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. 2011 Jan;119(1):63-70. doi: 10.1289/ehp.1002347. Epub 2010 Sep 8.
Interest and concern regarding potentially estrogenic substances have resulted in development of model systems to evaluate mechanisms of such chemicals. Microarray studies have indicated that estradiol (E2)-stimulated uterine responses can be divided into early and late phases. Comparison of E2 uterine transcript profiles and those of other estrogenic chemicals of interest in vivo indicates mechanisms and activities of test compounds.
We compared transcript responses and mechanisms of response using mouse reproductive tracts after treatment with E2, estriol (E3), bisphenol A (BPA), and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE).
Uterine RNA from ovariectomized wild-type mice, estrogen receptor α (ERα) knockout (αERKO) mice, and mice expressing a DNA-binding-deficient ERα (KIKO) treated with E2, E3, BPA, or HPTE for 2 or 24 hr was analyzed by microarray. Resulting regulated transcripts were compared by hierarchical clustering and correlation analysis, and response patterns were verified by reverse-transcription real-time polymerase chain reaction (RT-PCR).
Both xenoestrogens, BPA and HPTE, showed profiles highly correlated to that of E2 in the early response phase (2 hr), but the correlation diminished in the later response phase (24 hr), similar to the known weak estrogen E3. Both xenoestrogens also mimicked E2 in samples from KIKO mice, indicating that they are able to utilize the indirect tethering mode of ERα signaling. No response was detected in ERα-null uteri, indicating that ERα mediates the responses.
Our study forms a basis on which patterns of response and molecular mechanisms of potentially estrogenic chemicals can be assessed.
由于人们对潜在雌激素物质的兴趣和关注，已经开发出了模型系统来评估这些化学物质的作用机制。基因芯片研究表明，雌二醇（E2）刺激的子宫反应可以分为早期和晚期两个阶段。比较 E2 子宫转录谱和体内其他感兴趣的雌激素化学物质的转录谱，可指示测试化合物的作用机制和活性。
我们比较了用 E2、雌三醇（E3）、双酚 A（BPA）和 2,2-双（对羟苯基）-1,1,1-三氯乙烷（HPTE）处理的小鼠生殖器官后的转录反应和作用机制。
用基因芯片分析了经 E2、E3、BPA 或 HPTE 处理 2 或 24 小时的去卵巢野生型小鼠、雌激素受体 α（ERα）敲除（αERKO）小鼠和表达 DNA 结合缺陷型 ERα（KIKO）的小鼠的子宫 RNA。通过层次聚类和相关分析比较所得调节转录物，并通过逆转录实时聚合酶链反应（RT-PCR）验证反应模式。
两种外源性雌激素 BPA 和 HPTE 在早期反应阶段（2 小时）与 E2 的谱高度相关，但在晚期反应阶段（24 小时）相关性降低，类似于已知的弱雌激素 E3。两种外源性雌激素在 KIKO 小鼠的样本中也模拟了 E2 的作用，表明它们能够利用 ERα 信号的间接系链模式。在 ERα 缺失的子宫中未检测到反应，表明 ERα 介导了反应。
我们的研究为评估潜在雌激素化学物质的反应模式和分子机制奠定了基础。
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