Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis

Science Park Research Division, Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
Molecular Cancer Research (Impact Factor: 4.38). 04/2012; 10(4):546-57. DOI: 10.1158/1541-7786.MCR-11-0605
Source: PubMed


Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A-exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis.

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    • "normal ovary morphology: presence of corpora lutea, normal estrous cyclicity (Greathouse et al. 2012) "
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    ABSTRACT: The estrogenic properties of bisphenol A (BPA), a ubiquitous synthetic monomer that can leach into the food and water supply, have prompted considerable research into exposure-associated health risks in humans. Endocrine-disrupting properties of BPA suggest it may impact developmental plasticity during early life, predisposing individuals to disease at doses below the oral reference dose (RfD) established by the Environmental Protection Agency in 1982. Herein, we review the current in vivo literature evaluating the carcinogenic properties of BPA. We conclude that there is substantial evidence from rodent studies indicating that early-life BPA exposures below the RfD lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of "carcinogen" put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumor promoting properties.
    Reproductive Toxicology 10/2015; DOI:10.1016/j.reprotox.2015.09.006 · 3.23 Impact Factor
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    • "Environmental estrogens derived from natural plant compounds (phytoestrogens ), synthetic and industrial by-products (industrial estrogens) have been found to increase the incidence of uterine leiomyomas in animal models (Newbold et al., 2002, 2007). Both in vivo and in vitro models have shown that the enhanced sensitivity of uterine leiomyomas to environmental estrogens can be modulated via ERa (Di et al., 2008; Greathouse et al., 2012). Genistein, a soy-derived phytoestrogen, is commonly consumed in the diet, and there is some concern as to the beneficial and/or adverse physiological effects of this compound. "
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    ABSTRACT: BACKGROUNDUterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the 'Advances in Uterine Leiomyoma Research: 3rd NIH International Congress'. Congress recommendations and a review of the fibroid literature are also reported.METHODSThis review is a report of meeting proceedings, the resulting recommendations and a literature review of the subject.RESULTSThe research data presented highlights the complexity of uterine fibroids and the convergence of ethnicity, race, genetics, epigenetics and environmental factors, including lifestyle and possible socioeconomic parameters on disease manifestation. The data presented suggest it is likely that the majority of women with uterine fibroids will have normal pregnancy outcomes; however, additional research is warranted. As an alternative to surgery, an effective long-term medical treatment for uterine fibroids should reduce heavy uterine bleeding and fibroid/uterine volume without excessive side effects. This goal has not been achieved and current treatments reduce symptoms only temporarily; however, a multi-disciplined approach to understanding the molecular origins and pathogenesis of uterine fibroids, as presented in this report, makes our quest for identifying novel targets for noninvasive, possibly nonsystemic and effective long-term treatment very promising.CONCLUSIONSThe Congress facilitated the exchange of scientific information among members of the uterine leiomyoma research and health-care communities. While advances in research have deepened our knowledge of the pathobiology of fibroids, their etiology still remains incompletely understood. Further needs exist for determination of risk factors and initiation of preventive measures for fibroids, in addition to continued development of new medical and minimally invasive options for treatment.
    Human Reproduction Update 04/2014; 20(3). DOI:10.1093/humupd/dmt058 · 10.17 Impact Factor
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    • "In particular, isoflavones exposure during fetal life alters the estrogen receptor ratios, thus impairing the physiological action of estrogens. Surprisingly, genistein administration during fetal life resulted in an increased risk of uterine cancer and in a promotion of leiomyoma [125]. Perinatal exposure to isoflavones resulted in alterations in the uterus and ovaries of female pups [126, 127]. "
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    ABSTRACT: Phytoestrogens, polyphenolic compounds derived from plants, are more and more common constituents of human and animal diets. In most of the cases, these chemicals are much less potent than endogenous estrogens but exert their biological effects via similar mechanisms of action. The most common source of phytoestrogen exposure to humans as well as ruminants is soybean-derived foods that are rich in the isoflavones genistein and daidzein being metabolized in the digestive tract to even more potent metabolites-para-ethyl-phenol and equol. Phytoestrogens have recently come into considerable interest due to the increasing information on their adverse effects in human and animal reproduction, increasing the number of people substituting animal proteins with plant-derived proteins. Finally, the soybean becomes the main source of protein in animal fodder because of an absolute prohibition of bone meal use for animal feeding in 1995 in Europe. The review describes how exposure of soybean-derived phytoestrogens can have adverse effects on reproductive performance in female adults.
    International Journal of Endocrinology 04/2013; 2013(3):650984. DOI:10.1155/2013/650984 · 1.95 Impact Factor
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