Elucidation of molecular mechanism of ADHD based on a prospective birth cohort study

• Project/Area Number: 16K15352
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Epidemiology and preventive medicine
• Research Institution: Hokkaido University
• Principal Investigator: Reiko kishi 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)
• Co-Investigator(Kenkyū-buntansha): 荒木 敦子 北海道大学, 環境健康科学研究教育センター, 准教授 (00619885) ; 齊藤 卓弥 北海道大学, 医学研究院, 特任教授 (20246961) ; 三浦 りゅう 北海道大学, 環境健康科学研究教育センター, 特任助教 (20506414) ; 山崎 圭子 北海道大学, 環境健康科学研究教育センター, 特任講師 (60732120)
• Research Collaborator: AIT BAMAI Yu 北海道大学, 環境健康科学研究教育センター, 特任講師 (90752907) ; KOBAYASHI Sumitaka 北海道大学, 環境健康科学研究教育センター, 特任講師 (10733371)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 環境疫学 / ADHD / エピジェネティクス / DNAメチル化 / 胎児期曝露

Outline of Final Research Achievements

We targeted DNA methylation as a mediator between prenatal exposure to environmental chemicals and attention-deficit/hyperactivity disorder (ADHD). We assessed methylation levels at 450K cytosine-guanine dinucleotide sites (CpGs) in cord blood DNA using an Illumina HumanMethylation 450 BeadChip, and examined association between methylation and prenatal exposure to perfluoroalkyl substances, phthalates, and bisphenol A. The epigenome-wide analyses (EWAS) showed significant differences in methylation associated with prenatal exposure.
To investigate prospective association between DNA methylation at birth and ADHD-related behavior at 6 years, we extracted DNA from cord blood of ADHD groups (n=245) identified with ADHD rating scale (ADHD-RS) and control groups （n=317）. Using a next-generation sequencer, we have quantified methylation levels at CpGs that showed significant association with prenatal exposure in the EWAS.

Research Products

• [Journal Article] Association between DNA methylation in cord blood and maternal smoking: The Hokkaido Study on Environment and Children’s Health (2018)
  • Author(s): Miyake Kunio、Kawaguchi Akio、Miura Ryu、Kobayashi Sachiko、Tran Nguyen Quoc Vuong、Kobayashi Sumitaka、Miyashita Chihiro、Araki Atsuko、Kubota Takeo、Yamagata Zentaro、Kishi Reiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5654-5654
  • DOI: 10.1038/s41598-018-23772-x
  • NAID: 120006533154
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal organochlorine pesticide exposure and the disruption of steroids and reproductive hormones in cord blood: The Hokkaido study (2018)
  • Author(s): Araki Atsuko、Miyashita Chihiro、Mitsui Takahiko、Goudarzi Houman、Mizutani Futoshi、Chisaki Youichi、Itoh Sachiko、Sasaki Seiko、Cho Kazutoshi、Moriya Kimihiko、Shinohara Nobuo、Nonomura Katsuya、Kishi Reiko
  • Journal Title: The Hokkaido study. Environ Int. Volume: 110 Pages: 1-13
  • DOI: 10.1016/j.envint.2017.10.006
  • NAID: 120006776798
  • Peer Reviewed / Open Access
• [Journal Article] Association of prenatal exposure to PCDD/Fs and PCBs with maternal and infant thyroid hormones: The Hokkaido Study on Environment and Children's Health (2018)
  • Author(s): Baba Toshiaki、Ito Sachiko、Yuasa Motoyuki、Yoshioka Eiji、Miyashita Chihiro、Araki Atsuko、Sasaki Seiko、Kobayashi Sumitaka、Kajiwara Jumboku、Hori Tsuguhide、Kato Shizue、Kishi Reiko
  • Journal Title: Science of the Total Environment Volume: 615 Pages: 1239-1246
  • DOI: 10.1016/j.scitotenv.2017.09.038
  • NAID: 120006796030
  • Peer Reviewed / Open Access
• [Journal Article] Effects of low-level prenatal exposure to dioxins on cognitive development in Japanese children at 42 months (2018)
  • Author(s): Ikeno Tamiko、Miyashita Chihiro、Nakajima Sonomi、Kobayashi Sumitaka、Yamazaki Keiko、Saijo Yasuaki、Kita Toshiko、Sasaki Seiko、Konishi Kanae、Kajiwara Junboku、Hori Tsuguhide、Kishi Reiko
  • Journal Title: Science of The Total Environment Volume: 618 Pages: 1423-1430
  • DOI: 10.1016/j.scitotenv.2017.09.267
  • NAID: 120006812530
  • Peer Reviewed / Open Access
• [Journal Article] Birth cohorts in Asia: The importance, advantages, and disadvantages of different-sized cohorts (2018)
  • Author(s): Kishi Reiko、Araki Atsuko、Minatoya Machiko、Itoh Sachiko、Goudarzi Houman、Miyashita Chihiro
  • Journal Title: Science of The Total Environment Volume: 615 Pages: 1143-1154
  • DOI: 10.1016/j.scitotenv.2017.08.268
  • NAID: 120006796031
  • Peer Reviewed / Open Access
• [Journal Article] Association between Fetal Adipokines and Child Behavioral Problems at Preschool Age: The Hokkaido Study on Environment and Children’s Health (2018)
  • Author(s): Minatoya Machiko、Itoh Sachiko、Araki Atsuko、Tamura Naomi、Yamazaki Keiko、Miyashita Chihiro、Kishi Reiko
  • Journal Title: Int. J. Environ. Res. Public Health Volume: 15 Issue: 1 Pages: 120-120
  • DOI: 10.3390/ijerph15010120
  • NAID: 120006459317
  • Peer Reviewed / Open Access
• [Journal Article] An epigenome-wide study of cord blood DNA methylations in relation to prenatal perfluoroalkyl substance exposure: The Hokkaido study (2018)
  • Author(s): Miura Ryu、Araki Atsuko、Miyashita Chihiro、Kobayashi Sumitaka、Kobayashi Sachiko、Wang Shu-Li、Chen Chung-Hsing、Miyake Kunio、Ishizuka Mayumi、Iwasaki Yusuke、Ito Yoichi M.、Kubota Takeo、Kishi Reiko
  • Journal Title: Environment International Volume: 115 Pages: 21-28
  • DOI: 10.1016/j.envint.2018.03.004
  • NAID: 120006847752
  • Peer Reviewed
• [Journal Article] 「2万人規模の出生コーホートと，500人規模の小コーホートからなる北海道スタディが目指してきたもの：環境と子どもの健康―先天異常・発達・アレルギーの15年におよぶ経験と成果」 (2018)
  • Author(s): 岸玲子，荒木敦子，宮下ちひろ，伊藤佐智子，湊屋街子，小林澄貴，山﨑圭子，アイツバマイゆふ，三浦りゅう，田村菜穂美
  • Journal Title: 日本衛生学雑誌 Volume: -
  • NAID: 130007378561
  • Peer Reviewed
• [Journal Article] Association between prenatal exposure to organochlorine pesticides and the mental and psychomotor development of infants at ages 6 and 18 months: The Hokkaido Study on Environment and Children’s Health (2017)
  • Author(s): Yamazaki Keiko、Araki Atsuko、Nakajima Sonomi、Miyashita Chihiro、Ikeno Tamiko、Itoh Sachiko、Minatoya Machiko、Kobayashi Sumitaka、Mizutani Futoshi、Chisaki Yoichi、Kishi Reiko
  • Journal Title: Neurotoxicology Volume: 印刷中 Pages: 201-208
  • DOI: 10.1016/j.neuro.2017.11.011
  • NAID: 120006769937
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal di(2-ethylhexyl) phthalate exposure and disruption of adrenal androgens and glucocorticoids levels in cord blood: The Hokkaido Study (2017)
  • Author(s): Araki A., Mitsui T., Goudarzi H., Nakajima T., Miyashita C., Itoh S., Sasaki S., Cho K., Moriya K., Shinohara N., Nonomura K., Kishi R.
  • Journal Title: Science of the Total Environment Volume: 581-582 Pages: 297-304
  • DOI: 10.1016/j.scitotenv.2016.12.124
  • NAID: 120006558980
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Association of Prenatal Exposure to Perfluorinated Chemicals with Glucocorticoid and Androgenic Hormones in Cord Blood Samples: The Hokkaido Study. (2017)
  • Author(s): Goudarzi H, Araki A, Itoh S, Sasaki S, Miyashita C, Mitsui T, Nakazawa H, Nonomura K, Kishi R.
  • Journal Title: Environ Health Perspect Volume: 125 Issue: 1 Pages: 111-118
  • DOI: 10.1289/ehp142
  • NAID: 120006533152
  • Peer Reviewed / Open Access
• [Journal Article] The Hokkaido Birth Cohort Study on Environment and Children’s Health: cohort profile―updated 2017 (2017)
  • Author(s): Kishi Reiko、the members of The Hokkaido Study on Environment and Children’s Health、Araki Atsuko、Minatoya Machiko、Hanaoka Tomoyuki、Miyashita Chihiro、Itoh Sachiko、Kobayashi Sumitaka、Ait Bamai Yu、Yamazaki Keiko、Miura Ryu、Tamura Naomi、Ito Kumiko、Goudarzi Houman
  • Journal Title: Environ Health Prev Med Volume: 22 Issue: 1 Pages: 22-46
  • DOI: 10.1186/s12199-017-0654-3
  • NAID: 120006337770
  • Peer Reviewed / Open Access
• [Journal Article] Effects of prenatal perfluoroalkyl acid exposure on cord blood IGF2/H19 methylation and ponderal index: the Hokkaido study (2017)
  • Author(s): S. Kobayashi, K. Azumi, H. Goudarzi, A. Araki, C. Miyashita, S. Kobayashi, S. Itoh, S. Sasaki, M. Ishizuka, H. Nakazawa, T. Ikeno, R. Kishi
  • Journal Title: Journal of Exposure Science and Environmental Epidemiology Volume: 27 Pages: 251-259
  • NAID: 120006220016
  • Peer Reviewed
• [Journal Article] Gender-specific association of exposure to non-dioxin-like polychlorinated biphenyls during pregnancy with methylation levels of H19 and long interspersed nuclear element-1 in cord blood in the Hokkaido study (2017)
  • Author(s): Kobayashi Sumitaka、Sata Fumihiro、Miyashita Chihiro、Miura Ryu、Azumi Kaoru、Kobayashi Sachiko、Goudarzi Houman、Araki Atsuko、Ishizuka Mayumi、Todaka Takashi、Kajiwara Jumboku、Hori Tsuguhide、Kishi Reiko
  • Journal Title: Toxicology Volume: 390 Pages: 135-145
  • DOI: 10.1016/j.tox.2017.08.010
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal di-2-ethylhexyl phthalate exposure and cord blood adipokine levels and birth size: The Hokkaido study on environment and children's health (2017)
  • Author(s): Minatoya M., Araki A., Miyashita C., Sasaki S., Goto Y., Nakajima T., Kishi R.
  • Journal Title: Sci Total Environ Volume: 579 Pages: 606-611
  • DOI: 10.1016/j.scitotenv.2016.11.051
  • NAID: 120006551571
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cord blood BPA level and child neurodevelopment and behavioral problems: The Hokkaido Study on Environment and Children's Health (2017)
  • Author(s): Minatoya Machiko、Araki Atsuko、Nakajima Sonomi、Sasaki Seiko、Miyashita Chihiro、Yamazaki Keiko、Yamamoto Jun、Matumura Toru、Kishi Reiko
  • Journal Title: Science of The Total Environment Volume: 607-608 Pages: 351-356
  • DOI: 10.1016/j.scitotenv.2017.06.060
  • NAID: 120006776797
  • Peer Reviewed
• [Journal Article] Association of prenatal exposure to perfluoroalkyl substances with cord blood adipokines and birth size: The Hokkaido Study on environment and children's health. (2017)
  • Author(s): Minatoya M, Itoh S, Miyashita C, Araki A, Sasaki S, Miura R, Goudarzi H, Iwasaki Y, Kishi R.
  • Journal Title: Environ Res Volume: 156 Pages: 175-182
  • DOI: 10.1016/j.envres.2017.03.033
  • NAID: 120006649167
  • Peer Reviewed
• [Journal Article] Cord Blood Bisphenol A Levels and Reproductive and Thyroid Hormone Levels of Neonates: The Hokkaido Study on Environment and Children's Health. (2017)
  • Author(s): Minatoya M, Sasaki S, Araki A, Miyashita C, Itoh S, Yamamoto J, Matsumura T, Mitsui T, Moriya K, Cho K, Morioka K, Minakami H, Shinohara N, Kishi R.
  • Journal Title: Epidemiology. Volume: - Pages: S3-S9
  • DOI: 10.1097/ede.0000000000000716
  • NAID: 120006536947
  • Peer Reviewed / Open Access
• [Journal Article] Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children: Sapporo cohort study (2017)
  • Author(s): Nakajima Sonomi、Saijo Yasuaki、Miyashita Chihiro、Ikeno Tamiko、Sasaki Seiko、Kajiwara Junboku、Kishi Reiko
  • Journal Title: Environmental Research Volume: 159 Pages: 222-231
  • DOI: 10.1016/j.envres.2017.08.006
  • NAID: 120006734154
  • Peer Reviewed
• [Journal Article] Effects of prenatal perfluoroalkyl acid exposure on cord blood IGF2/H19 methylation and ponderal index: the Hokkaido study (2017)
  • Author(s): Kobayashi S., Azumi K., Goudarzi H., Araki A., Miyashita C., Kobayashi S., Itoh S., Sasaki S., Ishizuka M., Nakazawa H., Ikeno T., Kishi R.
  • Journal Title: Journal of Exposure Science and Environmental Epidemiology Volume: -
  • NAID: 120006220016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Associated factors of behavioural problems in children at preschool age: the Hokkaido study on environment and children's health (2016)
  • Author(s): Minatoya M., Itoh S., Araki A., Tamura N., Yamazaki K., Nishihara S., Miyashita C., Kishi R.
  • Journal Title: Child Care Health Dev. Volume: - Issue: 3 Pages: 1365-2214
  • DOI: 10.1111/cch.12424
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prenatal exposure to perfluorinated chemicals and neurodevelopment in early infancy: The Hokkaido Study (2016)
  • Author(s): H. Goudarzi, S. Nakajima, T. Ikeno, S. Sasaki, S. Kobayashi, C. Miyashita, S. Ito, A. Araki, H. Nakazawa and R. Kishi
  • Journal Title: Sci Total Environ Volume: 541 Pages: 1002-1010
  • DOI: 10.1016/j.scitotenv.2015.10.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 【講座 子どもを取り巻く環境と健康】第15回 ダイオキシン類曝露と児の神経発達 (2016)
  • Author(s): 中島そのみ, 岸玲子
  • Journal Title: 公衆衛生 Volume: 80（5） Pages: 371-378
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 【講座 子どもを取り巻く環境と健康】第16回 ADHD(注意欠如・多動性障害）とASD(自閉スペクトラム症） (2016)
  • Author(s): 池野多美子, 小林澄貴, 山崎圭子, 西原進吉, 岸玲子
  • Journal Title: 公衆衛生 Volume: 80（6） Pages: 445-450
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 【講座 子どもを取り巻く環境と健康】第17回 胎児期の化学物質曝露による後天的な遺伝子発現制御への影響 (2016)
  • Author(s): 宮下ちひろ, 小林祥子, 岸玲子
  • Journal Title: 公衆衛生 Volume: 80（7） Pages: 531-537
• [Presentation] 胎児期の有機塩素系農薬曝露が3.5 歳の児の知的機能に及ぼす影響- 北海道スタディ (2018)
  • Author(s): 山﨑圭子, 荒木敦子, 中島そのみ, 宮下ちひろ, 池野多美子, 伊藤佐智子, 湊屋街子, 水谷太, 苣木洋一, 岸玲子
  • Organizer: 第88回日本衛生学会学術総会
• [Presentation] 胎児期の両親の喫煙と幼児期におけるADHD 症状の関連 (2018)
  • Author(s): 湊屋街子, 伊藤佐智子, 小林澄貴, 山﨑圭子, 宮下ちひろ, 荒木敦子, 岸玲子
  • Organizer: 第88回日本衛生学会学術総会
• [Presentation] 胎児期のPCB 類曝露による児のH19・LINE-1のDNA メチル化への影響：北海道スタディ (2018)
  • Author(s): 小林澄貴, 佐田文宏, 宮下ちひろ, 三浦りゅう, ゴウダルジ・ホウマヌ, 荒木敦子, 梶原淳睦, 堀就英, 岸玲子
  • Organizer: 第88回日本衛生学会学術総会
• [Presentation] Exposure to bisphenol A and phthalates during pregnancy and child neurobehavioral development at preschool age: The Hokkaido Study (2017)
  • Author(s): Minatoya M., Itoh S., Miyashita C., Araki A., Tamura N., Yamamoto J., Onoda Y., Matsumura T., Kishi R.
  • Organizer: The 29th Annual Scientific Conference of the International Society of Environmental Epidemiology (ISEE) 2017
  • Int'l Joint Research
• [Presentation] 臍帯血アディポカイン濃度と子どもの発達：環境と子どもの健康に関する北海道スタディ (2017)
  • Author(s): 湊屋街子, 小林澄貴, 須山聡, 岸玲子
  • Organizer: 第76回日本公衆衛生学会
• [Presentation] 胎児期PCB・Dioxin曝露が学童期の脳活動に与える影響についての検討 (2017)
  • Author(s): 山﨑圭子, 岸玲子
  • Organizer: 第35回日本生理心理学会
• [Presentation] Identification of Risks of Endocrine Disrupting Chemicals Based on Early Life Exposure Assessment: The Hokkaido Study (2016)
  • Author(s): Kishi, R.
  • Organizer: International Frontier Forums of Reproductive Medicine and 2016 International Symposium on Construction and Application of Birth Cohort
  • Place of Presentation: Nanjing Medical University, Nanjing, China
  • Year and Date: 2016-11-19
  • Int'l Joint Research / Invited
• [Presentation] Environmental endocrine-disrupting chemicals and their effects to children: 13 years progress of the Hokkaido Birth Cohort Study (2016)
  • Author(s): Kishi, R.
  • Organizer: PPTOX V.
  • Place of Presentation: Kitakyushu International Conference Center, Kitakyushu, Japan
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] ssociated prenatal factors of behavioral and emotional problems in 5 year-old children: The Hokkaido Study (2016)
  • Author(s): Minatoya M., Tamura N., Ito S., Miyashita C., Araki A., Kishi R.
  • Organizer: ISEE2016: 28th Annual Conference International Society for Environmental Epidemiology
  • Place of Presentation: Auditorium Parco della Musica, Itaty, Roma
  • Year and Date: 2016-09-01
  • Int'l Joint Research
• [Presentation] Prenatal environment and child behavioral and coordination development at preschool age in the Hokkaido Study (2016)
  • Author(s): Minatoya M., Tamura N., Itoh S., Suyama S., Miyashita C., Araki A., Saito T., Nakai A., Kishi R.
  • Organizer: ISEE-ISES AC2016
  • Place of Presentation: Sapporo, Hokkaido, Japan
  • Year and Date: 2016-06-26
  • Int'l Joint Research
• [Presentation] Epigenome-wide Pathway Analyses of Prenatal Perfluoroalkyl Acids Exposure on Cord Blood DNA Methylation: The Hokkaido Study (2016)
  • Author(s): Kobayashi S., Miura R., Miyashita C., Araki A., Ishizuka M., Nakazawa H., Ito Y. M., Kubota T., Kishi R.
  • Organizer: ISEE-ISES AC2016
  • Place of Presentation: Sapporo, Hokkaido, Japan
  • Year and Date: 2016-06-26
  • Int'l Joint Research
• [Presentation] Epigenome-wide analyses of prenatal perfluoroalkyl acids exposure on cord blood DNA methylation: the Hokkaido study (2016)
  • Author(s): Kobayashi S., Miura R., Miyashita C., Araki A., Ishizuka M., Nakazawa H., Ito Y., Kubota T., Kishi R.
  • Organizer: ISEE-ISES AC2016
  • Place of Presentation: Sapporo, Hokkaido, Japan
  • Year and Date: 2016-06-26
  • Int'l Joint Research
• [Presentation] 臍帯血中ビスフェノールA濃度と子どもの行動発達：北海道スタディ (2016)
  • Author(s): 3.湊屋街子, 佐々木成子, 中島そのみ, 山本潤, 松村徹, 宮下ちひろ, 荒木敦子, 岸玲子
  • Organizer: 第86回日本衛生学会
  • Place of Presentation: 旭川市民文化会館（北海道・旭川市）
  • Year and Date: 2016-05-11