Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Environ Health Perspect. 2012 Jul;120(7):1029-35. doi: 10.1289/ehp.1104689. Epub 2012 Apr 11.
Endocrine-disrupting chemicals (EDCs) are widely found in the environment. Estrogen-like activity is attributed to EDCs, such as bisphenol A (BPA), bisphenol AF (BPAF), and zearalenone (Zea), but mechanisms of action and diversity of effects are poorly understood.
We used in vitro models to evaluate the mechanistic actions of BPA, BPAF, and Zea on estrogen receptor (ER) α and ERβ.
We used three human cell lines (Ishikawa, HeLa, and HepG2) representing three cell types to evaluate the estrogen promoter activity of BPA, BPAF, and Zea on ERα and ERβ. Ishikawa/ERα stable cells were used to determine changes in estrogen response element (ERE)-mediated target gene expression or rapid action-mediated effects.
The three EDCs showed strong estrogenic activity as agonists for ERα in a dose-dependent manner. At lower concentrations, BPA acted as an antagonist for ERα in Ishikawa cells and BPAF acted as an antagonist for ERβ in HeLa cells, whereas Zea was only a partial antagonist for ERα. ERE-mediated activation by BPA and BPAF was via the AF-2 function of ERα, but Zea activated via both the AF-1 and AF-2 functions. Endogenous ERα target genes and rapid signaling via the p44/42 MAPK pathway were activated by BPA, BPAF, and Zea.
BPA and BPAF can function as EDCs by acting as cell type-specific agonists (≥ 10 nM) or antagonists (≤ 10 nM) for ERα and ERβ. Zea had strong estrogenic activity and activated both the AF-1 and AF-2 functions of ERα. In addition, all three compounds induced the rapid action-mediated response for ERα.
环境中广泛存在着内分泌干扰化学物质（EDCs）。具有雌激素样活性的物质如双酚 A（BPA）、双酚 AF（BPAF）和玉米赤霉烯酮（Zea）都被认为属于 EDCs，但它们的作用机制和多样性的影响还不太清楚。
我们使用体外模型来评估 BPA、BPAF 和 Zea 对雌激素受体（ER）α和 ERβ的作用机制。
我们使用三种代表三种细胞类型的人细胞系（Ishikawa、HeLa 和 HepG2）来评估 BPA、BPAF 和 Zea 对 ERα 和 ERβ 的雌激素启动子活性。Ishikawa/ERα 稳定细胞用于确定雌激素反应元件（ERE）介导的靶基因表达或快速作用介导的变化。
这三种 EDC 均表现出较强的雌激素活性，作为 ERα 的激动剂呈剂量依赖性。在较低浓度下，BPA 在 Ishikawa 细胞中作为 ERα 的拮抗剂，BPAF 在 HeLa 细胞中作为 ERβ 的拮抗剂，而 Zea 仅对 ERα 具有部分拮抗剂作用。BPA 和 BPAF 通过 ERα 的 AF-2 功能介导 ERE 激活，但 Zea 通过 AF-1 和 AF-2 功能激活。BPA、BPAF 和 Zea 激活了内源性 ERα 靶基因和通过 p44/42 MAPK 通路的快速信号转导。
BPA 和 BPAF 可以作为细胞类型特异性激动剂（≥10 nM）或拮抗剂（≤10 nM），作用于 ERα 和 ERβ，充当 EDCs。Zea 具有很强的雌激素活性，并激活 ERα 的 AF-1 和 AF-2 功能。此外，这三种化合物都诱导了 ERα 的快速作用介导的反应。
