Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Toxicology. 2012 Aug 16;298(1-3):40-51. doi: 10.1016/j.tox.2012.04.014. Epub 2012 May 3.
Primary biliary cirrhosis (PBC) is a cholestatic liver disease of unknown cause that occurs most frequently in post-menopausal women. Since the female sex hormone oestrogen can be cholestatic, we hypothesised that PBC may be triggered in part by chronic exposure to xenoestrogens (which may be more active on a background of low endogenous oestrogen levels seen in post-menopausal women). A reporter gene construct employing a synthetic oestrogen response element predicted to specifically interact with oestrogen receptors (ER) was constructed. Co-transfection of this reporter into an ER null cell line with a variety of nuclear receptor expression constructs indicated that the reporter gene was trans-activated by ERα and ERβ, but not by the androgen, thyroid, progesterone, glucocorticoid or vitamin D receptors. Chemicals linked to PBC were then screened for xenoestrogen activity in the human ERα-positive MCF-7 breast cancer cell line. Using this assay, the coal-derived food and cosmetic colourings--sunset yellow and tartrazine--were identified as novel human ERα activators, activating the human ER with an EC(50%) concentration of 220 and 160 nM, respectively.
原发性胆汁性肝硬化（PBC）是一种原因不明的胆汁淤积性肝病，最常发生于绝经后妇女。由于女性性激素雌激素可能具有胆汁淤积作用，因此我们假设 PBC 可能部分是由慢性暴露于外源性雌激素（在绝经后妇女所见的低内源性雌激素水平背景下，外源性雌激素可能更活跃）引起的。构建了一种采用合成雌激素反应元件的报告基因构建体，该元件预测可特异性与雌激素受体（ER）相互作用。将该报告基因转染到具有各种核受体表达构建体的 ER 缺失细胞系中，表明报告基因可被 ERα 和 ERβ 转激活，但不能被雄激素、甲状腺素、孕激素、糖皮质激素或维生素 D 受体转激活。然后，在人 ERα 阳性 MCF-7 乳腺癌细胞系中筛选与 PBC 相关的化学品，以检测其是否具有外源性雌激素活性。使用该测定法，发现煤衍生的食品和化妆品着色剂——日落黄和酒石黄——是新型的人 ERα 激活剂，对人 ER 的 EC（50）浓度分别为 220 和 160 nM。
