Endocrine-disrupting chemicals such as environmental estrogens contaminate our surroundings and impair the reproductive health of animals, and probably humans. These compounds may act as inappropriate estrogens, and/or interfere with the actions of endogenous estrogens, but their mechanisms of action at low, environmentally relevant concentrations are largely unknown. We have recently shown that signal cascades leading to induced functions initiated by estradiol (E2) at the plasma membrane are also potently initiated by nonphysiological estrogens (xenoestrogens). In cells that express a membraneform of the estrogen receptor-a (mERa), each xenoestrogen elicited unique signaling patterns (temporal, dose-response) via activation of extracellular-regulated kinases (ERKs) and/or calcium elevation. We will now address (1) the structural requirements for activating mERa to generate signals and their linked functions, by comparing the effects of alkylphenol xenoestrogens having varying carbon- chain lengths and structures, and prominent physiological estrogens (E2, estriol, and estrone);(2) active alkylphenols'ability of to act in combination with physiological estrogens via additive, synergistic, and antagonistic mechanisms;and (3) the G protein coupling of these responses. G proteins likely lie upstream of the signaling responses shown by our previous work and others'. We will now seek direct evidence for G protein subtype interactions with mERa via co-immunoprecipitation, use of specific inhibitors, and dominant-negative G protein subtype and decoy interaction peptide approaches. Changes in G protein coupling in response to both physiological estrogens and alkylphenol xenoestrogens will be examined. Our long-term objective is to use our established model system to answer a variety of detailed mechanistic questions about how specific structural features of different physiological estrogens and xenoestrogen subclasses affect actions through the nongenomic pathway and the mERa, and thereby disrupt endocrine processes. Health relevance: Knowing how environmental estrogens disrupt normal signaling and reproductive functions will enable design of new prevention and treatment strategies to deal with their toxicity. Demonstrating their low-dose effects will also guide re-evaluation of Federal regulations setting legal contamination limits for environmental estrogens. The extent and mechanisms by which environmental estrogens contribute to diseases of estrogen overexposure (eg.breast and pituitary cancers, infertility) must be understood so that exposures can be limited to safe levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015292-04
Application #
7714348
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Heindel, Jerrold
Project Start
2006-12-01
Project End
2012-10-31
Budget Start
2009-11-01
Budget End
2012-10-31
Support Year
4
Fiscal Year
2010
Total Cost
$235,447
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; Koong, Luke; Jeng, Yow-Jiun et al. (2018) Xenoestrogen interference with nongenomic signaling actions of physiological estrogens in endocrine cancer cells. Steroids :
Watson, Cheryl S; Hu, Guangzhen; Paulucci-Holthauzen, Adriana A (2014) Rapid actions of xenoestrogens disrupt normal estrogenic signaling. Steroids 81:36-42
Viñas, René; Watson, Cheryl S (2013) Mixtures of xenoestrogens disrupt estradiol-induced non-genomic signaling and downstream functions in pituitary cells. Environ Health 12:26
Watson, Cheryl S; Jeng, Yow-Jiun; Hu, Guangzhen et al. (2012) Estrogen- and xenoestrogen-induced ERK signaling in pituitary tumor cells involves estrogen receptor-? interactions with G protein-?i and caveolin I. Steroids 77:424-32
Viñas, René; Jeng, Yow-Jiun; Watson, Cheryl S (2012) Non-genomic effects of xenoestrogen mixtures. Int J Environ Res Public Health 9:2694-714
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
Jeng, Yow-Jiun; Watson, Cheryl S (2011) Combinations of physiologic estrogens with xenoestrogens alter ERK phosphorylation profiles in rat pituitary cells. Environ Health Perspect 119:104-12
Jeng, Yow-Jiun; Kochukov, Mikhail; Watson, Cheryl S (2010) Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells. Environ Health 9:61
Watson, Cheryl S; Jeng, Yow-Jiun; Kochukov, Mikhail Y (2010) Nongenomic signaling pathways of estrogen toxicity. Toxicol Sci 115:1-11
Kochukov, Mikhail Y; Jeng, Yow-Jiun; Watson, Cheryl S (2009) Alkylphenol xenoestrogens with varying carbon chain lengths differentially and potently activate signaling and functional responses in GH3/B6/F10 somatomammotropes. Environ Health Perspect 117:723-30

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