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| Fetal programming by xenobiotic estrogens |
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| Hormonal disruption during fetal life has been linked with adverse outcomes that are not immediately obvious at birth. These effects, termed “long-latency birth defects,” are likely mediated by epigenetic (not involving gene mutation) programming. A good example of a long-latency birth defect is the case of women exposed to the synthetic estrogen diethylstilbestrol (DES) in utero (“DES daughters”). It was only after these women reached puberty that it was discovered that developmental DES exposure resulted in otherwise rare vaginal cancer and a myriad of abnormalities, including an 80% increased incidence of endometriosis. While women no longer take DES during pregnancy, fetuses are exposed to a wide variety of xenoestrogens (XE), chemicals made outside of the body that can interact with endogenous estrogen signaling pathways. For example, bisphenol A (BPA) is released from polycarbonate plastic, such as baby bottles, and the resin lining of metal food cans; genistein (GEN) is a plant estrogen found in soy products; and ethinyl estradiol (EE2) is a component of oral contraceptives. These three XE have been documented in a number of reports, including ours, to permanently program rodent fetal development at current human exposure levels. |
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My lab is currently investigating . |
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Fetal programming by xenoestrogen exposure and the susceptibility to endometriosis in adulthood |
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Fetal programming of endometriosis-related genes |
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DNA methylation of programmed genes |
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We aim to identify novel programmed genes whose altered expression may alter normal physiology and lead to a number of long latency birth defects. While these effects may not be apparent at birth, the epigenetic alteration promoted by developmental XE exposure would be present at birth. If a causal relationship between XE exposure and this type of birth defect can be demonstrated, it represents a prime target for prevention by reducing exposure to these environmental chemicals and potentially a novel treatment of endometriosis using demethylating agents |
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| Estrogen receptor conformation to predict biological activity of estrogens |
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| Estrogens function within target tissues by binding to specific estrogen receptors (ERs), alpha and beta, which are ligand activated transcription factors. It is known that different estrogens induce unique conformations in ER, and it is thought that ER conformation determines the specificity of the biological response, which leads to the proposed hypothesis: ER conformation, measured by peptide profiling, can be used to predict in vivo biological activity. This project centers on analyzing ER conformations induced by 12 mechanistically distinct ER ligands. Peptide profiling will be used with 15 specific ER-interacting peptides. The purpose of this research project is to answer the question: Can ER conformation, measured by peptide profiling, be used to predict tissue specific biological responses of xenoestrogens? ER conformation is known to influence tissue specificity, and this relationship has been examined on a ligand by ligand basis, however, this approach has not been systematically applied to predict biological responses. The significance of this research is threefold: (1) it will address the fundamental question of whether ER conformation can be used to predict in vivo tissue specificity, (2) potentially facilitate the development of new pharmaceutical SERMs and (3) potentially provide a high-throughput method for screening environmental estrogens |
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