Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A.
Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A.
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DOI：
10.1210/en.2005-0565
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发表时间：
2005-12
期刊：
影响因子：
4.8
通讯作者：
A. Zsarnovszky;Hoa H. Le;Hong-Sheng Wang;S. Belcher
中科院分区：
文献类型：
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作者：
A. Zsarnovszky;Hoa H. Le;Hong-Sheng Wang;S. Belcher
17β-雌二醇(E(2))除了调节雌激素受体依赖的基因表达外，还可以直接影响细胞内信号转导。在原代培养的小脑神经元中，E(2)被证明通过快速刺激ERK1/2信号来调节生长和肿瘤性细胞死亡。在这里，我们发现新生大鼠和成年大鼠小脑中的ERK1/2信号对E(2)和发育过程中的环境雌激素双酚A(BPA)快速反应。通过小脑内短暂(6min)注射，然后进行快速固定和磷酸化状态特异性免疫组织化学来定量表征激活的ERK1/2(Perk)免疫阳性细胞数量的变化，进行体内剂量反应分析。从出生后第8天开始，E(2)以一种细胞特异性的方式显著影响PERK阳性细胞的数量，这种方式依赖于浓度和年龄，而不是性别。低剂量(10(-12)~10(-10)M)和较高浓度(10(-7)~10(-6)M)的E(2)或BPA均能增加出生后第10天小脑颗粒细胞的PERK阳性细胞数。中等浓度的两种雌激素化合物都不会改变基础ERK信号。E(2)诱导的PERK免疫反应性的快速增加是ERK1/2途径所特有的，共同注射丝裂原激活的ERK激活的激酶(MEK)1/2抑制剂U0126就证明了这一点。BPA(10(-12)~10(-10)M)与10(-10)M E(2)合用可剂量依赖性地抑制E(2)诱导的小脑神经元ERK1/2的快速激活。双酚A作为高度有效的E(2)模拟物的能力，以及在小脑发育过程中在非常低的浓度下也干扰E(2)的快速作用的能力，突显了异种雌激素对发育中的大脑的潜在低剂量影响。
In addition to regulating estrogen receptor-dependent gene expression, 17beta-estradiol (E(2)) can directly influence intracellular signaling. In primary cultured cerebellar neurons, E(2) was previously shown to regulate growth and oncotic cell death via rapid stimulation of ERK1/2 signaling. Here we show that ERK1/2 signaling in the cerebellum of neonatal and mature rats was rapidly responsive to E(2) and during development to the environmental estrogen bisphenol A (BPA). In vivo dose-response analysis for each estrogenic compound was performed by brief (6-min) intracerebellar injection, followed by rapid fixation and phosphorylation-state-specific immunohistochemistry to quantitatively characterize changes in activated ERK1/2 (pERK) immunopositive cell numbers. Beginning on postnatal d 8, E(2) significantly influenced the number of pERK-positive cells in a cell-specific manner that was dependent on concentration and age but not sex. In cerebellar granule cells on postnatal d 10, E(2) or BPA increased pERK-positive cell numbers at low doses (10(-12) to 10(-10) M) and at higher (10(-7) to 10(-6) M) concentrations. Intermediate concentrations of either estrogenic compound did not modify basal ERK signaling. Rapid E(2)-induced increases in pERK immunoreactivity were specific to the ERK1/2 pathway as demonstrated by coinjection of the mitogen-activated, ERK-activating kinase (MEK)1/2 inhibitor U0126. Coadministration of BPA (10(-12) to 10(-10) M) with 10(-10) M E(2) dose-dependently inhibited rapid E(2)-induced ERK1/2 activation in developing cerebellar neurons. The ability of BPA to act as a highly potent E(2) mimetic and to also disrupt the rapid actions of E(2) at very low concentrations during cerebellar development highlights the potential low-dose impact of xenoestrogens on the developing brain.