Schmidt Simone, Degen Gisela H, Seibel Jan, Hertrampf Torsten, Vollmer Günter, Diel Patrick
Institut Kreislaufforschung und für Sportmedizin, Abt. Molekulare und Zelluläre Sportmedizin, Deutsche Sporthochschule Köln, Carl-Diem-Weg 6, 50933 Cologne, Germany.
Arch Toxicol. 2006 Dec;80(12):839-45. doi: 10.1007/s00204-006-0102-4.
Phytoestrogens have been described as weak estrogens, selective estrogen receptor mediators (SERMs) or to exhibit antiestrogenic properties. However, information about their activity in combination with xenoestrogens and 17beta-estradiol in vivo, is limited. Therefore, the combinatory activity of the phytoestrogen genistein (Gen), the industrial chemical bisphenol A (BPA), and ethinylestradiol (EE) in ovariectomized Wistar rats was analyzed in this study. All compounds were administered orally on three consecutive days (EE at 30 microg, Gen at 100 mg and BPA at 200 mg per kg body weight per day). The pure antiestrogen fulvestrant (3 mg/kg) served as estrogen receptor (ER) antagonist control. Effects on uterine wet weight, height of the uterine epithelium, uterine clusterin (Clu) and complement C3 expression, and the height of the vaginal epithelium were examined. Treatment with Gen alone resulted in a moderate stimulation of uterine weight; in the vagina the height of the epithelium was strongly stimulated. BPA did not stimulate any of the above-mentioned parameters significantly. In combination with EE, Gen acted on most of the analyzed parameters in an additive manner, whereas BPA significantly antagonized the effects of EE on the uterine epithelium and uterine Clu expression. Given in combination with Gen, BPA was also able to antagonize the stimulatory effect of Gen on the uterine epithelium. In summary, our results demonstrate that Gen, in contrast to BPA, does not exhibit any antiestrogenic properties, even if given at high concentrations. The results of this study characterize BPA as a functional antiestrogen, very likely the result of a lack of ability to activate ER-mediated transactivation after binding to the receptor. This is not the case for Gen. Our results point to the involvement of complex molecular mechanisms in the action of Gen. These mechanisms, especially the role of ERbeta have to be characterized in further investigations.
植物雌激素被描述为弱雌激素、选择性雌激素受体调节剂（SERM）或具有抗雌激素特性。然而，关于它们在体内与外源性雌激素和17β - 雌二醇联合作用的信息有限。因此，本研究分析了植物雌激素染料木黄酮（Gen）、工业化学品双酚A（BPA）和乙炔雌二醇（EE）在去卵巢Wistar大鼠中的联合活性。所有化合物连续三天口服给药（EE每天每千克体重30微克，Gen每天每千克体重100毫克，BPA每天每千克体重200毫克）。纯抗雌激素氟维司群（3毫克/千克）用作雌激素受体（ER）拮抗剂对照。检测了对子宫湿重、子宫上皮高度、子宫簇集蛋白（Clu）和补体C3表达以及阴道上皮高度的影响。单独使用Gen治疗导致子宫重量适度增加；在阴道中，上皮高度受到强烈刺激。BPA对上述任何参数均无显著刺激作用。与EE联合使用时，Gen对大多数分析参数具有相加作用，而BPA显著拮抗EE对子宫上皮和子宫Clu表达的影响。与Gen联合使用时，BPA也能够拮抗Gen对子宫上皮的刺激作用。总之，我们的结果表明，与BPA不同，即使高浓度给予Gen也不表现出任何抗雌激素特性。本研究结果将BPA表征为一种功能性抗雌激素，很可能是由于其与受体结合后缺乏激活ER介导的反式激活的能力。Gen并非如此。我们的结果表明Gen的作用涉及复杂的分子机制。这些机制，尤其是ERβ的作用，有待进一步研究表征。
