Dioxin exerts anti-estrogenic actions in a novel dioxin-responsive telomerase-immortalized epithelial cell line of the porcine oviduct (TERT-OPEC)
Dioxin exerts anti-estrogenic actions in a novel dioxin-responsive telomerase-immortalized epithelial cell line of the porcine oviduct (TERT-OPEC)
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DOI：
10.1093/toxsci/kfj102
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发表时间：
2006-04-01
影响因子：
3.8
通讯作者：
Klonisch, T
中科院分区：
文献类型：
--
作者：
Hombach-Klonisch, S;Pocar, P;Klonisch, T
输卵管上皮细胞对排卵卵母细胞和早期胚胎的营养和存活非常重要，它们对类固醇激素雌激素和孕酮做出反应。内分泌干扰性多卤代芳香烃(PHAH)是一种环境毒素，部分通过配体激活的转录因子芳烃受体(AhR；二恶英受体)起作用，暴露于PHAH可降低生育力。为了研究PHAHs对输卵管上皮细胞作为二恶英类内分泌干扰物潜在靶向组织的作用，我们建立了一种新型的端粒酶永生化输卵管猪上皮细胞系(TERT-OPEC)。TERT-OPEC表达端粒酶活性和免疫阳性的上皮标志物细胞角蛋白，但缺乏间质标志物Vimentin。TERT-OPEC含有功能性雌激素受体(ER)-α和AhR，通过检测ER-α和AhR特异的靶分子确定。用AhR配体2，3，7，8-四氯二苯并对二恶英(TCDD)处理TERT-OPEC后，细胞色素P-450微粒体酶CYP1A1的产量显著增加。ERE-荧光素酶瞬时转染实验显示，激活的AhR导致TERT-OPEC中ER核蛋白含量下调，ER信号显著降低。总之，TCDD诱导和AhR介导的TERT-OPEC抗雌激素反应表明，PHAH影响输卵管内主要依赖雌激素的输卵管上皮的分化。这一行为随后改变了当地的内分泌环境，潜在地导致了胚胎发育受损和女性不孕的一个很大程度上未知的原因。
Oviduct epithelial cells are important for the nourishment and survival of ovulated oocytes and early embryos, and they respond to the steroid hormones estrogen and progesterone. Endocrine-disrupting polyhalogenated aromatic hydrocarbons (PHAH) are environmental toxins that act in part through the ligand-activated transcription factor arylhydrocarbon receptor (AhR; dioxin receptor), and exposure to PHAH has been shown to decrease fertility. To investigate effects of PHAHs on the oviduct epithelium as a potential target tissue of dioxin-type endocrine disruptors, we have established a novel telomerase-immortalized oviduct porcine epithelial cell line (TERT-OPEC). TERT-OPEC exhibited active telomerase and the immunoreactive epithelial marker cytokeratin but lacked the stromal marker vimentin. TERT-OPEC contained functional estrogen receptor (ER)-alpha and AhR, as determined by the detection of ER-alpha- and AhR-specific target molecules. Treatment of TERT-OPEC with the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a significant increase in the production of the cytochrome P-450 microsomal enzyme CYP1A1. Activated AhR caused a downregulation of ER nuclear protein fraction and significantly decreased ER-signaling in TERT-OPEC as determined by ERE-luciferase transient transfection assays. In summary, the TCDD-induced and AhR-mediated anti-estrogenic responses by TERT-OPEC suggest that PHAH affect the predominantly estrogen-dependent differentiation of the oviduct epithelium within the fallopian tube. This action then alters the local endocrine milieu, potentially resulting in a largely unexplored cause of impaired embryonic development and female infertility.