2019 Fiscal Year Final Research Report

Mechanism responsible for brain-programming causing irreversible suppression of reproductive function in mammals

Research Project

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Project/Area Number	18K19267
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 42:Veterinary medical science, animal science, and related fields
Research Institution	Nagoya University
Principal Investigator	Tsukamura Hiroko 名古屋大学, 生命農学研究科, 教授 (00212051)
Project Period (FY)	2018-06-29 – 2020-03-31
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
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.
Free Research Field	家畜繁殖、生殖科学，神経内分泌
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。