エストロゲン様内分泌攪乱物質が雄マウスの妊孕能に及ぼす重要な要因かつ用量依存性の変化は, 視床下部-下垂体-生殖器系で異なる Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

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Author(s)

    • 割田 克彦 WARITA Katsuhiko
    • 神戸大学大学院自然科学研究科資源生命科学専攻 Department of Bioresource and Agrobiosciences, Graduate School of Science and Technology, Kobe University
    • 菅原 照夫 SUGAWARA Teruo
    • 北海道大学大学院医学研究科分子生化学教室 Department of Molecular Biochemistry, Graduate School of Medicine, Hokkaido University
    • 塚原 伸治 TSUKAHARA Shinji
    • 国立環境研究所環境健康研究領域 Division of Environmental Health Sciences, National Institute for Environmental Studies
    • 武藤 顕一郎 MUTOH Ken-ichiro
    • 北里大学獣医畜産学部獣医解剖学教室 Department of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University
    • 長谷川 喜久 HASEGAWA Yoshihisa
    • 北里大学獣医畜産学部実験動物学教室 Department of Experimental Animal Science, School of Veterinary Medicine and Animal Sciences, Kitasato University
    • 北川 浩 KITAGAWA Hiroshi
    • 神戸大学大学院自然科学研究科資源生命科学専攻 Department of Bioresource and Agrobiosciences, Graduate School of Science and Technology, Kobe University
    • 森 千里 MORI Chisato
    • 千葉大学大学院医学研究院環境生命医学教室 Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University
    • 星 信彦 HOSHI Nobuhiko
    • 神戸大学大学院自然科学研究科資源生命科学専攻 Department of Bioresource and Agrobiosciences, Graduate School of Science and Technology, Kobe University

Abstract

ICRマウスの胎子・新生子期にエストロゲン様内分泌攪乱物質を曝露し,成熟時の雄マウスの生殖器について,曝露量とその影響を評価した.胎子の子宮内曝露(IUE)群としてジエチルスチルベストロール(DES)10μg/day/頭を妊娠マウスに皮下投与し,さらに新生子期曝露(IUE+NE)群として,新生子マウスにDES 0.1-10μg/day/頭を皮下投与した.妊孕能は対照群で100%であったのに対し,IUE群で60%,IUE+NE 0.1μg群で25%であり,IUE+NE 1,10μg群では全例不妊であった.精巣では,IUE+NE 10μg群で精上皮の非薄化,さらにIUE+NE 0.1-10μg群でLeydig細胞の低形成およびエオジンの染色性の低下が顕著に認められた.IUE+NE 1-10μg群ではLeydig細胞のアンドロゲン受容体およびエストロゲン受容体(AR, ERα)の免疫染色性が用量相反性に減弱した.さらに性成熟時の性腺刺激ホルモンおよびテストステロン分泌の低下,ならびにAR, ERα遺伝子とステロイド産生急性調節性(StAR)蛋白遺伝子の発現変化が引き起こされ,長期にわたる視床下部-下垂体-性腺軸の機能障害が示唆された.ゴナドトロピン分泌の制御は,生殖器よりもより低濃度のエストロゲン様物質で影響を受けることが示された.さらに,雄マウスの妊孕能はテストステロン濃度,特にステロイドホルモン産生の律速因子であるStAR遺伝子発現と密接に関わっており,内分泌攪乱物質がStAR遺伝子に与える影響の重要性が示唆された.

For the purpose of investigation of working mechanisms in endocrine disruptors, we evaluated the dose-related effects of fetal and/or neonatal exposure to an estrogenic compound on the male reproductive organs in adult mice, particularly with respect to gene expression of steroidogenic acute regulatory protein (StAR). The pregnant ICR mice were given subcutaneous injections of 10 μg/day/animal of diethylstilbestrol (DES) to subject the fetal mice to <i>in utero</i> exposure (IUE). Subsequently, the newborn male mice were subjected to neonatal exposure (NE) by treatment with vehicle or 0.1-10 μg/day/animal of DES. Fertility rates of each group were as follows: control, 100%; IUE only, 60%; IUE+NE 0.1 μg, 25%; IUE+NE 1 μg, 0%; IUE+NE 10 μg, 0%. In general histology, germ cell layers in the seminiferous tubules were thinned in the group of IUE+NE 10 μg. Hypoplasia of the Leydig cells, in which the staining intensity of eosin was diminished, was also observed in the groups of IUE+NE 0.1-10 μg. The androgen receptor (AR) and estrogen receptor alpha (ERα) immunoexpression in the Leydig cells of IUE+NE 1-10 μg was slightly lower than that in the controls. Long-term dysfunction of the hypothalamo-pituitary-testicular axis, including sustained hypoproduction of gonadotropin and testosterone, and altered expressions of steroid hormone receptors and <i>StAR</i> genes were observed. The hypothalamo-pituitary control of gonadotropin secretion may be affected by the smaller doses of estrogenic agents than the reproductive organs. Furthermore, the fertility rate in the male mice exposed to this estrogenic agent was closely correlated with the testosterone levels, and even more so with the rate-limiting factor of steroidogenesis, <i>StAR</i>. This finding suggests that endocrine disruptors have an important pronounced effect on <i>StAR</i> gene expression.<br>

Journal

  • Journal of Veterinary Medical Science

    Journal of Veterinary Medical Science 68(12), 1257-1267, 2006-12-25

    Japanese Society of Veterinary Science

References:  40

Cited by:  5

Codes

  • NII Article ID (NAID)
    110005716366
  • NII NACSIS-CAT ID (NCID)
    AA10796138
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    09167250
  • NDL Article ID
    8626697
  • NDL Source Classification
    ZR22(科学技術--農林水産--畜産)
  • NDL Call No.
    Z18-350
  • Data Source
    CJP  CJPref  NDL  NII-ELS  J-STAGE  JASI 
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