Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways

Nataliya N. Bulayeva, Cheryl S. Watson

    Research output: Contribution to journalArticle

    136 Citations (Scopus)

    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 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.

    Original languageEnglish (US)
    Pages (from-to)1481-1487
    Number of pages7
    JournalEnvironmental Health Perspectives
    Volume112
    Issue number15
    DOIs
    StatePublished - Nov 2004

    Fingerprint

    Phosphotransferases
    Chemical activation
    membrane
    Membranes
    inhibitor
    Estrogen Receptors
    Coumestrol
    dieldrin
    endosulfan
    Endosulfan
    Dieldrin
    Dichlorodiphenyl Dichloroethylene
    DDE
    nitric oxide
    detergent
    steroid
    abnormality
    Phytoestrogens
    tumor
    1-Phosphatidylinositol 4-Kinase

    Keywords

    • Environmental estrogens
    • ERKs
    • Estradiol
    • Phytoestrogens
    • Prolactinoma cell line
    • Rapid estrogen effects

    ASJC Scopus subject areas

    • Environmental Science(all)
    • Environmental Chemistry
    • Public Health, Environmental and Occupational Health

    Cite this

    Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. / Bulayeva, Nataliya N.; Watson, Cheryl S.

    In: Environmental Health Perspectives, Vol. 112, No. 15, 11.2004, p. 1481-1487.

    Research output: Contribution to journalArticle

    Bulayeva, Nataliya N. ; Watson, Cheryl S. / Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. In: Environmental Health Perspectives. 2004 ; Vol. 112, No. 15. pp. 1481-1487.
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