| Xenoestrogen-Induced ERK-1 and ERK-2 Activation via Multiple Membrane-Initiated Signaling Pathways Nataliya N. Bulayeva and Cheryl S. Watson Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas, USA Abstract
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 invitro or invivo 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-  (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 bisphenolA) produced rapid (3-30min 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. Key words: environmental estrogens, ERKs, estradiol, phytoestrogens, prolactinoma cell line, rapid estrogen effects. Environ Health Perspect 112:1481-1487 (2004) . doi:10.1289/ehp.7175 available via http://dx.doi.org/ [Online 28 July 2004]
Address correspondence to C.S. Watson, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0645 USA. Telephone/fax: (409) 772-2382. E-mail: cswatson@utmb.edu We thank D. Konkel for his scientific comments and skilled editing. This work was supported by National Institute of Environmental Health Sciences grant 010987. The authors declare they have no competing financial interests. Received 13 April 2004 ; accepted 28 July 2004.
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