Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis
ABSTRACT 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.
- SourceAvailable from: Xiaohua Gao
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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. "
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 · 8.66 Impact Factor
- 12/2012; DOI:10.4172/2168-9849.1000e101
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ABSTRACT: Transient exposure to methoxychlor (MXC), an environmental endocrine disrupting chemical, during fetal and neonatal stages causes ovarian dysfunction in pubertal, adult, and aging animals. Adult animals have reduced number of ovulations and abnormal follicular composition associated with altered gene expression and DNA methylation patterns. To test the hypothesis that the ovarian epigenomic changes induced by MXC are detectable following the exposure period, leading to altered gene expression by adulthood, we conducted a targeted genome-wide methylation study using Nimblegen 3x720K CpG Island Plus RefSeq Promoter Arrays. Control (vehicle), low dose MXC (20 μg/kg/day), or high dose MXC (100 mg/kg/day) treatments were administered between embryonic day (E) 19 and postnatal day (PND) 7. Ovaries were collected at PND 7 immediately after exposure or at adulthood, PND 60. Array hybridizations were conducted with genomic DNA after methylated DNA immunoprecipitation and array data analyzed. DNA methylation events were functionally annotated and candidate loci common to all treatments or unique to some treatments were identified. Specific signaling molecules such as the regulatory subunit p85 of phospho inositide-3-kinase, insulin like growth factor-1 receptor, Harvey rat sarcoma viral oncogene, insulin receptor, forkhead box protein O3 were identified to be hypermethylated in MXC-treated ovaries at PND 7 and/or PND 60. Examination of gene expression changes with Taqman low-density arrays revealed that nearly 25% of the genes that were assayed had down-regulation. These data demonstrate that key molecules in specific signaling pathways such as PTEN signaling, IGF-1 signaling or rapid estrogen signaling, are epigenetically altered in MXC-exposed ovaries, which is associated with ovarian dysfunction and female infertility.Biology of Reproduction 01/2013; DOI:10.1095/biolreprod.112.104802 · 3.45 Impact Factor