Inappropriate exposure to environmental agents during critical, sensitive periods of development can reprogram target tissues via epigenetic mechanisms to increase the risk for disease later in adult life. The reproductive tract is particularly sensitive to this type of developmental programming in response to xenoestrogen exposure, a major class of endocrine disrupting chemicals that are ubiquitously present in our environment. We have recently shown that developmental programming following neonatal xenoestrogen exposure can increase the risk of developing hormone-dependent leiomyoma by increasing the responsiveness to hormone of estrogen-responsive genes in the myometrium. Although the epigenetic mechanism(s) responsible for developmental programming are unknown, recent data indicate that one type of epigenetic modification, histone methylation, is altered in response to activation of PI3K signaling via phosphorylation of histone methyltransferases by AKT. Since estrogens can activate PI3K via nongenomic signaling, we hypothesize that xenoestrogens, via activation of cell signaling pathways, can modify the activity of histone methyltransferases, leading to epigenetic alterations in histone methylation patterns that contribute to developmental programming in the uterus. To test this hypothesis, we propose the following Specific Aims:
Specific Aim 1 : Test the hypothesis that estrogen-activation of cell signaling results in changes in histone modifications that alter gene expression.
Specific Aim 2 : Determine if phosphorylation of methyltransferases by AKT or ERK is responsible for changes in histone modifications that occur in response to estrogens.
Specific Aim 3 : Determine the contribution of histone modifications to developmental programming of gene expression in the uterus. These studies will explore activation of cell signaling as a novel mechanism by which histone methyltransferase activity can be modulated by estrogens, resulting in epigenetic alterations in histone methylation patterns. In addition, they will determine if changes in histone methylation induced by neonatal exposure to xenoestrogens are heritable and contribute to developmental programming by modulating gene expression in adult animals. Project Narrative Uterine leiomyoma are the most common gynecologic tumor of women and they have a tremendous negative affect on the health of millions of women in the US. Surprisingly, we know very little about what causes these tumors, although hormones, including environmental estrogens, have been implicated in the etiology of this disease. We propose that a potential mechanism by which environmental estrogens may contribute to the development of these tumors is through developmental programming. In this application we will test the hypothesis that during development of the uterus, exposure to environmental estrogens reprograms gene expression in the myometrium to predispose to the development of these tumors later in life. The mechanism that we propose for this reprogramming is the activation of nongenomic signaling pathways to modulate the activity of histone methyltransferases and induce alterations in epigenetic patterns of histone methylation.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Heindel, Jerrold
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Texas A&M University
Other Clinical Sciences
Schools of Medicine
College Station
United States
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Wong, Rebecca Lee Yean; Walker, Cheryl Lyn (2013) Molecular pathways: environmental estrogens activate nongenomic signaling to developmentally reprogram the epigenome. Clin Cancer Res 19:3732-7
Greathouse, K Leigh; Bredfeldt, Tiffany; Everitt, Jeffrey I et al. (2012) Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 10:546-57
Walker, Cheryl Lyn (2011) Epigenomic reprogramming of the developing reproductive tract and disease susceptibility in adulthood. Birth Defects Res A Clin Mol Teratol 91:666-71
Bredfeldt, Tiffany G; Greathouse, K Leigh; Safe, Stephen H et al. (2010) Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol 24:993-1006
McCampbell, Adrienne S; Broaddus, Russell R; Walker, Cheryl L (2010) Loss of inhibitory insulin receptor substrate-1 phosphorylation: An early event in endometrial hyperplasia and progression to carcinoma. Cell Cycle 9:2698-9
Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39
Short, John D; Houston, Kevin D; Dere, Ruhee et al. (2008) AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27. Cancer Res 68:6496-506
McCampbell, Adrienne S; Walker, Cheryl L; Broaddus, Russell R et al. (2008) Developmental reprogramming of IGF signaling and susceptibility to endometrial hyperplasia in the rat. Lab Invest 88:615-26
Greathouse, K L; Cook, J D; Lin, K et al. (2008) Identification of uterine leiomyoma genes developmentally reprogrammed by neonatal exposure to diethylstilbestrol. Reprod Sci 15:765-78
Woodruff, Teresa K; Walker, Cheryl Lyn (2008) Fetal and early postnatal environmental exposures and reproductive health effects in the female. Fertil Steril 89:e47-51

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