Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways.
Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways.
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DOI：
10.1289/ehp.7175
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发表时间：
2004-11
影响因子：
10.4
通讯作者：
Watson CS
中科院分区：
文献类型：
--
作者：
Bulayeva NN;Watson CS
异种雌激素可以模拟或拮抗生理雌激素的活性，异种雌激素的作用机制涉及与雌激素受体（ER）的结合。然而，各种体外或体内试验未能显示异种雌激素与雌二醇（E2）相比具有更强的基因组活性，这使得很难解释它们通过这种类固醇作用途径导致动物（也许还有人类）生殖功能异常的能力。 E2 还被证明可以通过膜上的作用启动快速的细胞内信号传导，例如细胞内钙、cAMP 和一氧化氮水平的变化，以及多种激酶的激活。在这项研究中，我们证明了几种异种雌激素可以快速激活垂体肿瘤细胞系 GH3/B6/F10 中的细胞外调节激酶 (ERK)，该细胞系表达高水平的 ER-α (mER) 膜受体。我们测试了植物雌激素（香豆雌酚）、有机氯农药或其代谢物（硫丹、狄氏剂和 DDE）以及塑料制造的洗涤剂副产品（对壬基酚和双酚 A）。这些异种雌激素（双酚 A 除外）产生快速（应用后 3–30 分钟）、浓度 (10−14–10−8 M) 依赖性 ERK-1/2 磷酸化，但激活模式明显不同。为了确定参与 ERK 激活的信号通路，我们使用了 ER 的特异性抑制剂、表皮生长因子受体、Ca2+ 信号传导、Src 和磷酸肌醇 3 激酶以及膜结构破坏剂。多种抑制剂阻断 ERK 激活，表明同时使用多种途径和复杂的信号网络相互作用。然而，抑制剂对所检查的每种异雌激素反应的影响不同。这些作用可能有助于解释异种雌激素在低浓度下破坏生殖功能的独特能力。
Xenoestrogens can mimic or antagonize the activity of physiological estrogens, and the suggested mechanism of xenoestrogen action involves binding to estrogen receptors (ERs). However, the failure of various in vitro or in vivo assays to show strong genomic activity of xenoestrogens compared with estradiol (E2) makes it difficult to explain their ability to cause abnormalities in animal (and perhaps human) reproductive functions via this pathway of steroid action. E2 has also been shown to initiate rapid intracellular signaling, such as changes in levels of intracellular calcium, cAMP, and nitric oxide, and activations of a variety of kinases, via action at the membrane. In this study, we demonstrate that several xenoestrogens can rapidly activate extracellular-regulated kinases (ERKs) in the pituitary tumor cell line GH3/B6/F10, which expresses high levels of the membrane receptor for ER-α(mER). We tested a phytoestrogen (coumestrol), organochlorine pesticides or their metabolites (endosulfan, dieldrin, and DDE), and detergent by-products of plastics manufacturing (p-nonylphenol and bisphenol A). These xenoestrogens (except bisphenol A) produced rapid (3–30 min after application), concentration (10−14–10−8 M)-dependent ERK-1/2 phosphorylation but with distinctly different activation patterns. To identify signaling pathways involved in ERK activation, we used specific inhibitors of ERs, epidermal growth factor receptors, Ca2+ signaling, Src and phosphoinositide-3 kinases, and a membrane structure disruption agent. Multiple inhibitors blocked ERK activation, suggesting simultaneous use of multiple pathways and complex signaling web interactions. However, inhibitors differentially affected each xenoestrogen response examined. These actions may help to explain the distinct abilities of xenoestrogens to disrupt reproductive functions at low concentrations.
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影响因子：
3.8
作者：
Hodges, LC;Bergerson, JS;Walker, CL
通讯作者：
Walker, CL
DOI：
10.1073/pnas.91.18.8517
发表时间：
1994-08-30
影响因子：
11.1
作者：
ARONICA, SM;KRAUS, WL;KATZENELLENBOGEN, BS
通讯作者：
KATZENELLENBOGEN, BS
影响因子：
15.9
作者：
Chen, Z;Yuhanna, IS;Shaul, PW
通讯作者：
Shaul, PW
影响因子：
7.7
作者：
MacDonald, MJ;AlMasri, H;Cruz, MO
通讯作者：
Cruz, MO
影响因子：
4.8
作者：
Haynes, MP;Li, L;Bender, JR
通讯作者：
Bender, JR