RECEPTOR MEDIATED GENE REGULATION BY XENOESTROGENS

异种雌激素(XE)是一种模拟雌激素作用的化合物， 存在于环境中，并代表公共卫生问题，原因是 对生理过程的潜在颠覆性影响，由 雌激素包括生殖、胎儿发育和发育。 生殖组织癌的风险。有很多这样的例子 在被污染的生态系统中出生的野生动物的生殖异常 XE，强调了人类接触的潜在后果。这个 基于结构分析不能可靠地预测雌激素活性 有必要开发功能性筛查系统来 维护人类健康。转录激活试验，其中细胞是 共转染含ERa基因的报告基因 卵黄蛋白原A2(Vit)雌激素反应元件(ERE)已被 用于评估ERAlpha介导的XE的转录活性。 然而，关于基因特异性转录活性的报告显示 XES和其他雌激素类似物表明，雌激素是 不仅是配体的固有性质，而且是配体的功能 特定的基因和细胞背景。ERE序列和/或可变性 辅活化子/辅抑制子的细胞补体可能有助于 基因激活的不同模式。因此，为了提供更多 XE生物活性的完整评估，反式激活 检测将利用含有ERE的报告质粒进行。 源自PS2和乳铁蛋白基因的序列，除了 这就是。转录将在酵母和RL95-2人身上进行评估 转小鼠ERα和ERa基因的子宫内膜癌细胞株 包含上述ERE的报告构建体。已建立 关于细胞和基因特异性转录活性的报道 其他雌激素类似物证明了这项实验的重要性。 建立准确的雌激素样活性图谱的方法 关于XE的。调查结果将产生关于以下方面的实质性信息 这些化合物的雌激素活性、ERE序列和 细胞类型对转录效率的影响，以及体外转录效率的应用 反式激活实验作为XEs的功能筛选系统。

Xenoestrogens (XE), compounds that mimic the action of estrogen, are present in the environment and represent a public health concern due to potentially disruptive effects on physiological processes regulated by estrogen including reproduction, fetal development, and the development of cancers of reproductive tissues. There are numerous examples of reproductive anomalies in wildlife born in ecosystems contaminated with XE, highlighting the potential consequences of human exposure. The inability to reliably predict estrogenicity based on structural analysis necessitates the development of functional screening systems to safeguard human health. The transactivation assay, in which cells are cotransfected with the cDNA for ERalpha and a reporter gene containing the Vitellogenin A2 (Vit) estrogen response element (ERE) has been utilized to assess ERalpha-mediated transcriptional activity of XEs. However, reports of gene-specific transcriptional activity exhibited by XEs, as well as other estrogen analogs, suggest that estrogenicity is not merely an inherent property of a ligand, but also a function of the specific gene and cellular context. Variability in ERE sequence and/or cellular complements of coactivators/corepressors may contribute to differential patterns of gene activation. Therefore, to provide a more complete assessment of the biological activity of XEs, transactivation assays will be carried out utilizing reporter plasmids containing ERE sequences derived from the pS2 and lactoferrin genes, in addition to the Vit ERE. Transcription will be assessed in yeast and RL95-2 human endometrial carcinoma cell lines transfected with the mouse ERalpha and reporter constructs containing the aforementioned EREs. Established reporters of the cell- and gene-specific transcriptional activity of other estrogen analogs demonstrated the importance of this experimental approach in establishing an accurate profile of the estrogenic potency of XEs. The findings will generate substantive information regarding the estrogenicity of these compounds, the effect of ERE sequence and cell type on transcriptional efficacy, and the utility of the in vitro transactivation assay as a functional screening system for XEs.