Botanical estrogens are widely consumed by women with the expectation that they provide a safe, natural source of estrogens to replace the loss of endogenous estrogen in the menopause. Because estrogens can have diverse effects in target cells, including the stimulation of some breast cancers, this unregulated consumption of botanical estrogens might not contribute uniformly to healthy aging. Estrogens regulate gene transcriptional programs and the physiology of many reproductive and non-reproductive tissues, and the mechanisms by which they act are multi-faceted, involving two estrogen receptors, ERa and ER?, and nuclear-initiated and extra-nuclear-initiated, kinase-mediated pathways. With botanical estrogens, little is known about these mechanistic and cellular aspects. Our overall goal is to use a systems biology approach to provide a molecular and cellular profile of the activity of the botanical estrogens we will be studying, from soy, wild yam, licorice root, and dong quai, to enable determination of whether these botanical estrogens have activities similar to or distinct from estradiol or selective estrogen receptor modulators (SERMs).
In Aim 1, we will examine the molecular interactions of botanical estrogens with ERa and ER? by analysis of ligand binding, conformation and dynamics of the ligand-receptor complexes, and their interaction with key co-regulatory proteins.
In Aim 2, we will examine how the patterns of ER and protein kinase recruitment to chromatin binding sites (cistromes) and changes in gene expression (transcriptomes) in target cells are regulated by botanical estrogens through nuclear and extranuclear pathways on a genome-wide basis.
In Aim 3, we will generate mechanistic systems biology profiles that relate the cistromes, transcriptomes, and pathway-specific actions of botanical estrogens to their effects on cell functional properties. In this way, we will be able to place cell response to botanical estrogens on a firm mechanistic basis that will allow determination of whether botanical estrogens have similar or unique activities from those of other estrogens and provide fundamental information to inform future clinical studies. Our mechanistic and cellular findings will also be relevant in guiding and interpreting the work in other projects in this P50 program.

Public Health Relevance

Little is known about the efficacy and safety of botanical estrogens that are being widely consumed by women for relief from menopausal symptoms. The botanical estrogen systems biology profiles generated through this project will provide crucial mechanistic information and a new conceptual framework for determining whether botanical estrogens have similar or unique activities from those of other estrogens.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Specialized Center (P50)
Project #
5P50AT006268-03
Application #
8329639
Study Section
Special Emphasis Panel (ZAT1-SM (19))
Program Officer
Hopp, Craig
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$1,452,374
Indirect Cost
$545,236
Name
University of Illinois Urbana-Champaign
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Mahalingam, Sharada; Gao, Liying; Eisner, Jacqueline et al. (2016) Effects of isoliquiritigenin on ovarian antral follicle growth and steroidogenesis. Reprod Toxicol 66:107-114
Patel, Shreya; Peretz, Jackye; Pan, Yuan-Xiang et al. (2016) Genistein exposure inhibits growth and alters steroidogenesis in adult mouse antral follicles. Toxicol Appl Pharmacol 293:53-62
Mahalingam, Sharada; Gao, Liying; Gonnering, Marni et al. (2016) Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro. Toxicol Appl Pharmacol 295:47-55
Chambliss, Ken L; Barrera, Jose; Umetani, Michihisa et al. (2016) Nonnuclear Estrogen Receptor Activation Improves Hepatic Steatosis in Female Mice. Endocrinology 157:3731-3741
Pisani, Samantha L; Neese, Steven L; Katzenellenbogen, John A et al. (2016) Estrogen Receptor-Selective Agonists Modulate Learning in Female Rats in a Dose- and Task-Specific Manner. Endocrinology 157:292-303
Madak-Erdogan, Zeynep; Gong, Ping; Zhao, Yiru Chen et al. (2016) Dietary licorice root supplementation reduces diet-induced weight gain, lipid deposition, and hepatic steatosis in ovariectomized mice without stimulating reproductive tissues and mammary gland. Mol Nutr Food Res 60:369-80
Aumsuwan, Pranapda; Khan, Shabana I; Khan, Ikhlas A et al. (2016) The anticancer potential of steroidal saponin, dioscin, isolated from wild yam (Dioscorea villosa) root extract in invasive human breast cancer cell line MDA-MB-231 in vitro. Arch Biochem Biophys 591:98-110
Boonmuen, Nittaya; Gong, Ping; Ali, Zulfiqar et al. (2016) Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities. Steroids 105:42-9
Madak-Erdogan, Zeynep; Kim, Sung Hoon; Gong, Ping et al. (2016) Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. Sci Signal 9:ra53
Smirnova, Natalia F; Fontaine, Coralie; Buscato, Mélissa et al. (2015) The Activation Function-1 of Estrogen Receptor Alpha Prevents Arterial Neointima Development Through a Direct Effect on Smooth Muscle Cells. Circ Res 117:770-8

Showing the most recent 10 out of 54 publications