Elucidation of underlying mechanism of onset of stress vulnerability by environmental chemicals to explore biomakers

• Project/Area Number: 17H06706
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hygiene and public health
• Research Institution: University of Toyama
• Principal Investigator: Hirano Tetsushi 富山大学, 研究推進機構 研究推進総合支援センター, 助教 (70804590)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 環境化学物質 / ストレス脆弱性 / ネオニコチノイド / バイオマーカー

Outline of Final Research Achievements

Although the disruptions of stress responses are involved in stress-related mental disorders such as depression and anxiety disorder, it still remains unknown how environmental factors make us vulnerable to stress. The purpose of this study is to elucidate the underlying mechanism of onset of stress vulnerability by environmental chemicals and to explore new biomarkers.
Our study demonstrated that a neonicotinoid pesticide, clothianidin induced various stress-related behavioral changes of mice in a novel environment in addition to increasing the number of neural cells in particular areas of brain. We also found that clothianidin evoked the transient intracellular calcium flux in human neuroblastoma SH-SY5Y cells immediately after exposure and induced changes of the gene expression profile. Taken together, the alteration of gene expression in neural cells could be new biomarkers to detect risks of environmental chemicals.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は，哺乳類へ及ぼす影響に関するデータが不足している農薬のリスク評価に対し、新たな知見を提供することで毒性学および予防医学的において多大な波及効果をもたらす．また、本研究の応用により、「化学物質が高次脳機能に対して影響を及ぼすのか否か」を簡便かつ高感度に検出可能な新規リスク評価法の開発が期待でき、将来的な実験動物の使用数削減等にも繋がると考えられる．

Research Products

• [Journal Article] The mechanisms underlying the effects of AMH on Müllerian duct regression in male mice (2018)
  • Author(s): Yamamoto A, Omotehara, Miura Y, Takada T, Yoneda N, Hirano T, Mantani Y, Kitagawa H, Yokoyama T, Hoshi N
  • Journal Title: Journal of Veterinary Medical Science Volume: 80 Issue: 4 Pages: 557-567
  • DOI: 10.1292/jvms.18-0023
  • NAID: 130006708370
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Verification of the causal relationship between subchronic exposures to dinotefuran and depression-related phenotype in juvenile mice (2018)
  • Author(s): Takada T, Yoneda N, Hirano T, Yanai S, Yamamoto A, Mantani Y, Yokoyama T, Kitagawa H, Tabuchi Y, Hoshi N
  • Journal Title: Journal of Veterinary Medical Science Volume: 80 Issue: 4 Pages: 720-724
  • DOI: 10.1292/jvms.18-0022
  • NAID: 130006727595
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Peripubertal exposure to the neonicotinoid pesticide dinotefuran affects dopaminergic neurons and causes hyperactivity in male mice (2018)
  • Author(s): Yoneda N, Takada T, Hirano T, Yanai S, Yamamoto A, Mantani Y, Yokoyama T, Kitagawa H, Tabuchi Y, Hoshi N
  • Journal Title: Journal of Veterinary Medical Science Volume: 80 Issue: 4 Pages: 634-637
  • DOI: 10.1292/jvms.18-0014
  • NAID: 130006708369
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Identification of reference genes for quantitative PCR analyses in developing mouse gonads (2018)
  • Author(s): YOKOYAMA Toshifumi、OMOTEHARA Takuya、HIRANO Tetsushi、KUBOTA Naoto、YANAI Shogo、HASEGAWA Chinatsu、TAKADA Tadashi、MANTANI Yohei、HOSHI Nobuhiko
  • Journal Title: Journal of Veterinary Medical Science Volume: 80 Issue: 10 Pages: 1534-1539
  • DOI: 10.1292/jvms.18-0417
  • NAID: 130007502949
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Identification of genes and genetic networks associated with BAG3?dependent cell proliferation and cell survival in human cervical cancer HeLa cells (2018)
  • Author(s): Furusawa Yukihiro、Yunoki Tatsuya、Hirano Tetsushi、Minagawa Satsuki、Izumi Hironori、Mori Hisashi、Hayashi Atsushi、Tabuchi Yoshiaki
  • Journal Title: Molecular Medicine Reports Volume: 18 Pages: 4138-4146
  • DOI: 10.3892/mmr.2018.9383
  • Peer Reviewed
• [Journal Article] Gene networks in basal cell carcinoma of the eyelid, analyzed using gene expression profiling. (2018)
  • Author(s): Yunoki T, Tabuchi Y, Hirano T, Miwa S, Imura J, Hayashi A
  • Journal Title: Oncology letters Volume: 16(5) Pages: 6729-6734
  • DOI: 10.3892/ol.2018.9484
  • Peer Reviewed
• [Journal Article] NOAEL-dose of a neonicotinoid pesticide, clothianidin, acutely induce anxiety-related behavior with human-audible vocalizations in male mice in a novel environment. (2018)
  • Author(s): Hirano T, Yanai S, Takada T, Yoneda N, Omotehara T, Kubota N, Minami K, Yamamoto A, Mantani Y, Yokoyama T, Kitagawa H, Hoshi N
  • Journal Title: Toxicol Lett Volume: 282 Pages: 57-63
  • DOI: 10.1016/j.toxlet.2017.10.010
  • NAID: 120006733121
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal and early postnatal NOAEL-dose clothianidin exposure leads to a reduction of germ cells in juvenile male mice (2017)
  • Author(s): Yanai S, Hirano T, Omotehara T, Takada T, Yoneda N, Kubota N, Yamamoto A, Mantani Y, Yokoyama T, Kitagawa H, Hoshi N
  • Journal Title: Journal of Veterinary Medical Science Volume: 79 Issue: 7 Pages: 1196-1203
  • DOI: 10.1292/jvms.17-0154
  • NAID: 130005712487
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Presentation] Adverse effects on cognitive-emotional behavior and immune system function in experimental animals administered a NOAEL-dose of neonicotinoids (2019)
  • Author(s): Nobuhiko Hoshi, Tetsushi Hirano, Yoshinori Ikenaka, Shuji Ohno, Kanoko Onaru, Shizuka Kubo, Mizuki Maeda, Yuka Miyata, Kosuke Sugita, Mayumi Ishizuka, Youhei Mantani, Toshifumi Yokoyama
  • Organizer: International CHEMICAL HAZARD Symposium in Hokkaido
  • Int'l Joint Research / Invited
• [Presentation] マウスMC3T3-E1前骨芽細胞様細胞に対する低出力パルス超音波の効果． (2018)
  • Author(s): 田渕圭章，轟 勇人，鈴木信雄，平野哲史，竹内真一，椎葉倫久，近藤 隆，長谷川英之．
  • Organizer: 日本超音波医学会第91回学術集会
• [Presentation] ヒト子宮頸がんHeLa細胞の温熱誘導細胞障害におけるBAG3の役割． (2018)
  • Author(s): 田渕圭章，柚木達也，古澤之裕，平野哲史，鳥越美沙子，皆川沙月，林 篤志．
  • Organizer: 日本ハイパーサーミア学会第35回大会
• [Presentation] 浸透性農薬とその代謝産物の胎子移行量の解明． (2018)
  • Author(s): 大野周嗣，大成果乃子，久保静花，坂田奈那美，杉田晄佑，宮田結佳，高田 匡，平野哲史，万谷洋平，横山俊史，石塚真由美，池中良徳，星 信彦．
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] ネオニコチノイド系農薬が老齢動物に及ぼす影響． (2018)
  • Author(s): 宮田結佳，大成果乃子，大野周嗣，久保静花，杉田晄佑，高田 匡，前田瑞稀，中西怜稀，平野哲史，万谷洋平，横山俊史，星 信彦．
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] ネオニコチノイド系農薬における哺乳動物への免疫毒性の検証． (2018)
  • Author(s): 大成果乃子，大野周嗣，久保静花，中西怜稀，荒井真也，杉田晄佑，宮田結佳，高田 匡，前田瑞稀，平野哲史，万谷洋平，横山俊史，星 信彦．
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] 浸透性農薬の行動影響の性差． (2018)
  • Author(s): 久保静花，宮田結佳，大成果乃子，大野周嗣，杉田晄佑，前田瑞稀，高田 匡，平野哲史，万谷洋平，横山俊史，星 信彦．
  • Organizer: 第161回日本獣医学会学術集会
• [Presentation] がん細胞の温熱誘導細胞死におけるBAG3の役割． (2018)
  • Author(s): 田渕圭章，柚木達也，古澤之裕，平野哲史，鳥越美沙子，皆川沙月，林 篤志．
  • Organizer: 第91回 日本生化学会大会
• [Presentation] 低出力パルス超音波の細胞応答． (2018)
  • Author(s): 田渕圭章，轟 勇人，鈴木信雄，平野哲史，竹内真一，椎葉倫久，長谷川英之．
  • Organizer: 平成30年度第4回アコースティックイメージング研究会
• [Presentation] ネオニコチノイド系農薬クロチアニジンはヒト神経芽細胞腫においてCa2+シグナルのかく乱を引き起こす． (2018)
  • Author(s): 平野哲史，皆川沙月，古澤之裕，柚木達也，横山俊史，星 信彦，田渕圭章．
  • Organizer: 第21回環境ホルモン学会研究発表会
• [Presentation] 母子間移行における浸透性農薬およびその代謝産物の定量的な解明． (2018)
  • Author(s): 大野周嗣，大成果乃子，久保静花，坂田奈那美，平野哲史，万谷洋平，横山俊史，石塚真由美，池中良徳，星 信彦．
  • Organizer: 第21回環境ホルモン学会研究発表会
• [Presentation] 無毒性量のネオニコチノイド系農薬曝露による行動影響の性差． (2018)
  • Author(s): 久保静花，宮田結佳，大成果乃子，大野周嗣，高田 匡，平野哲史，横山俊史，星 信彦．
  • Organizer: 第21回環境ホルモン学会研究発表会
• [Presentation] ネオニコチノイド系農薬が老年動物に及ぼす影響． (2018)
  • Author(s): 宮田結佳，久保静花，大野周嗣，前田瑞稀，荒井真也，中西怜稀，高田 匡，平野哲史，横山俊史，星 信彦．
  • Organizer: 第21回環境ホルモン学会研究発表会
• [Presentation] ネオニコチノイド系農薬が哺乳類の脳神経系に及ぼす影響に関する包括的リスク評価 (2017)
  • Author(s): 平野哲史，星 信彦，田渕圭章．
  • Organizer: 環境ホルモン学会第20回研究発表会
  • Invited
• [Presentation] 環境ストレスおよびネオニコチノイド系農薬ジノテフランの複合影響評価 (2017)
  • Author(s): 高田 匡，米田直起，大成果乃子，大野周嗣，久保静花，杉田晄佑，宮田結佳，平野哲史，万谷洋平，横山俊史，北川 浩，星 信彦
  • Organizer: 環境ホルモン学会第20回研究発表会
• [Presentation] 発達期におけるネオニコチノイド系農薬曝露により引き起こされたドーパミン神経系の攪乱を伴う多動 (2017)
  • Author(s): 米田直起，高田 匡，大成果乃子，大野周嗣，久保静花，杉田晄佑，宮田結佳，平野哲史，万谷洋平，横山俊史，北川 浩，星 信彦
  • Organizer: 環境ホルモン学会第20回研究発表会
• [Remarks] researchmap (平野哲史)
  • URL: https://researchmap.jp/thirano0128/