2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and protein expression in human endometrium.
2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and protein expression in human endometrium.
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DOI：
10.1210/jc.2004-2064
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发表时间：
2005-08
期刊：
影响因子：
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通讯作者：
M. Mueller;J. Vigne;Matthias Streich;M. Tee;L. Raio;E. Dreher;N. Bersinger;Robert N. Taylor
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文献类型：
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作者：
M. Mueller;J. Vigne;Matthias Streich;M. Tee;L. Raio;E. Dreher;N. Bersinger;Robert N. Taylor
Glycodelin（GdA）是一种免疫抑制性子宫内膜糖蛋白，对胚胎着床和妊娠建立至关重要。目的研究二恶英（2，3，7，8-tetrachlorodibenzo-p-dioxin，TCDD）对人子宫内膜细胞GdA合成的影响。设计：采用可控的子宫内膜组织块培养和细胞培养。研究在瑞士伯尔尼和加州的弗朗西斯科的大学医院研究实验室进行。排卵期妇女提供增生期或分泌期子宫内膜活检。干预（S）EE和细胞在不加和加TCDD的情况下培养。主要观察指标（S）GdA蛋白和基因表达定量。结果10 nm TCDD作用9d后，EEs GdA生成量增加2.5倍。荧光显示TCDD处理的子宫内膜上皮细胞中新GdA的生物合成和分泌增加了3至4倍。由于二恶英的作用是由芳香烃受体（AhR）介导的，我们确定，原代上皮细胞和石川细胞表达AhR。在瞬时转染的石川细胞中，使用荧光素酶融合载体（相对于GdA转录起始位点含有1.0 kb的5'侧翼DNA）建立了对TCDD和表达的AhR的剂量反应，但当使用较短的启动子构建体时则没有。二恶英反应元件被定位到基因启动子的核苷酸-539到-533，并通过定点突变进行验证。结论：我们证明了直接AhR介导的二恶英对GdA基因转录和蛋白分泌的影响，可能会影响人类女性生育能力。
CONTEXT Glycodelin (GdA) is an immunosuppressive endometrial glycoprotein critical for embryonic implantation and pregnancy establishment. OBJECTIVE The aim of the present study was to examine the effect of dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] on GdA production in human endometrial cells. DESIGN Controlled endometrial explant (EE) and cell cultures were used in this study. SETTING Work was conducted at university hospital research laboratories in Bern, Switzerland, and in San Francisco, California. PATIENTS Ovulatory women provided endometrial biopsies in the proliferative or secretory phase. INTERVENTION(S) EEs and cells were cultured without and with TCDD. MAIN OUTCOME MEASURE(S) GdA protein and gene expression were quantified. RESULTS A 2.5-fold increase in GdA production was demonstrated in EEs treated with 10 nm TCDD for 9 d. Fluorography revealed a 3- to 4-fold increase in new GdA biosynthesis and secretion in TCDD-treated endometrial epithelial cells. Because the action of dioxin is mediated by the aryl hydrocarbon receptor (AhR), we ascertained that primary epithelial and Ishikawa cells express AhR. Dose responses to TCDD and expressed AhR were established in transiently transfected Ishikawa cells using luciferase fusion vectors containing 1.0 kb of 5' flanking DNA relative to the GdA transcriptional start site but not when shorter promoter constructs were used. A dioxin response element was mapped to nucleotides -539 to -533 of the gene promoter and verified by site-directed mutagenesis. CONCLUSIONS We demonstrated a direct AhR-mediated effect of dioxin on GdA gene transcription and protein secretion that might influence human female fertility.