Perfluorinated alkyl substances exposure and onset of puberty - birth cohort and in vitro studies

2019 Fiscal Year Annual Research Report

• Project/Area Number: 18H03035
• Research Institution: Hokkaido University
• Principal Investigator: 荒木 敦子 北海道大学, 環境健康科学研究教育センター, 特任准教授 (00619885)
• Co-Investigator(Kenkyū-buntansha): 小島 弘幸 北海道医療大学, 薬学部, 教授 (10414286) ; 小林 澄貴 北海道大学, 環境健康科学研究教育センター, 特任講師 (10733371) ; 守屋 仁彦 北海道大学, 医学研究院, 客員研究員 (20374233) ; 宮下 ちひろ 北海道大学, 環境健康科学研究教育センター, 特任准教授 (70632389) ; 岸 玲子 北海道大学, 環境健康科学研究教育センター, センター特別招へい教授 (80112449) ; アイツバマイ ゆふ 北海道大学, 環境健康科学研究教育センター, 特任講師 (90752907)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 内分泌かく乱物質 / 有機フッ素化合物 / 出生コーホート / 遺伝子多型 / 核内受容体 / 細胞アッセイ系 / 生殖ホルモン

Outline of Annual Research Achievements

北海道スタディに参加者504名の母体血清中のPFOS/PFOA濃度と臍帯血中の性ホルモン濃度、臍帯血中DNAのCYP17A1、CYP19A1、HSD3B1、HSD3B2、HSD17B1、HSD17B3遺伝子にある12か所の一塩基多型(SNPs)を解析した。PFOS濃度とHSD17B1（rs676387およびrs2675531）遺伝型との交互作用がDHEA/A-dione濃度と関連を示した。HSD17B1遺伝型で層別解析したところ、HSD17B1(rs676387)-GG/GA型ではPFOS濃度が2倍増えるとDHEA/A-dioneは0.115（95%CI: -0.294, 0.065）減少したのに対し、AA型では0.476（-0.276, 0.979）増加した。HSD17B1(rs2676531)-CC/CT型ではPFOS濃度が2倍増えるとDHEA/A-dioneは0.138（95%CI: -0.335, 0.060）減少したのに対し、TT型では0.535（0.013, 1.057）増加した。児のHSD17B1遺伝型は、母体血清PFOS濃度と児の性ホルモン濃度との関連に違いを及ぼす可能性が示唆された。
in vitro細胞アッセイ系を用いてPFAS11化合物のpregnane X receptor(PXR)、constitutive androstane receptor(CAR)、peroxisome proliferators-activated receptor(PPAR)α、PPARβ、PPARγの各種ヒト核内受容体に対するアゴニスト活性を調べた。PFOA及びPFNAが高用量でPPARalpha;アゴニスト活性を示したが、PXR・CAR・PPARalpha,PPARganmaに対するアゴニスト活性は認められなかった。また、PFASsの遺伝子発現に及ぼす影響評価として、ヒト血中濃度の高いPFOA及びPFNAをそれぞれヒト肝細胞株に曝露してmRNAを採取した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

ほぼ順調に進んでいる。第二次性徴に関する調査票を約1365人に発送し691人から回答を得た。併せて尿検体の収集を363人に依頼し319件の検体を保存した。胎児期PFOS/PFOA曝露と臍帯血中性ホルモン値に児がもつ特定のHSD17B1遺伝型が、関連の影響に違いを及ぼす可能性が示唆された。この結果は現在論文投稿中である。

Strategy for Future Research Activity

第二次性徴に関する調査を継続し、男児の身長体重に関するデータを合わせて児の思春期発来の時期を確認する。胎児期のPFAS曝露濃度が児の思春期発来の時期と関連するか、解析を行う。in vitroアッセイについては、ヒト血中濃度の高いPFOA及びPFNAのヒト肝細胞株HepaRGに対する遺伝子発現変化をマイクロアレイ解析で調べ、典型的な変動遺伝子についてRT-PCR法で確認する。さらに、そのタンパク質の発現についてもWB法で確認する。ヒト血中の曝露マーカーとなり得るタンパク質である場合、検出感度の良い酵素抗体法（ELISA系）を確立する。

Research Products

• [Journal Article] Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children (2020)
  • Author(s): Araki Atsuko、Ait Bamai Yu、Bastiaensen Michiel、Van den Eede Nele、Kawai Toshio、Tsuboi Tazuru、Miyashita Chihiro、Itoh Sachiko、Goudarzi Houman、Konno Satoshi、Covaci Adrian、Kishi Reiko
  • Journal Title: Environmental Research Volume: 183 Pages: 109212～109212
  • DOI: 10.1016/j.envres.2020.109212
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of exposure to prenatal phthalate esters and bisphenol A and polymorphisms in the ESR1 gene with the second to fourth digit ratio in school-aged children: Data from the Hokkaido study (2020)
  • Author(s): Nishimura Yoko、Moriya Kimihiko、Kobayashi Sumitaka、Araki Atsuko、Sata Fumihiro、Mitsui Takahiko、Itoh Sachiko、Miyashita Chihiro、Cho Kazutoshi、Kon Masafumi、Nakamura Michiko、Kitta Takeya、Murai Sachiyo、Kishi Reiko、Shinohara Nobuo
  • Journal Title: Steroids Volume: 159 Pages: 108637～108637
  • DOI: 10.1016/j.steroids.2020.108637
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal exposure to 11 perfluoroalkyl substances and fetal growth: A large-scale, prospective birth cohort study (2020)
  • Author(s): Kashino Ikuko、Sasaki Seiko、Okada Emiko、Matsuura Hideyuki、Goudarzi Houman、Miyashita Chihiro、Okada Eisaku、Ito Yoichi M.、Araki Atsuko、Kishi Reiko
  • Journal Title: Environment International Volume: 136 Pages: 105355～105355
  • DOI: 10.1016/j.envint.2019.105355
  • Peer Reviewed / Open Access
• [Journal Article] The mixture effects of bisphenol derivatives on estrogen receptor and androgen receptor (2020)
  • Author(s): Park Choa、Song Heewon、Choi Junyeong、Sim Seunghye、Kojima Hiroyuki、Park Joonwoo、Iida Mitsuru、Lee YoungJoo
  • Journal Title: Environmental Pollution Volume: 260 Pages: 114036～114036
  • DOI: 10.1016/j.envpol.2020.114036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between perfluoroalkyl substance exposure and thyroid hormone/thyroid antibody levels in maternal and cord blood: The Hokkaido Study (2019)
  • Author(s): Itoh Sachiko、Araki Atsuko、Miyashita Chihiro、Yamazaki Keiko、Goudarzi Houman、Minatoya Machiko、Ait Bamai Yu、Kobayashi Sumitaka、Okada Emiko、Kashino Ikuko、Yuasa Motoyuki、Baba Toshiaki、Kishi Reiko
  • Journal Title: Environment International Volume: 133 Pages: 105139～105139
  • DOI: 10.1016/j.envint.2019.105139
  • Open Access
• [Journal Article] Effects of prenatal sex hormones on behavioral sexual dimorphism (2019)
  • Author(s): Mitsui Takahiko、Araki Atsuko、Miyashita Chihiro、Ito Sachiko、Ikeno Tamiko、Sasaki Seiko、Kitta Takeya、Moriya Kimihiko、Cho Kazutoshi、Morioka Keita、Kishi Reiko、Shinohara Nobuo、Takeda Masayuki、Nonomura Katsuya
  • Journal Title: Pediatrics International Volume: 61 Pages: 140～146
  • DOI: 10.1111/ped.13756
  • Peer Reviewed
• [Journal Article] Multiple exposures to organophosphate flame retardants alter urinary oxidative stress biomarkers among children: The Hokkaido Study (2019)
  • Author(s): Ait Bamai Yu、Bastiaensen Michiel、Araki Atsuko、Goudarzi Houman、Konno Satoshi、Ito Sachiko、Miyashita Chihiro、Yao Yiming、Covaci Adrian、Kishi Reiko
  • Journal Title: Environment International Volume: 131 Pages: 105003～105003
  • DOI: 10.1016/j.envint.2019.105003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative study of the effect of 17 parabens on PXR-, CAR- and PPARα-mediated transcriptional activation (2019)
  • Author(s): Fujino Chieri、Watanabe Yoko、Sanoh Seigo、Hattori Shoko、Nakajima Hiroyuki、Uramaru Naoto、Kojima Hiroyuki、Yoshinari Kouichi、Ohta Shigeru、Kitamura Shigeyuki
  • Journal Title: Food and Chemical Toxicology Volume: 133 Pages: 110792～110792
  • DOI: 10.1016/j.fct.2019.110792
  • Peer Reviewed
• [Journal Article] Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes (2019)
  • Author(s): Fujino Chieri、Watanabe Yoko、Sanoh Seigo、Nakajima Hiroyuki、Uramaru Naoto、Kojima Hiroyuki、Yoshinari Kouichi、Ohta Shigeru、Kitamura Shigeyuki
  • Journal Title: Heliyon Volume: 5 Pages: e02466～e02466
  • DOI: 10.1016/j.heliyon.2019.e02466
  • Peer Reviewed / Open Access
• [Journal Article] Distribution of 58 semi-volatile organic chemicals in the gas phase and three particle sizes in indoor air and house dust in residential buildings during the hot season in Japan (2019)
  • Author(s): 3.Takeuchi S, Tanaka-Kagawa T, Saito I, Kojima H, Jinno H
  • Journal Title: BPB reports Volume: 2(6) Pages: 91-98
  • Peer Reviewed
• [Journal Article] Dietary Fucoxanthin Induces Anoikis in Colorectal Adenocarcinoma by Suppressing Integrin Signaling in a Murine Colorectal Cancer Model (2019)
  • Author(s): Terasaki Masaru、Ikuta Mimori、Kojima Hiroyuki、Tanaka Takuji、Maeda Hayato、Miyashita Kazuo、Mutoh Michihiro
  • Journal Title: Journal of Clinical Medicine Volume: 9 Pages: 90～90
  • DOI: 10.3390/jcm9010090
  • Peer Reviewed / Open Access
• [Presentation] 妊娠中有機フッ素化合物曝露と臍帯血中の性ホルモン濃度との関連：遺伝環境相互作用の影響－北海道スタディ (2020)
  • Author(s): 小林澄貴, 佐田文宏, 荒木敦子, 宮下ちひろ, 伊藤佐智子, グウダルジホウマヌ, 岩崎雄介, 三井貴彦, 守屋仁彦, 篠原信雄, 長和俊, 岸玲子
  • Organizer: 第30回日本疫学会学術総会
• [Presentation] マイクロプラスチック由来化学物質におけるヒトエストロゲン受容体alpha/beta;アゴニスト活性の比較 (2020)
  • Author(s): 桜木優太、寺崎将、武内伸治、小島弘幸
  • Organizer: 日本薬学会第140年会
  • Invited
• [Presentation] Prenatal environmental chemical exposure on children’s health: The Hokkaido Study. (2019)
  • Author(s): Atsuko Araki
  • Organizer: CHEMICAL HAZARD Symposium
  • Int'l Joint Research / Invited
• [Presentation] Effect of prenatal exposure to persistent organic pollutants on children’s health in the Hokkaido Study on Environment and Children’s Health (2019)
  • Author(s): Chihiro Miyashita, and Reiko Kishi
  • Organizer: 39th International Symposium on Halogenated Persistent Organic Pollutants
  • Int'l Joint Research
• [Presentation] Effects of Prenatal Exposure to Perfluoroalkyl Substances (PFAS) on Childhood Allergies and Infectious Diseases; Hokkaido Study (2019)
  • Author(s): Yu Ait Bamai, Houman Goudarzi, Emiko Okada, Atsuko Araki, Chihiro Miyashita, Hideyuki Matsuura, and Reiko Kishi
  • Organizer: 39th International Symposium on Halogenated Persistent Organic Pollutants
  • Int'l Joint Research
• [Presentation] Effects of perfluorocarboxylic acids on transcriptional activity via human nuclear receptors and gene expression in human macrophage-like THP-1 cells. (2019)
  • Author(s): Kojima H, Takeuchi S, Okuda K, Muromoto R, Kishi R, Araki A.
  • Organizer: 39th International Symposium on Halogenated Persistent Organic Pollutants (Dioxin2019)
  • Int'l Joint Research
• [Presentation] Distribution of 58 semi-volatile organic chemicals in the gas phase and three particle sizes in indoor air and house dust in residential buildings during the hot season in Japan. (2019)
  • Author(s): Takeuchi S, Tanaka-Kagawa T, Saito I, Kojima H, Jinno H.
  • Organizer: 39th International Symposium on Halogenated Persistent Organic Pollutants (Dioxin2019)
  • Int'l Joint Research
• [Presentation] Measurement of dioxin-related compounds in trace biological samples using highly sensitive cells, DR-EcoScreenHS bioassay. (2019)
  • Author(s): Matsuda R, Nakamura M, Kojima H, Iida M.
  • Organizer: 39th International Symposium on Halogenated Persistent Organic Pollutants (Dioxin2019)
  • Int'l Joint Research
• [Presentation] 環境化学物質による核内受容体活性の探索と免疫毒性作用 (2019)
  • Author(s): 小島弘幸
  • Organizer: 第162回日本獣医学会学術集会（日本比較薬理学・毒性学会シンポジウム）
  • Invited
• [Presentation] The Hokkaido Study on Environment and Children’s Health: Overview of the study and collaborations with cohorts in Asia (2019)
  • Author(s): Atsuko Araki, Chihiro Miyashita, Machiko Minatoya, and Reiko Kishi.
  • Organizer: ISESISEE-AC2019
  • Int'l Joint Research / Invited
• [Presentation] Mixture Chemical Exposure in Utero and Boys Reproductive Hormone Levels at Birth: the Hokkaido Study (2019)
  • Author(s): Atsuko Araki, Chihiro Miyashita, Sachiko Itoh, Takahiko Mitsui, Houman Goudarzi, Kazutoshi Cho, Kimihiko Moriya, Tamie Nakajima, Yusuke Iwasaki, Tsuguhide Hori, Junboku Kajiwara, Nobuo Shinohara, Reiko Kishi.
  • Organizer: ISESISEE-AC2019
  • Int'l Joint Research
• [Remarks] 環境と子どもの健康に関する北海道研究・北海道スタディ「これまでにわかったこと」
  • URL: https://www.cehs.hokudai.ac.jp/hokkaidostudy/report/