Mechanism responsible for brain-programming causing irreversible suppression of reproductive function in mammals
| Project/Area Number |
18K19267
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 42:Veterinary medical science, animal science, and related fields
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Project Period (FY) |
2018-06-29 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
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| Keywords | キスペプチン / 性腺刺激ホルモン / 性腺刺激ホルモン放出ホルモン（GnRH） / 黄体形成ホルモン（LH） / エストロゲン / 視床下部 / 環境ホルモン / 生殖中枢 / GnRH / メタスチン / 視床下部弓状核 / KNDyニューロン / GPR54 / 発達脳 / プログラミング / Kiss1 |
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| Outline of Final Research Achievements |
Exposure to estrogen-like compounds during the developmental period often causes improper hypothalamic programming, thus resulting in reproductive dysfunction in mammals. The present study showed that exposure to exogenous estrogen during the neonatal period caused an irreversible suppression of kisspeptin gene expression in the arcuate nucleus (ARC), resulting in reproductive dysfunction, such as smaller gonads and profound suppression of luteinizing hormone (LH) pulses in adult male rats. LH secretory response to kisspeptin challenge and gonadotropin-releasing hormone (GnRH) expression were spared in male rats treated with neonatal EB, suggesting that the LH pulse suppression is due to ARC kisspeptin deficiency. Taken together, this study indicates that exposure to estrogenic chemicals in the developing brain causes a defect of ARC kisspeptin neurons, resulting in an inhibition of pulsatile GnRH/LH release and the failure of reproductive function in mammals.
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| Academic Significance and Societal Importance of the Research Achievements |
哺乳類において、発達期の脳へのエストロゲン様化学物質の感作が生涯にわたり生殖機能を抑制することが知られる。本研究では、新生児期のラットにエストロゲンを投与すると脳内弓状核のキスペプチンニューロン（哺乳類の生殖中枢）におけるキスペプチン遺伝子（Kiss1）発現を不可逆かつ特異的に抑制し性腺刺激ホルモンが著しく抑制されることを明らかとし、生涯に渡る生殖機能抑制がこのKiss1発現抑制に起因することを明らかにした。本成果は、ヒトや家畜に見られる視床下部性の生殖障害の原因のひとつを解明した点で、社会的・学術的に大きな意義がある。
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Report
(3 results)
Research Products
(57 results)
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[Journal Article] GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release <i>via</i> activation of kisspeptin neurons in female rats2020
Author(s)
Ieda N, Assadullah, Minabe S, Ikegami K, Watanabe Y, Sugimoto Y, Sugimoto A, Kawai N, Ishii H, Inoue N, Uenoyama Y, Tsukamura H
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Journal Title
Endocrine Journal
Volume: 67
Issue: 4
Pages: 409-418
DOI
NAID
ISSN
0918-8959, 1348-4540
Related Report
Peer Reviewed / Open Access
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[Journal Article] Establishment of long-term chronic recording technique of <i>in vivo</i> ovarian parenchymal temperature in Japanese Black cows2020
Author(s)
Morita Y, Ozaki R, Mukaiyama A, Sasaki T, Tatebayashi R, Morishima A, Kitagawa Y, Suzumura R, Abe R, Tsukamura H, Matsuyama S, Ohkura S.
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Journal Title
Journal of Reproduction and Development
Volume: 66
Issue: 3
Pages: 271-275
DOI
NAID
ISSN
0916-8818, 1348-4400
Related Report
Peer Reviewed / Open Access
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[Journal Article] Peripheral administration of SB223412, a selective neurokinin-3 receptor antagonist, suppresses pulsatile luteinizing hormone secretion by acting on the gonadotropin-releasing hormone pulse generator in estrogen-treated ovariectomized female goats.2020
Author(s)
Sasaki T, Sonoda T, Tatebayashi R, Kitagawa Y, Oishi S, Yamamoto K, Fujii N, Inoue N, Uenoyama Y, Tsukamura H, Maeda KI, Matsuda F, Morita Y, Matsuyama S, Ohkura S.
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Journal Title
J Reprod Dev
Volume: -
Issue: 4
Pages: 351-357
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice2020
Author(s)
Shiori Minabe, Sho Nakamura, Eri Fukushima, Marimo Sato, Kana Ikegami, Teppei Goto, Makoto Sanbo, Masumi Hirabayashi, Junko Tomikawa, Takuya Imamura, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-Ichiro Maeda, Fuko Matsuda
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Journal Title
Journal of Reproduction and Development
Volume: Epub
Issue: 4
Pages: 369-375
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Conditional Kisspeptin Neuron-Specific Kiss1 Knockout With Newly Generated Kiss1-floxed and Kiss1-Cre Mice Replicates a Hypogonadal Phenotype of Global Kiss1 Knockout Mice2020
Author(s)
Kana Ikegami, Teppei Goto, Sho Nakamura, Youki Watanabe, Arisa Sugimoto, Sutisa Majarune, Kei Horihata, Mayuko Nagae, Junko Tomikawa, Takuya Imamura, Makoto Sanbo, Masumi Hirabayashi, Naoko Inoue, Kei-Ichiro Maeda, Hiroko Tsukamura, Yoshihisa Uenoyama
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Journal Title
J Reprod Dev.
Volume: in press
Issue: 4
Pages: 359-367
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Establishment of immortalised cell lines derived from female Shiba goat KNDy and GnRH neurones.2020
Author(s)
Suetomi Y, Tatebayashi R, Sonoda S, Munetomo A, Matsuyama S, Inoue N, Uenoyama Y, Takeuchi Y,Tsukamura H, Ohkura S, Matsuda F.
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Journal Title
Neuroendocrinology
Volume: 32(6)
Issue: 6
Pages: 12857-12857
DOI
Related Report
Peer Reviewed
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