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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZES1-TN-D (ST))
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Ravindranath, Neelakanta
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Yale University
Obstetrics & Gynecology
Schools of Medicine
New Haven
United States
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Naqvi, Hanyia; Mamillapalli, Ramanaiah; Krikun, Graciela et al. (2016) Endometriosis Located Proximal to or Remote From the Uterus Differentially Affects Uterine Gene Expression. Reprod Sci 23:186-91
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