Estrogen mimetics are known to contaminate our environment, and may contribute to toxic consequences of endocrine functional disruption, and initiation or support of tumor growth. Environmental estrogens have previously been tested for their abilities to elicit genomic responses; however, nongenomic responses to these compounds have not been explored. We have characterized the alpha form of the estrogen receptor (ERalpha) in the plasma membrane of GH3/B6 pituitary tumor cells, which serve as a model for membrane-initiated actions of estrogens (rapid estrogen-induced release of prolactin). Cells enriched for the membrane estrogen receptor (mER) are much more responsive to the proliferative effects of estradiol and DES; this could be related to either prolactin release (prolactin acting as a growth factor) or activation of kinases which regulate cell division. Xenoestrogens were recently implicated in several nongenomic responses. Therefore, it is very important to learn if xenoestrogens can act through membrane-initiated mechanisms linked to the mER in our model system. To test our hypothesis we have selected a repertoire of 7 compounds representing different classes of xenoestrogens. They will be tested for their ability to produce effects in mER4 vs. mER- cells in order to corrate responses to the presence of this receptor. Specifically, our aims are to: (1) Test the selected xenoestrogens for their ability to cause rapid secretion of prolactin, increases in intracellular calcium levels, and rapid activation of MAP kinases; and (2) examine the ability of the same compounds to bind to the membrane form of ERalpha using assays for competition for binding of E2 -BSA-fluorescein to the mER, and for ligand-mediated masking of an mERa epitope. The function-eliciting and binding abilities of these compounds will then be compared to each other; they may be more potent through this pathway than through the genomic pathway. Elucidating another pathway for estrogen mimetic actions should help to develop future guidelines for environmental handling, therapeutic interventions after exposures, and the identification of environmental and dietary estrogens as disease-causing or -preventing agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010987-03
Application #
6686368
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
2002-02-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$211,740
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Watson, Cheryl S; Jeng, Yow-Jiun; Guptarak, Jutatip (2011) Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways. J Steroid Biochem Mol Biol 127:44-50
Watson, C S; Alyea, R A; Jeng, Y-J et al. (2007) Nongenomic actions of low concentration estrogens and xenoestrogens on multiple tissues. Mol Cell Endocrinol 274:1-7
Watson, Cheryl S; Bulayeva, Nataliya N; Wozniak, Ann L et al. (2007) Xenoestrogens are potent activators of nongenomic estrogenic responses. Steroids 72:124-34
Wozniak, Ann L; Bulayeva, Nataliya N; Watson, Cheryl S (2005) Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells. Environ Health Perspect 113:431-9
Bulayeva, Nataliya N; Wozniak, Ann L; Lash, L Leanne et al. (2005) Mechanisms of membrane estrogen receptor-alpha-mediated rapid stimulation of Ca2+ levels and prolactin release in a pituitary cell line. Am J Physiol Endocrinol Metab 288:E388-97
Watson, Cheryl S; Lange, Carol A (2005) Steadying the boat: integrating mechanisms of membrane and nuclear-steroid-receptor signalling. EMBO Rep 6:116-9
Watson, Cheryl S; Bulayeva, Nataliya N; Wozniak, Ann L et al. (2005) Signaling from the membrane via membrane estrogen receptor-alpha: estrogens, xenoestrogens, and phytoestrogens. Steroids 70:364-71
Bulayeva, Nataliya N; Gametchu, Bahiru; Watson, Cheryl S (2004) Quantitative measurement of estrogen-induced ERK 1 and 2 activation via multiple membrane-initiated signaling pathways. Steroids 69:181-92
Bulayeva, Nataliya N; Watson, Cheryl S (2004) Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. Environ Health Perspect 112:1481-7
Watson, Cheryl S; Gametchu, Bahiru (2003) Proteins of multiple classes may participate in nongenomic steroid actions. Exp Biol Med (Maywood) 228:1272-81

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