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Effects of exposure to environmental chemicals on child's neurodevelopment, puberty onset, and allergies in the Hokkaido Study:Clarification of molecular mechanism

Research Project

Project/Area Number 16H02645
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Hygiene and public health
Research InstitutionHokkaido University

Principal Investigator

Kishi Reiko  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)
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)
中島 そのみ  札幌医科大学, 保健医療学部, 准教授 (70325877)
花岡 知之  北海道大学, 環境健康科学研究教育センター, 客員教授 (00228503)
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)
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)
湊屋 街子  北海道大学, 環境健康科学研究教育センター, 特任講師 (50733367)
有賀 正  北海道大学, 医学研究院, 名誉教授 (60322806)
齊藤 卓弥  北海道大学, 医学研究院, 特任教授 (20246961)
鈴川 晶夫  北海道大学, 公共政策学連携研究部, 教授 (00277287)
Research Collaborator Kajiwara Junboku  
Sata Fumihiro  
Saijo Yasuaki  
Yoshioka Eiji  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥45,240,000 (Direct Cost: ¥34,800,000、Indirect Cost: ¥10,440,000)
Fiscal Year 2018: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Fiscal Year 2016: ¥31,980,000 (Direct Cost: ¥24,600,000、Indirect Cost: ¥7,380,000)
Keywords母子保健 / 出生コーホート / フタル酸エステル / 第二次性徴 / 環境化学物質 / 母子健康 / 生後の曝露評価 / 尿中フタル酸エステル類代謝物一斉分析 / 出生コホート
Outline of Final Research Achievements

To investigate the effects of pre-and postnatal exposure to environmental chemicals on child’s neurodevelopment, puberty onset, and allergies, we evaluated these adverse health impacts in terms of single and multiple exposures, as well as gene-environment interaction.
A significant decreasing secular trend of urinary MEHP concentration of 7 years old children was found in the sample collected between 2012 and 2017. Prenatal exposures to MECPP was associated with increase a risk of behavioral problems among 5 years old children and MnBP, MiBP, MEHP were associated with early puberty onset among girls. Prenatal exposure to BPA did not have any associations with neurodevelopment or puberty onset. Prenatal exposure to multiple chemicals disrupted sex hormone levels in cord blood, especially MEHP and PFOS were highly contributions to hormone levels. A significant decreasing 2D:4D ratio was found in cord blood XbaI polymorphism of estrogen receptor 1 gene.

Academic Significance and Societal Importance of the Research Achievements

大規模な出生コホートの保存生体試料から環境化学物質の胎児期および生後の曝露評価を行い、児の神経行動発達や第二次性徴発来などのアウトカムへの影響、ならびに環境-遺伝交互作用も含めて検討した研究は世界でも限られており、日本ではこれまでほとんど報告されていない。胎児期のフタル酸エステル類曝露が就学前の児の問題行動や女児の第二次性徴早発、性ホルモン濃度攪乱の影響が見られ、短半減期化合物であっても児の健康アウトカムに影響する可能性を示した。また日本の児のDEHP曝露レベルが減少傾向である可能性を本研究で初めて報告した。これらの成果は、規制等の施策への疫学的知見として提供することができる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (85 results)

All 2019 2018 2017 2016 Other

All Journal Article (40 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 36 results,  Open Access: 28 results,  Acknowledgement Compliant: 7 results) Presentation (44 results) (of which Int'l Joint Research: 22 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Association Between Maternal Serum Folate Concentrations in the First Trimester and the Risk of Birth Defects: The Hokkaido Study of Environment and Children’s Health2019

    • Author(s)
      Ito Kumiko、Hanaoka Tomoyuki、Tamura Naomi、Sasaki Seiko、Miyashita Chihiro、Araki Atsuko、Ito Sachiko、Minakami Hisanori、Cho Kazutoshi、Endo Toshiaki、Baba Tsuyoshi、Miyamoto Toshinobu、Sengoku Kazuo、Tamakoshi Akiko、Kishi Reiko
    • Journal Title

      Journal of Epidemiology

      Volume: 29 Issue: 4 Pages: 164-171

    • DOI

      10.2188/jea.JE20170185

    • NAID

      130007624300

    • ISSN
      0917-5040, 1349-9092
    • Year and Date
      2019-04-05
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of prenatal sex hormones on behavioral sexual dimorphism.2019

    • Author(s)
      Mitsui T, Araki A, Miyashita C, Ito S, Ikeno T, Sasaki S, Kitta T, Moriya K, Cho K, Morioka K, Kishi R, Shinohara N, Takeda M, Nonomura K.
    • Journal Title

      Pediatr Int.

      Volume: 61 Issue: 2 Pages: 140-146

    • DOI

      10.1111/ped.13756

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between maternal passive smoking and increased risk of delivering small-for-gestational-age infants at full-term using plasma cotinine levels from The Hokkaido Study: a prospective birth cohort.2019

    • Author(s)
      Kobayashi S, Sata F, Hanaoka T, Braimoh TS, Ito K, Tamura N, Araki A, Itoh S, Miyashita C, Kishi R.
    • Journal Title

      BMJ Open

      Volume: 9(2) Issue: 2 Pages: e023200-e023200

    • DOI

      10.1136/bmjopen-2018-023200

    • NAID

      120006552871

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between ESR1 polymorphisms and second to fourth digit ratio in school-aged children in the Hokkaido Study.2019

    • Author(s)
      Nishimura Y, Moriya K, Kobayashi S, Araki A, Sata F, Mitsui T, Itoh S, Miyashita C, Cho K, Kon M, Nakamura M, Kitta T, Murai S, Kishi R, Shinohara N.
    • Journal Title

      Steroids

      Volume: 141 Pages: 55-62

    • DOI

      10.1016/j.steroids.2018.11.011

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of maternal serum concentration of hydroxylated polychlorinated biphenyls with maternal and neonatal thyroid hormones: The Hokkaido birth cohort study.2018

    • Author(s)
      Itoh Sachiko、Baba Toshiaki、Yuasa Motoyuki、Miyashita Chihiro、Kobayashi Sumitaka、Araki Atsuko、Sasaki Seiko、Kajiwara Jumboku、Hori Tsuguhide、Todaka Takashi、Fujikura Kaori、Nakajima Sonomi、Kato Shizue、Kishi Reiko
    • Journal Title

      Environmental Research

      Volume: 167 Pages: 583-590

    • DOI

      10.1016/j.envres.2018.08.027

    • NAID

      120006941678

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Determinants and Temporal Trends of Perfluoroalkyl Substances in Pregnant Women: The Hokkaido Study on Environment and Children’s Health.2018

    • Author(s)
      Tsai Meng-Shan、Miyashita Chihiro、Araki Atsuko、Itoh Sachiko、Bamai Yu、Goudarzi Houman、Okada Emiko、Kashino Ikuko、Matsuura Hideyuki、Kishi Reiko
    • Journal Title

      International Journal of Environmental Research and Public Health

      Volume: 15 Issue: 5 Pages: 989-989

    • DOI

      10.3390/ijerph15050989

    • NAID

      120006533153

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Contrasting associations of maternal smoking and pre-pregnancy BMI with wheeze and eczema in children.2018

    • Author(s)
      Goudarzi H, Konno S, Kimura H, Araki A, Miyashita C, Itoh S, Ait Bamai Y, Kimura H, Shimizu K, Suzuki M, Ito YM, Nishimura M, Kishi R.
    • Journal Title

      Science of the Total Environment

      Volume: 639 Pages: 1601-1609

    • DOI

      10.1016/j.scitotenv.2018.05.152

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Relationship between adrenal steroid hormones in cord blood and birth weight: The Sapporo Cohort, Hokkaido Study on Environment and Children's Health2018

    • Author(s)
      Mitsui Takahiko、Araki Atsuko、Goudarzi Houman、Miyashita Chihiro、Ito Sachiko、Sasaki Seiko、Kitta Takeya、Moriya Kimihiko、Cho Kazutoshi、Morioka Keita、Kishi Reiko、Shinohara Nobuo、Takeda Masayuki、Nonomura Katsuya
    • Journal Title

      American Journal of Human Biology

      Volume: - Issue: 4

    • DOI

      10.1002/ajhb.23127

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sex-related differences in the associations between maternal dioxin-like compounds and reproductive and steroid hormones in cord blood: The Hokkaido study.2018

    • Author(s)
      Miyashita C, Araki A, Mitsui T, Itoh S, Goudarzi H, Sasaki S, Kajiwara J, Hori T, Cho K, Moriya K, Shinohara N, Nonomura K, Kishi R.
    • Journal Title

      Environ Int

      Volume: 117 Pages: 175-185

    • DOI

      10.1016/j.envint.2018.04.046

    • NAID

      120006876269

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between DNA methylation in cord blood and maternal smoking: The Hokkaido Study on Environment and Children’s Health2018

    • 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

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of prenatal di(2-ethylhexyl) phthalate exposure on childhood allergies and infectious diseases: The Hokkaido Study on Environment and Children's Health2018

    • Author(s)
      Ait Bamai Yu、Miyashita Chihiro、Araki Atsuko、Nakajima Tamie、Sasaki Seiko、Kishi Reiko
    • Journal Title

      The Science of the total environment

      Volume: 618 Pages: 1408-1415

    • DOI

      10.1016/j.scitotenv.2017.09.270

    • Related Report
      2017 Annual Research Report
    • 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 Health2018

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children’s Health2018

    • Author(s)
      T. Hanaoka, N. Tamura, K. Ito, S. Sasaki, A. Araki, T. Ikeno, C. Miyashita, S. Ito, H. Minakami, K. Cho, T. Endo, T. Baba, T. Miyamoto, K. Sengoku, R. Kishi; other members of the Hokkaido Study on Environment and Children’s Health
    • Journal Title

      Journal of Epidemiology

      Volume: 28 Issue: 3 Pages: 125-132

    • DOI

      10.2188/jea.JE20160108

    • NAID

      130006434072

    • ISSN
      0917-5040, 1349-9092
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of low-level prenatal exposure to dioxins on cognitive development in Japanese children at 42 months2018

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Birth cohorts in Asia: The importance, advantages, and disadvantages of different-sized cohorts2018

    • 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

    • Related Report
      2017 Annual Research Report
    • 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 Health2018

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Different Risk Factors for Very Low Birth Weight, Term-Small-for-Gestational-Age, or Preterm Birth in Japan2018

    • Author(s)
      Tamura Naomi、Hanaoka Tomoyuki、Ito Kumiko、Araki Atsuko、Miyashita Chihiro、Ito Sachiko、Minakami Hisanori、Cho Kazutoshi、Endo Toshiaki、Sengoku Kazuo、Ogasawara Katsuhiko、Kishi Reiko
    • Journal Title

      Int. J. Environ. Res. Public Health

      Volume: 15 Issue: 2 Pages: 369-369

    • DOI

      10.3390/ijerph15020369

    • NAID

      120006398772

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prenatal exposure to dioxin-like compounds is associated with decreased cord blood IgE and increased risk of wheezing in children aged up to 7 years: The Hokkaido study2018

    • Author(s)
      Miyashita Chihiro、Bamai Yu Ait、Araki Atsuko、Itoh Sachiko、Minatoya Machiko、Kobayashi Sumitaka、Kajiwara Jumboku、Hori Tsuguhide、Kishi Reiko
    • Journal Title

      Science of The Total Environment

      Volume: 610-611 Pages: 191-199

    • DOI

      10.1016/j.scitotenv.2017.07.248

    • NAID

      120006776809

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2017 Annual Research Report
    • 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 Health2017

    • 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

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prenatal exposure to perfluoroalkyl acids and prevalence of infectious diseases up to 4years of age.2017

    • Author(s)
      Goudarzi H, Miyashita C, Okada E, Kashino I, Chen CJ, Ito S, Araki A, Kobayashi S, Matsuura H, Kishi R.
    • Journal Title

      Environ Int

      Volume: - Pages: 132-138

    • DOI

      10.1016/j.envint.2017.01.024

    • NAID

      120006649165

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Hokkaido Birth Cohort Study on Environment and Children’s Health: cohort profile―updated 20172017

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dioxin-metabolizing genes in relation to effects o prenatal dioxin levels and reduced birth size: The Hokkaido study.2017

    • Author(s)
      Kobayashi S, Sata F, Miyashita C, Sasaki S, Ban S, Araki A, Goudarzi H, Kajiwara J, Todaka T, Kishi R.
    • Journal Title

      Reprod Toxicol

      Volume: 67 Pages: 111-116

    • DOI

      10.1016/j.reprotox.2016.12.002

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Modification of adverse health effects of maternal active and passive smoking by genetic susceptibility: Dose-dependent association of plasma cotinine with infant birth size among Japanese women?The Hokkaido Study2017

    • Author(s)
      Kobayashi Sumitaka、Sata Fumihiro、Sasaki Seiko、Braimoh Titilola Serifat、Araki Atsuko、Miyashita Chihiro、Goudarzi Houman、Kobayashi Sachiko、Kishi Reiko
    • Journal Title

      Reprod Toxicol.

      Volume: 74 Pages: 94-103

    • DOI

      10.1016/j.reprotox.2017.09.002

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prenatal di-2-ethylhexyl phthalate exposure and cord blood adipokine levels and birth size: The Hokkaido study on environment and children's health2017

    • 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

    • Related Report
      2017 Annual Research Report
    • 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 Health2017

    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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

    • Related Report
      2017 Annual Research Report
    • 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 study2017

    • 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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Interaction of maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido Study.2017

    • Author(s)
      Sasaki S, Limpar M, Sata F, Kobayashi S, Kishi R.
    • Journal Title

      Pediatr Res

      Volume: - Issue: 1 Pages: 19-28

    • DOI

      10.1038/pr.2017.70

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [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

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 【特集】 環境化学物質曝露は思春期児童の肥満や糖尿病と関係するか?2017

    • Author(s)
      湊屋街子, 岸玲子
    • Journal Title

      思春期学

      Volume: 81(2) Pages: 133-138

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Journal Article] 【講座 子どもを取り巻く環境と健康】第23回 社会経済要因の影響(2)認知/行動発達2017

    • Author(s)
      喜多歳子, 岸玲子
    • Journal Title

      公衆衛生

      Volume: 81(1) Pages: 79-84

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Prenatal Exposure to Perfluoroalkyl Acids and Prevalence of Infectious Diseases up to 4 Years of Age2017

    • Author(s)
      Goudarzi H., Miyashita C, Okada E., Kashino I., Chen C.-J., Ito S., Araki A., Kobayashi S., Matsuura H., Kishi R.
    • Journal Title

      Environment International

      Volume: - Pages: 124-132

    • DOI

      10.1016/j.envint.2016.05.020

    • NAID

      120006649165

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Quantifying bisphenol A in maternal and cord whole blood using isotope dilution liquid chromatography/tandem mass spectrometry and maternal characteristics associated with bisphenol A2016

    • Author(s)
      Yamamoto J., Minatoya M., Sasaki S., Araki A., Miyashita C., Matsumura T., Kishi R.
    • Journal Title

      Chemosphere

      Volume: 164 Pages: 25-31

    • DOI

      10.1016/j.chemosphere.2016.08.001

    • NAID

      120006540041

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Effects of prenatal phthalate exposure on thyroid hormone levels, mental and psychomotor development of infants: The Hokkaido Study on Environment and Children's Health2016

    • Author(s)
      Minatoya M., Nakajima S., Sasaki S., Araki A., Miyashita C., Ikeno T., Nakajima T., Goto Y., Kishi R.
    • Journal Title

      Sci Total Environ.

      Volume: 565 Pages: 1037-1043

    • DOI

      10.1016/j.scitotenv.2016.05.098

    • NAID

      120006536939

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Associated factors of behavioural problems in children at preschool age: the Hokkaido study on environment and children's health2016

    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Prenatal exposure to perfluorinated chemicals and neurodevelopment in early infancy: The Hokkaido Study2016

    • 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

    • Related Report
      2016 Annual Research Report
    • 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

    • Related Report
      2016 Annual Research Report
    • 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

    • Related Report
      2016 Annual Research Report
    • Acknowledgement Compliant
  • [Presentation] 胎児期の有機塩素系農薬曝露と3.5歳の児の問題行動の関連・北海道スタディ.2019

    • Author(s)
      山崎圭子, 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89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 胎児期の喫煙曝露と学童期の子どもの体格:北海道スタディ2019

    • Author(s)
      湊屋街子, 宮下ちひろ, 荒木敦子, 岸玲子
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 胎児期の環境化学物質への混合曝露による児の性ホルモンへの影響2019

    • Author(s)
      荒木敦子, 宮下ちひろ, 伊藤佐智子, 三井貴彦, ホウマヌゴウダルジ, 長和俊, 守屋仁彦, 那須民江, 岩崎雄介, 堀就英, 梶原淳睦, 篠原信雄, 岸玲子
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 学童の尿中リン酸トリエステル類代謝物濃度と尿中炎症関連マーカーとの関連2019

    • Author(s)
      アイツバマイゆふ, Michiel Bastiaensen, 荒木敦子, Goudarzi Houman, 今野哲、伊藤佐智子、宮下ちひろ、Adrian Covaci
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Urinary phthalate metabolites concentration and temporal trends in 7 years old children.2019

    • Author(s)
      Ketema Rahe, Yu Ait Bamai, Atsuko Araki, Takeshi Saito, Reiko Kishi.l
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 胎児期有機フッ素化合物濃度と出生体重との関連:異物代謝酵素遺伝型の修飾による影響-北海道スタディ.2019

    • Author(s)
      小林澄貴, 佐田文宏, 荒木敦子, 宮下ちひろ, 佐々木成子, 坂晋, 岩崎雄介, 岸玲子
    • Organizer
      第29回日本疫学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ERP P3 of school age children and prenatal exposure to dioxin: the Hokkaido Study on Environment and Children’s Health.2018

    • Author(s)
      Yamazaki K., Araki A., Miyashita C., Itoh S., Ikeno T., Nakajima S., Kajiwara J., Hori T., R Kishi
    • Organizer
      IOP 2018(International organization of psychophysiology), IMT School for Advanced Studies
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Environmental tobacco smoke exposure among children at 7 years of age in Japan: Associated factors and urinary cotinine levels.2018

    • Author(s)
      Minatoya M., Araki A., Ait Bamai Y., Miyashita C., Ikeno T., Kobayashi S., Kishi R.
    • Organizer
      The Joint Annual Meeting of the International Society of Exposure Science and the International Society for Environmental Epidemiology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effect of Prenatal Exposure to Perfluoroalkyl Substances on Childhood Infectious Diseases Up to 7 years of age: The Hokkaido Study.2018

    • Author(s)
      Ait Bamai Y., Arak A., Okada E., Kashino I., Miyashita C., Goudarzi H., Matsuura H., Kishi R.
    • Organizer
      The Joint Annual Meeting of the International Society of Exposure Science and the International Society for Environmental Epidemiology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Autism Spectrum Disorder screening in general Japanese toddlers using M-CHAT: an adjunct study of the Japan Environment & Children's Study.2018

    • Author(s)
      Minatoya M., Yamazaki K., Itoh S., Miyashita C., Araki A., Kobayashi S., Ait Bamai Y., Tamura N., Ito Y., Kishi R.
    • Organizer
      The 9th INCHES(International Conference on Children's Health and the Environment)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Update and the recent findings from the Hokkaido Study.2018

    • Author(s)
      Minatoya M., Arak A., Miyashita C., itoh S., Kobayashi S., Yamazaki K., Ait Bamai Y., Miura R., Tamura N., Kishi R.
    • Organizer
      The 9th INCHES(International Conference on Children's Health and the Environment)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Organohosphate flame retardants in house dust and their association with school children’s asthma and allergies.2018

    • Author(s)
      Araki A., Ait Bamai Y., Kawai T., Tsuboi T., Kishi R.
    • Organizer
      ISEE/ES International Society for Environmental Epidemiology/International Society of Exposure Science Asia Chapter 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prenatal exposure to perfluorinated alkyl substances and behavioral and coordination development of children at preschool age: The Hokkaido Study on Environment and Children’s Health.2018

    • Author(s)
      Minatoya M., Itoh S., Araki A., Miyashita C., Yamazaki K., Suyama S., Goudarzi H., Okada E., Kashino I., Kishi R.
    • Organizer
      ISEE/ES AC2018(International Society for Environmental Epidemiology/International Society of Exposure Science Asia Chapter 2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prenatal exposure to perfluorinated alkyl substances and childhood ADHD risk at 6 years old: the Hokkaido Study on Environment and Children’s Health. ISEE/ES AC2018(International Society for Environmental2018

    • Author(s)
      Yamazaki K., Itoh S., Araki A., Miyashita C., Minatoya M., Tamura N., Goudarzi H., Okada E., Kashino I., Kishi R.
    • Organizer
      ISEE/ES AC2018(International Society for Environmental Epidemiology/International Society of Exposure Science Asia Chapter 2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 胎児期の喫煙曝露と子どものADHD関連症状との関係の検討:北海道スタディ2018

    • Author(s)
      湊屋街子, 小林澄貴, 須山聡, 岸玲子
    • Organizer
      第77回日本公衆衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 13歳児におけるGo/NoGo課題時のERPと両親・児の特徴との関連:予備的検討.2018

    • Author(s)
      山崎圭子, 岸玲子
    • Organizer
      第36回日本生理心理学会大会
    • Related Report
      2018 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [Presentation] 胎児期の有機フッ素化合物曝露が7 歳のアレルギーに及ぼす影響- 北海道スタディ2018

    • Author(s)
      アイツバマイゆふ, 荒木敦子, 宮下ちひろ, 岡田恵美子, 樫野郁子, ゴウダルジ・ホウマヌ, 松浦英幸, 岸玲子
    • Organizer
      第88回日本衛生学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 両親の教育歴と児のSmall for gestational age との媒介要因分析:北海道スタディ2018

    • Author(s)
      田村菜穂美, 花岡知之, 伊藤久美子, 伊藤佐智子, 宮下ちひろ, 荒木敦子, 小笠原克彦, 岸玲子
    • Organizer
      第88回日本衛生学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 尿中リン酸トリエステル類と児の喘息・アレルギーとの関連-札幌市学童調査2018

    • Author(s)
      荒木敦子, アイツバマイゆふ, Bastiaensen Michiel, Eede Nele van den, Mesfin Rahel Ketem, 伊藤佐智子, 宮下ちひろ, Covaci Adrian, 岸玲子
    • Organizer
      第88回日本衛生学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Exposure to bisphenol A and phthalates during pregnancy and child neurobehavioral development at preschool age: The Hokkaido Study2017

    • 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
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mediatory factors between parental education and infants’ small for gestational age: Hokkaido study on Environment and Children’s Health2017

    • Author(s)
      Tamura N., Hanaoka T., Ito K., Ito S., Miyashita C., Araki A., Ogasawara K., Kishi R.
    • Organizer
      The Third FHS International conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genetic modification of adverse health effects of prenatal active and passive smoking: dose-dependent association of plasma cotinine levels with infant birth weight in the Hokkaido Study2017

    • Author(s)
      Kobayashi S., Sata F., Sasaki S., Braimoh T. S., Araki A., Miyashita C., Goudarzi H., Kobayashi S., Kishi R.
    • Organizer
      The 29th Annual Scientific Conference of the International Society of Environmental Epidemiology (ISEE) 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development and validation of a reliable method for te analysis of phthalate metabolites in human urine2017

    • Author(s)
      Ketema R. M., Ait Bamai Y., Araki A., Kishi R., Saito T.
    • Organizer
      The 3rd FHS International conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Urinary biomonitoring of organophosphate flame retardants in Japanese children and correlations with house dust concentrations2017

    • Author(s)
      Bastiaensen M., Van den Eede N., Araki A., Ait Bamai Y., KIshi R., Covaci A.
    • Organizer
      The 37th International Symposium on Halogenated Environmental, Organic Pollutants and POPs DIOXIN 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Phthalates and organophosphate flame retardants in house dust and their relation to asllergies and oxidative stress marker 8-OHdG: the Hokkaido Study2017

    • Author(s)
      Araki A., Ait Bamai Y., Kawai T., Tsuboi T., Miyashita C., Kishi R.
    • Organizer
      International Society of Exposure Science 27th Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The associations between prenatal phthalates exposure and cryptorchidism: The Hokkaido Study on Environment and Children's Health2017

    • Author(s)
      Ait Bamai, Y., Miyashita, C., Onoda, Y., Araki, A., Moriya, K., Shinohara, N., Matsumuar, T., Kishi, R.
    • Organizer
      The 29th Annual Scientific Conference of the International Society of Environmental Epidemiology (ISEE) 2017
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
  • [Presentation] 正期産における妊婦の受動・能動喫煙とSGAとの関連:北海道スタディ2017

    • Author(s)
      小林澄貴, 岸玲子
    • Organizer
      第76回日本公衆衛生学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 妊娠中の母の受動喫煙と児の3歳までの発育との関連:北海道スタディ2017

    • Author(s)
      小林澄貴, プライモーチチローラ, 佐田文宏, 佐々木成子, ホウマヌゴウダルジ, イーラタマ, 荒木敦子, 宮下ちひろ, 岸玲子
    • Organizer
      平成29年日本産業衛生学会北海道地方会総会(第97回北海道医学大会産業衛生分科会)
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [Presentation] Environmental endocrine-disrupting chemicals and their effects to children: 13 years progress of the Hokkaido Birth Cohort Study2016

    • Author(s)
      Kishi, R.
    • Organizer
      PPTOX V.
    • Place of Presentation
      Kitakyushu International Conference Center, Kitakyushu, Japan
    • Year and Date
      2016-11-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 母親の精神健康と児の自閉傾向との関連-子供の健康と環境に関する北海道スタディ-2016

    • Author(s)
      池野多美子
    • Organizer
      第75回日本公衆衛生学会総会
    • Place of Presentation
      グランフロント大阪(大阪府・大阪市)
    • Year and Date
      2016-10-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] 家庭内での分煙行動と子どもの尿中コチニン値の関係-北海道スタディ-2016

    • Author(s)
      西原進吉, 小林澄貴, 池野多美子, 湊屋街子, 岸玲子
    • Organizer
      第75回日本公衆衛生学会総会
    • Place of Presentation
      グランフロント大阪(大阪府・大阪市)
    • Year and Date
      2016-10-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] Environmental chemicals and related adverse effects of children. International Conference “Tackling Infectious Diseases: Information for Action”2016

    • Author(s)
      Kishi R.
    • Organizer
      The International Conference on Prevention and Control of Infectious Diseases
    • Place of Presentation
      Blue Sky Tower, Ulan Bator, Mongolia
    • Year and Date
      2016-10-20
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Associated prenatal factors of behavioral and emotional problems in 5 year-old children: The Hokkaido Study2016

    • 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
      Audirorium Parco della Musica, Roma, Italy
    • Year and Date
      2016-09-01
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effects of prenatal exposure to perfluoroalkyl acids on risk of allergic and infections diseases in early life2016

    • Author(s)
      Goudarzi H., Miyashita C., Okada E., Kashino I., Kobayashi S., Chen C.-J., Ito S., Araki A., Matsuura H., Kishi R.
    • Organizer
      ISEE2016: 28th Annual Conference International Society for Environmental Epidemiology
    • Place of Presentation
      Audirorium Parco della Musica, Roma, Italy
    • Year and Date
      2016-09-01
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prenatal exposure to DEHP and childhood wheeze and atopic dermatitis: The Hokkaido Study on the Environment and Children's Health2016

    • Author(s)
      Ait Bamai Y., Araki A., Sasaki S., Nakajima T., Miyashita C., Kishi R.
    • Organizer
      ISEE2016: 28th Annual Conference International Society for Environmental Epidemiology
    • Place of Presentation
      Audirorium Parco della Musica, Roma, Italy
    • Year and Date
      2016-09-01
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prenatal environment and child behavioral and coordination development at preschool age in the Hokkaido Study2016

    • 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
      Hokkaido Univ., Sapporo, Japan
    • Year and Date
      2016-06-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hokkaido Study on Environment and Children's Health: Endocrine Disruption Effect of Perfluoroalkyl Substances Exposure in Utero2016

    • Author(s)
      Itoh S., Araki A., Miyashita C., Goudarzi H., Kato S., Iwasaki Y., Nakazawa H., Shinohara N., Kishi R.
    • Organizer
      ISEE-ISES AC2016
    • Place of Presentation
      Hokkaido Univ., Sapporo, Japan
    • Year and Date
      2016-06-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒト血清中フタル酸エステル代謝物の分析2016

    • Author(s)
      小野田優, 梅原美加, 西岡宗一郎, 水谷太, 佐藤修乃, 苣木洋一, 湊屋街子, 宮下ちひろ, 荒木敦子, 岸玲子
    • Organizer
      第25回環境化学討論会
    • Place of Presentation
      新潟コンベンションセンター(新潟県・新潟市)
    • Year and Date
      2016-06-08
    • Related Report
      2016 Annual Research Report
  • [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)
      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回日本衛生学会学術総会
    • Place of Presentation
      旭川市民文化会館(北海道・旭川市)
    • Year and Date
      2016-05-11
    • Related Report
      2016 Annual Research Report
  • [Presentation] FLG変異とフタル酸エステル曝露による児のアトピー性皮膚炎への影響:北海道スタディ2016

    • Author(s)
      アイツバマイゆふ, 荒木敦子, 乃村俊史, 河合俊夫, 坪井樹, 叢石, 宮下ちひろ, 池野多美子, 清水宏, 岸玲子
    • Organizer
      第86回日本衛生学会学術総会
    • Place of Presentation
      旭川市民文化会館(北海道・旭川市)
    • Year and Date
      2016-05-11
    • Related Report
      2016 Annual Research Report
  • [Remarks] 環境と子どもの健康に関する研究・北海道スタディ

    • URL

      https://www.cehs.hokudai.ac.jp/hokkaidostudy/%e6%88%90%e6%9e%9c%e5%a0%b1%e5%91%8a/publications/original-articles-reviews-wpeer/

    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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