(provided by candidate): Following reports touting a myriad of health benefits, soy has become a ubiquitous part of the American diet. However, early observational studies have raised concerns regarding the reproductive toxicity of phytoestrogens consumed in the diet. Phytoestrogens, including soy-derived GEN, bind to and compete for the estrogen receptor (ER), inducing uterotrophic effects similar to estradiol. However, unlike estradiol, the biological effects of genistein (GEN) are not regulated through feedback mechanism in the hypothalamic-pituitary- gonadal (HPG) axis and can lead to aberrant signal transduction in the uterus. Furthermore, the developing organ systems in immature mammals are typically more sensitive to chemical exposures than adults, and early life exposure to soy has been proven to impact may organs of the HPG axis. Neonatal GEN exposure disrupts female reproductive tract development in mice, resulting in posteriorization of the oviduct and uterus and significant alterations to inflammatory response pathways during pregnancy. The glucocorticoid receptor (GCR) mediates immune-related homeostasis throughout the body. Mice lacking uterine GCR demonstrate altered signal transduction in the uterus, as well as a subfertile phenotype, suggesting intact GCR signaling in the uterus is required to maintain female reproductive tract function. Cross-talk between GCR and ER regulates gene expression and biological functions in the uterus, providing a mechanism by which the immune and reproductive systems integrate their functions. The estrogen-like action of GEN in the uterus may impact GCR signaling, which may play a role in the immune-modulatory effects evident following neonatal GEN exposure. Whole genome microarray analysis indicates GEN regulates glucocorticoid-responsive gene expression in a human uterine cell line and the mouse uterus. The long-term objective of this application is to determine the impact of neonatal GEN exposure on GCR signaling and functions in the uterus. Specifically, the investigators propose to 1) define the glucocorticoid-regulated gene targets altered by neonatal GEN exposure, 2) determine if neonatal GEN exposure results in immediate or persistent GCR modifications, 3) evaluate the effect of neonatal GEN exposure on the GCR-mediated immune response. Under the mentorship of Dr. John A. Cidlowski (K99 period), the candidate will evaluate changes to glucocorticoid- mediated gene expression in the uterus, focusing on demonstrated targets of glucocorticoids and GEN. During this time period, the candidate will also evaluate genome-wide changes in methylation. The proposed training and research will prepare the candidate to independently continue investigation into the impact of neonatal GEN exposure on GCR signaling and functions in the uterus during the R00 phase of the award. The proposed studies address a significant public health issue and will provide mechanistic understanding of how early life exposure to GEN regulates signal transduction, and immune functions in the uterus. These studies have potential implications for alternative estrogen-like endocrine disruptors.

Public Health Relevance

The environmental estrogen genistein exerts endocrine disrupting activity through mechanisms that mimic estradiol in the uterus. However, unlike estradiol, the biological effects of genistein are not regulated through feed-back control by the hypothalamic-pituitary-gonadal axis and can lead to impaired reproductive function, ranging from temporary to permanent infertility. This application will use an integrated training plan in reproductive endocrinology and toxicology to examine the long-term consequences in the uterus of early life exposure to genistein in order to prepare Dr. Shannon Whirledge for success as an independent researcher.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Tyson, Frederick L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
Zip Code
Whirledge, Shannon D; Kisanga, Edwina P; Oakley, Robert H et al. (2018) Neonatal Genistein Exposure and Glucocorticoid Signaling in the Adult Mouse Uterus. Environ Health Perspect 126:047002
Joseph, Dana N; Whirledge, Shannon (2017) Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci 18:
Whirledge, Shannon; Cidlowski, John A (2017) Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction. Trends Endocrinol Metab 28:399-415