Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cellsReportar como inadecuado

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Environmental Health

, 9:61

First Online: 15 October 2010Received: 07 July 2010Accepted: 15 October 2010DOI: 10.1186-1476-069X-9-61

Cite this article as: Jeng, YJ., Kochukov, M. & Watson, C.S. Environ Health 2010 9: 61. doi:10.1186-1476-069X-9-61


BackgroundXenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these xenoestrogens.

MethodsWe studied the effects of low concentrations of endogenous estrogens estradiol, estriol, and estrone at 10 pM representing pre-development levels, and 1 nM representing higher cycle-dependent and pregnancy levels in combinations with the same levels of xenoestrogens in GH3-B6-F10 pituitary cells. These levels of xenoestrogens represent extremely low contamination levels. We monitored calcium entry into cells using Fura-2 fluorescence imaging of single cells. Prolactin release was measured by radio-immunoassay. Extracellular-regulated kinase 1 and 2 phospho-activations and the levels of three estrogen receptors in the cell membrane ERα, ERβ, and GPER were measured using a quantitative plate immunoassay of fixed cells either permeabilized or nonpermeabilized respectively.

ResultsAll xenoestrogens caused responses at these concentrations, and had disruptive effects on the actions of physiologic estrogens. Xenoestrogens reduced the % of cells that responded to estradiol via calcium channel opening. They also inhibited the activation phosphorylation of extracellular-regulated kinases at some concentrations. They either inhibited or enhanced rapid prolactin release, depending upon concentration. These latter two dose-responses were nonmonotonic, a characteristic of nongenomic estrogenic responses.

ConclusionsResponses mediated by endogenous estrogens representing different life stages are vulnerable to very low concentrations of these structurally related xenoestrogens. Because of their non-classical dose-responses, they must be studied in detail to pinpoint effective concentrations and the directions of response changes.

List of abbreviationsEP4-n-ethylphenol





BPAbisphenol A





ERestrogen receptor

ERKsextracellular-signal regulated kinases

mERsmembrane estrogen receptors

MAPKsmitogen-activated protein kinases


Electronic supplementary materialThe online version of this article doi:10.1186-1476-069X-9-61 contains supplementary material, which is available to authorized users.

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Autor: Yow-Jiun Jeng - Mikhail Kochukov - Cheryl S Watson


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