In humans, exposure to xenoestrogens such as diethylstilbestrol (DES) and bisphenol A (BPA) has been associated with developmental disorders of the female reproductive tract. The investigators have previously shown that fetal exposure to these agents alters the methylation of estrogen response elements (EREs) in the endometrium. The change in ERE methylation results in altered ERE occupancy by estrogen receptor (ER) in vivo and altered gene expression in response to estrogens throughout life. The uterine endometrium is replaced in each menstrual cycle or estrus cycle in humans or rodents, respectively. The investigators were the first to identify the stem cells that regenerate this tisse. As the epigenetic changes in estrogen response persist in the adult, they are likely to be encoded in the stem cells that regenerate the endometrium in each reproductive cycle. The investigators hypothesize that xenoestrogen exposure affects methylation of multiple EREs in uterine stem cells leading to altered estrogen sensitivity as an adult. To test this hypothesis the investigators will determine the extent of uterine ERE methylation in the entire genome after DES or BPA exposure as well as the effect of exposure to these agents on endometrial stem cell growth and estrogen response in vitro and in vivo.
The specific aims i nclude 1) the use of chromatin precipitation, massively parallel sequencing and bisulfite sequencing to determine if exposure leads to preferential methylation of multiple EREs and if this occurs in uterine stem cells;2) determine if exposure leads to altered endometrial stem cell estrogen response in vitro;and 3) use of an in vivo model to determine if endometrial stem cells from exposed animals are more prone to endometriosis or endometrial cancer. These studies will test the hypothesis that methylation of EREs in uterine stem cells and resultant altered estrogen responsiveness will lead to an increased incidence of estrogen mediated disorders, thus providing an epigenetic mechanism for reproductive tract disease associated with xenoestrogen exposure. This model explains how a weak estrogen results in an estrogenic response disproportionate to its intrinsic estrogenic activity and how this epigenetic signal persists despite loss of endometrium in each reproductive cycle due to altered methylation in endometrial stem cells.

Public Health Relevance

Stem cells regenerate the endometrial lining of the uterus which is shed with each menstrual period. These studies will determine if the effects of fetal environmental estrogen exposure are epigenetically encoded in the endometrial stem cells. Knowledge of the molecular and cellular mechanisms that underlie the effects of environmental estrogen exposure will allow the design of preventive and therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD076422-03
Application #
8669743
Study Section
Special Emphasis Panel ()
Program Officer
Ravindranath, Neelakanta
Project Start
2012-08-10
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$404,595
Indirect Cost
$161,595
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Goetz, Laura G; Mamillapalli, Ramanaiah; Sahin, Cagdas et al. (2018) Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE-/- Mice. Endocrinology 159:754-762
Liu, Ying; Tal, Reshef; Pluchino, Nicola et al. (2018) Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med 22:67-76
Flores, Valerie A; Vanhie, Arne; Dang, Tran et al. (2018) Progesterone Receptor Status Predicts Response to Progestin Therapy in Endometriosis. J Clin Endocrinol Metab 103:4561-4568
Sahin, Cagdas; Mamillapalli, Ramanaiah; Yi, Kyong W et al. (2018) microRNA Let-7b: A Novel treatment for endometriosis. J Cell Mol Med 22:5346-5353
Pluchino, Nicola; Mamillapalli, Ramanaiah; Moridi, Irene et al. (2018) G-Protein-Coupled Receptor CXCR7 Is Overexpressed in Human and Murine Endometriosis. Reprod Sci 25:1168-1174
Sahin, Cagdas; Mamillapalli, Ramanaiah; Taylor, Hugh S (2018) Bone Marrow-Derived Cells Trafficking to the Oviduct: Effect of Ischemia-Reperfusion Injury. Reprod Sci 25:1037-1044
Sahin Ersoy, Gulcin; Zolbin, Masoumeh Majidi; Cosar, Emine et al. (2017) CXCL12 Promotes Stem Cell Recruitment and Uterine Repair after Injury in Asherman's Syndrome. Mol Ther Methods Clin Dev 4:169-177
Goetz, Laura G; Mamillapalli, Ramanaiah; Devlin, Maureen J et al. (2017) Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture. Am J Physiol Endocrinol Metab 313:E540-E551
Ilagan, Ysabel; Mamillapalli, Ramanaiah; Goetz, Laura G et al. (2017) Bisphenol-A exposure in utero programs a sexually dimorphic estrogenic state of hepatic metabolic gene expression. Reprod Toxicol 71:84-94

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