理学
ステント留置血管の治癒における初期の組織反応
寺尾壽子 1 , 早場純子 1 , 麻生良平 1 , 田崎雅子 1 , 磯部厚志 1 , 井上知紀 1 , 坂岡

篤 1 , 臼見憲司 , 斉藤義明 ,蟹澤成好 2 , 萩原仁美 1
第 30 回日本毒性病理学会 2014 . 1 . 30～1 . 31
（徳島）
同会講演要旨集 , p. 112
1テルモ株式会社 ; 2 横浜市立大学

Developmental Origins of Health and Disease（DOHaD）説に基づいた新生児期栄養変化による生後発達への影響
桑形麻樹子 , 瀬沼美華 , 熊谷文明 , 柴藤淳子 1 , Rakwal Randeep 1 , 斉藤義明 , 丸茂秀樹 , 小川哲郎 2 ,塩田清二 1
第 30 回日本毒性病理学会 2014 . 1 . 30～1 . 31（徳島）
同会講演要旨集 , p. 113
1

昭和大学医学部顕微解剖学部門 ; 2 埼玉医科大学医学部生理学教室

一般毒性学
ラットにおいてトラネキサム酸により誘発されるカオリン摂取とそのメカニズムの解明
垣内仁志 1 , 川原井（島村）麻子 2 , 桑形麻樹子 , 折戸謙介 1
第 156 回日本獣医学会学術集会 2013 . 9 . 20～9 . 22（岐阜）
同会講演要旨集 , p. 377
1

麻布大学獣医学部生理学第二研究室 ; 2 アニコム ホールディングス株式会社

酸化チタンナノ粒子の点鼻投与がラットの行動に及ぼす影響
横田俊二 , 瀬沼美華 , 根倉司 , 古谷真美 , 吉田由香 , 堀内伸二 , 安藤栄里子

日本薬学会第 134 年会 2014 . 3 . 27～3 . 30（熊本）
同会要旨集 3 , p. 144

生殖・発生毒性学
Hatano 高および低回避雌ラットの性成熟 , 性周期および体重推移に及ぼす新生児期ジエチルスチルベス
トロール曝露の影響
太田亮 , 根倉司 , 大向英夫 , 新藤智子

環境ホルモン学会第 16 回研究発表会 2013 . 12 . 12～12 . 13（東京）
同会要旨集 , p. 66

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食品衛生学
食品添加物検査の外部精度管理調査について
渡辺卓穂
第 105 回日本食品衛生学会 2013 . 5 . 17～5 . 18（東京）
同会講演要旨 , p. 30
食品衛生外部精度管理調査のための残留動物用医薬品調査試料の作成検討について
渡辺卓穂 , 高坂典子 , 鈴木達也 , 小島幸一
日本食品化学学会第 19 回総会・学術大会 2013 . 8 . 29～8 . 30
（名古屋）
同会講演要旨集 , p. 104

動物実験代替法IL-8 Luc assay の施設間差試験およびデータセットの作製
木村裕 1 , 渡辺美香 , 斎藤るみ子 , 鈴木紀之 2 , 岩城知子 3 , 山影康次 , 斎藤幸一 2 , 中島芳浩 3 ,近江谷克裕 5 , 酒井綾子 , 丸谷あおい 4 , 大森

崇 4 , 山崎晶次郎 , 小島

肇 6 , 田中憲穂 , 相場節也 1

日本動物実験代替法学会第 26 回大会 2013 . 12 . 19～12 . 21
（京都）同会プログラム / 講演要旨集 , p. 116
1

東北大学大学院医学系研究科皮膚科学講座 ; 2 住友化学株式会社生物環境科学研究所 ; 3 独立行政法

人 産業技術総合研究所・健康工学研究部門 ; 4 同志社大学 ; 5 独立行政法人 産業技術総合研究所・バイオメディカル研究部門 ; 6 国立医薬品食品衛生研究所
IL-8 Luc assay におけるばらつきを考慮した判定基準の提案
丸谷あおい 1 , 相場節也 2 , 木村

裕 2 , 渡辺美香 , 鈴木紀之 3 , 岩城知子 4 , 山影康次 , 斎藤幸一 3 ,中島芳浩 4 , 近江谷克裕 5 , 山崎晶次郎 , 小島

肇 6 , 田中憲穂 , 小林眞弓 1 , 森

梓 1 , 大森崇1

日本動物実験代替法学会第 26 回大会 2013 . 12 . 19～12 . 21
（京都）同会プログラム / 講演要旨集 , p. 117
1同志社大学 ; 2 東北大学大学院医学系研究科皮膚科学講座 ; 3 住友化学株式会社生物環境科学研究所 ;4独立行政法人 産業技術総合研究所・健康工学研究部門学 ; 5 独立行政法人 産業技術総合研究所・バイオメディカル研究部門 ; 6 国立医薬品食品衛生研究所
Vitrigel-EIT（Eye Irritancy Test）
法のプレバリデーション研究小島肇 1 , Nicole Kleinstreuer 2 , Chae-Hyung Lim 3 , 寒水孝司 4 , 渡辺美香 , 新妻

山下邦彦 , 福田隆之 , 山口典子 , 藤原
566

聖6-8, 山口宏之

7,8, 竹澤俊明

健,7

日本動物実験代替法学会第 26 回大会 2013 . 12 . 19～12 . 21（京都）同会プログラム / 講演要旨集 , p. 150
1

国立医薬品食品衛生研究所 ; 2 ILS/NICEATEM/ICCVAM; 3 KOCVAM/MFDS; 4 京都大学 ; 5 株式会社

ダイセル ; 6 株式会社ボゾリサーチセンター; 7 独立行政法人 農業生物資源研所 ; 8 関東化学株式会社

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研究業績その他
DOHaD 説に基づいた精神疾患のリスクに関与する遺伝子の検索瀬沼美華 , Rakwal, Randeep 1 , 柴藤淳子 1 , 齋藤智美 1 , 宗岡克政 1 , 小川哲郎 1 , 塩田清二 1 , 桑形麻樹子
第 53 回日本先天異常学会学術集会 2013 . 7 . 21～7 . 23（大阪）
同会プログラム・要旨集 , p. 84
1

昭和大学医学部第一解剖学教室

Developmental Origins of Health and Disease（DOHaD）
責任遺伝子の解析
小川哲郎 1 , 柴藤淳子 1 , Rakwal Randeep 1 , 斎藤智美 1 , 桑形麻樹子 , 塩田清二 1
第 53 回日本先天異常学会学術集会 2013 . 7 . 21～7 . 23
（大阪）
同会プログラム・要旨集 , p. 84
1

昭和大学医学部第一解剖学教室

39

秦野37.indb 39

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