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Uterine fibroids are the most frequent gynecologic tumor, affecting 70–80% of women over their lifetime. Although these tumors are benign, they can cause significant morbidity and may require invasive treatments such as myomectomy and hysterectomy. Many risk factors for these tumors have been identified, including environmental exposures to endocrine disrupting chemicals (EDCs), e.g. genestein, diethylstilbestrol etc. Uterine development may be a particularly sensitive window to environmental exposures, as some perinatal EDC exposures have been shown to increase tumorigenesis in both rodent models and human epidemiological studies. While the mechanisms by which EDC exposures may increase tumorigenesis are still being elucidated, epigenetic reprogramming of the developing uterus is an emerging hypothesis. Given the remarkably high incidence of uterine fibroids, and their significant impact on women’s health, understanding more about how prenatal exposures to EDCs (and other environmental agents) may increase fibroid risk could be key to developing prevention and treatment strategies in the future.
Uterine fibroids (UFs) affect 70–80% of women during their lifetime, and are the leading indication for hysterectomies in premenopausal women, with over 200,000 per year in the US (1–4) at a cost of up to 34 billion dollars each year (5). Medical management and uterine preserving procedures are available to treat this disease, but a lack of comprehensive data comparing treatment options leads most practitioners to resort to the classic treatment of hysterectomy (6). Although UFs are benign tumors, they can cause a variety of symptoms such as pain, bleeding, and bladder dysfunction as well as complications leading to infertility, miscarriage and other reproductive disorders (7–10).
Arising in the myometrial layer of the uterus, UFs are hormonally responsive to estradiol and progesterone as well as other steroid hormones, and regress after menopause (11). The cause of uterine fibroids is largely unknown but there are established risk factors: increased age up to menopause, increased BMI, nulliparity, early age at menarche, family history, and African American ethnicity (11,12). While many of the risk factors for this disease are hormone-related, the mechanism underlying the increase in risk for African American women compared to Caucasians remains to be identified (1,2,13–16).
The incidence of UFs is likely underestimated, as only 20–50% of women with fibroids will develop symptoms (1,17). Data on latency for development of these tumors is limited, although the time of onset is thought to be 10–15 years earlier for African American women (1,12,18). Ultrasound has been used to find clinically undiagnosed UFs (1,18–20), but only one study has found fibroid free women prospectively to ascertain the timing of fibroid onset (21). The Study of Environment, Lifestyle, and Fibroids (SELF) was designed to investigate the timing of UFs onset. The SELF study enrolled 1696 African American women aged 23–34 without UFs in the Detroit area from 2010 to 2012 and plans to follow up every 20 months with ultrasound assessment to determine more precisely the onset of UFs (21).
In addition to hormones, these lesions are influenced by genetic aberrations as well as growth factor signaling pathways. Translocations in the high mobility group genes HMGA1 and HMGA2 have been described, possibly influencing fibroblast growth factor (FGF) pathway activity and resulting in increased tumor size (22,23). The Mediator Complex Subunit 12 (MED12) gene has been reported to be mutated in UFs in multiple cohorts of women, including American, South African, and Finnish studies (24–28). There are also genetic factors that predispose to these tumors as part of heritable cancer syndromes, including mutations in fumarate hydratase (FH) seen in patients with hereditary leiomyomatosis and renal cancer (HLRCC) (29,30). FH is an enzyme in the TCA cycle and acts as a classical tumor suppressor, with mutations in FH significantly increasing risk of fibroids in the uterus and other tissues in patients with HLRCC (31).
As defined by the National Institute of Environmental Health Sciences, endocrine disrupting chemicals (EDCs) are “chemicals that interfere with the body’s endocrine system and produce adverse developmental, reproductive, neurological and immune effects.” The endocrine system is comprised of glands that are distributed throughout the body and synthesize the hormones that are released in the circulatory system to regulate development, physiological processes and homeostatic functions. These glands include, but are not limited to, the hypothalamus, pituitary, thyroid and reproductive organs. EDCs can be natural or man-made, such as pharmaceuticals, plasticizers, dioxins, polychlorinated biphenyls (PCBs), organochlorines, polyfluoroalkyls (PFOAs), phthalates and pesticides. Although the route of exposure is dependent on the individual EDC, common routes of exposure in humans are ingestion, inhalation and dermal absorption. Importantly, EDCs can exhibit non-monotonic dose response curves and low doses of EDCs can produce a pathophysiological effect (32).
Numerous EDCs have been shown to interact with nuclear receptors to exert their actions in target tissues (32). EDC binding to nuclear receptors can alter hormonal functions by mimicking naturally occurring hormones in the body, blocking the endogenous hormone from binding or interfering with the production or regulation of hormones and/or their receptors. An individual EDC may interact with more than one receptor, and multiple EDCs can interact with the same receptor, highlighting the complexity of in the response of animals and humans to environmental EDC exposures. For example, the xenoestrogen bisphenol A (BPA) has been shown to bind and activate estrogen receptor (ER) (33,34), estrogen-related receptor gamma (ERRγ) (35) and pregnane X receptor (PXR) (36). In addition to BPA, a variety of other EDCs (i.e. diethylstilbestrol (DES), PCBs, PFOA, and phthalates) can also bind to ERs (33,37–40).
Liganded nuclear hormone receptors that function as transcription factors interact with DNA, producing what are termed “genomic” effects that regulate gene transcription, but are also capable of action outside the nucleus via what is termed “non-genomic signaling” (41,42). EDCs are also capable of inducing both genomic and non-genomic signaling: both BPA and DES, for example, have been shown to activate nongenomic signaling pathways through the ER (43–48). Regardless of the mode of action, EDCs have been linked to several adverse health outcomes including diabetes, obesity, cardiovascular disease, reproductive tract disorders, and neurodevelopmental disorders (32).
In contrast to mutations that are inherited from a parent and present throughout a person’s life in virtually every cell in the body, somatic mutations associated with clonal tumors such as fibroids occur in a single progenitor cell in tissues, from which the tumor arises. Most of uterine fibroid cases are sporadic in nature, however few rare familial syndromes are associated with development of UFs. In these syndromes, genetic alterations occur in the FH, COL4A5 and COL4A6 genes (49). In sporadic tumors, several recurrent genetic aberrations have been identified, including deletions in 7q, trisomy of chromosome 12, reciprocal translocation of chromosome 12, and monosomy of chromosome 22, among others (50–52). However, these genetic alterations occur at relatively low frequency.
In contrast, MED12 somatic gene mutations have been found in sporadic UFs with a very high frequency (70–80%) (25). The MED12 gene encodes one of the components of the Mediator complex, which consists of 26 subunits that bridge DNA regulatory sequences to the RNA polymerase II initiation complex. The Mediator complex is highly conserved in eukaryotes, and can participate in transcriptional repression or act as a positive co-regulator (25,53). Pathway analysis in MED12-deficient UFs demonstrated that focal adhesion, extracellular matrix receptor interaction, and Wnt signaling are substantially altered in these tumors (25). Subsequent studies have confirmed the important role of MED12 mutation in UFs (24,25,28,54–56), making MED12 somatic mutations the most widely detected DNA mutation in human fibroid lesions.
A striking feature of UFs is their dependency on the ovarian steroids estrogen and progesterone (50,57). Both clinical and experimental data suggest that estrogen stimulates the growth of UFs during reproductive years. Regression is seen after menopause, and continuous gonadotropin-releasing hormone (GnRH) agonist treatment inhibits UF growth by decreasing ovarian hormone production. Estrogens, such as 17β-estradiol, exert their biological effects on target cells, including myometrial cells, through the activation of ERs.
The cellular effects of estrogen are the result of a combination of non-genomic and genomic actions via membrane and nuclear-ER-mediated signaling pathways (42). There are two classes of ERs, ERα and ERβ, and both are capable of rapid membrane signaling (i.e. non-genomic signaling) (58–61). These non-genomic effects are independent of gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. These signaling cascades include extracellular signal-related kinase/mitogen-activated protein kinases (ERK/MAPK), p38/MAPK, the phosphatidylinositol 3-kinase/Akt (PI3K/Akt), phospholipase C/Protein Kinase C (PLC/PKC), and cAMP/Protein Kinase A (cAMP/PKA) (62–66). In addition, steroid hormone receptor modulation of other cell membrane-associated molecules, such as ion channels and G-protein-coupled receptors (e.g., GPR30) has also been reported (67,68).
The more classical pathway for ligand-activation of ER occurs in the nucleus, and both ER subtypes have a DNA-binding domain and can function as transcription factors to regulate gene expression by binding to specific estrogen response elements (i.e. genomic mechanism) (69) (Table 1). In the absence of hormone, ERs are largely located in the cytosol. When estrogen binds to the receptor, a cascade of events is triggered, starting with the migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to estrogen response elements. The DNA/receptor complex then recruits other proteins that are responsible for transcriptional activation of repression, which eventually alters target gene expression.
Progesterone is an endogenous steroid hormone involved in the menstrual cycle and pregnancy; therefore, it is essential in female reproduction. Similar to estrogen, progesterone exerts its effects through progesterone receptor (PR), a member of the steroid hormone nuclear receptor superfamily. There are two PR isoforms, PR-A and PR-B, which are identical except for an additional 165 amino acids present only in the PR-B isoform (70). Similar to ERs, PRs signal through both genomic and non-genomic pathways (71–76). The ability of PR isoforms to target distinct promoters and modulate the expression of diverse downstream genes is influenced in a cell- and context-specific manner, including the functional interaction of PRs with other transcriptional factors, post-translational modifications, etc. (72).
In UFs, progesterone regulates many targets, which may play an important role in UF pathogenesis (Table 1) (77–79). A direct functional link between progesterone and UF development was shown in a mouse xenograft model, where fibroid tumor growth was associated with administration of estrogen plus progesterone, but not with estrogen administration alone. Moreover, fibroid tumor size was significantly decreased in response to progesterone withdrawal using the PR antagonist mifepristone (RU486) (80,81). As a result of these and other studies, several selective progesterone receptor modulators (SPRMs) have been shown in clinical trials to inhibit UF growth (49,50,82–87).
UFs are monoclonal tumors that arise from the uterine smooth muscle tissue (50,88). Somatic mutations in genes such as MED12 support clonality and indicate that each fibroid lesion originates from the transformation of a single cell (89–97). Furthermore, tumor-initiating stem cells (TICs) derived from UFs carry MED12 mutations seen in UFs (50). Interestingly, distinct MED12 mutations have been detected in different UF lesions in the same uterus (25), consistent with the emergence of each MED12 mutation as an independent, somatic clonal event. Recently, in an animal model of MED12 deficiency, mutations in this gene were shown to act as a driver promoting development of UFs and genomic instability (98).
Tissue-specific stem cells have been identified in a variety of tissues and organs (99). The presence of a myometrial stem cell (MSC) population in the uterus was first shown in 2007 in mouse myometrium and non-pregnant human myometrium, using 5-bromo-2′-deoxyuridine and sorting of a side population, respectively (89,100). In contrast to the main population of myometrial cells, the side population of MSCs is capable of generating functional human myometrial tissues efficiently when transplanted into the uteri of severely immunodeficient mice (89). In addition, MSCs from the differentiated myometrial cell population, exhibit high levels of OCT4 expression (an embryonic stem cell marker) and very low expression of ER, PR and smooth muscle cell-specific markers including smoothelin and calponin (89). Moreover, MSCs prefer a hypoxic environment for survival and growth, which is consistent with known uterine physiology: during pregnancy mechanical stretching of the uterine wall induces hypoxia in the myometrium that could promote MSC proliferation (101), which is required to support the growing fetus and enlarging uterus. However, the connection of this observation to future development of UFs is not clear at the moment.
Recently, MSCs expressing Stro1 and CD44 markers were identified (102). Using Stro-1/CD44 surface markers, the stem cells from adjacent myometrium and human fibroid tissues were isolated (102). The undifferentiated status of isolated cells was confirmed by expression of the ABCG2 transporter, as well as expression of additional stem cell markers OCT4, NANOG, and GDB3, and the low expression of steroid receptors ERα and PR-A/PR-B. Mesodermal cell origin was established by the presence of typical mesenchymal markers (CD90, CD105, and CD73) and absence of hematopoietic stem cell markers (CD34, CD45), and confirmed by the ability of these cells to differentiate in vitro into adipocytes, osteocytes, and chondrocytes. The functional capability of these cells to form myometrium-like lesions was established in a xenotransplantation mouse model. The injected cells labeled with superparamagnetic iron oxide were tracked by both magnetic resonance imaging and fluorescence imaging, thus demonstrating the regenerative potential of Stro-1/CD44 stem cells in vivo (102).
Several studies have been performed to identify tumor-initiating cells (TICs) in UFs (89,90,94,95). One principal difference between MSCs and TICs at the DNA level is that MED12 mutations are found only in UF TICs, but not normal myometrium or MSCs (90). TICs derived from UFs have stem cell characteristics, and are proliferative, give rise to tumors in vivo (90,95) and comprise~1% of UF cells, (99). Similar to MSCs, TICs express low levels of ER and PR, although they are paradoxically dependent on estrogen/progesterone for growth (90,102). This suggests important paracrine interactions may occur between TICs and surrounding myometrial cells that mediate estrogen/progesterone induced UF growth (91). In a cell co-culture system, with both UF TICs and mature myometrial cells, treatment with estrogen/progesterone results in secretion of WNT ligands, which selectively induce nuclear translocation of β-catenin in UF TICs, eventually leading to the growth and proliferation of TICs (91). These observations suggest a role for WNT/β-catenin signaling in response to estrogen/progesterone, similar to the aberrant WNT/β-catenin/GSK-3 axis reported to be involved in the formation and maintenance of other TICs (103).
The effect of developmental exposure to DES on UF development later in life has been investigated (104–108). Two large prospective studies found a positive association between developmental DES exposure and UF risk (104,107). In the Nurses Health Study II 11,831 cases of UFs were diagnosed in 1.3 million person-years of follow-up (over 20 years), making this the largest prospective study investigating the influence of prenatal DES exposure on UFs. In this study prenatal exposure to DES increased risk for UFs by 13% in women over 35 years of age (107). Additionally, exposure during the first trimester of gestation was the most hazardous with an increased risk of 21% compared to unexposed women. The second study to find a positive association between DES exposure and UFs is the NIEHS Uterine Fibroid Study, in which 1364 DES exposed or unexposed women aged 35–49 in the Washington DC area were screened for UFs (104). In this study large fibroids were more common in those exposed to prenatal DES. The odds ratio for Caucasian women exposed to DES was 2.4, which was even higher for large fibroids. Unfortunately, there were not enough exposed AA women to make meaningful comparisons (104). Another study used a subset of the NIEHS Sister Study cohort to evaluate the risk for UFs after prenatal exposures in 3,534 AA women aged 35–59. In this study the strongest factors associated with increased risk of UFs were DES exposure, maternal or gestational diabetes, and monozygotic twins with RR of 2.02, 1.54, and 1.94 respectively (106).
However, not all data were concordant. When a larger portion of NIEHS Sister Study data was evaluated the association between DES and UFs was less clear. This study included 19,972 Caucasian women in a prospective analysis and found five early life factors to be associated with greater than 20% increased risk for UFs: prenatal DES exposure, gestational diabetes, pregnancy diabetes (mothers who were diabetic prior to pregnancy), soy formula, and gestational age at birth. The strongest associations were in women whose mothers had pregnancy diabetes and in those who were born more than a month early. DES exposure resulted in an adjusted relative risk (RR) of 1.42, and gestational diabetes and soy formula had similar RR of 1.28 and 1.25 respectively. Although there is a discrepancy in this study: when separating out women who reported to have ‘definitely’ or ‘probably’ been exposed to DES, women who were definitely exposed showed no increased risk, while those who identified as being probably exposed had a RR of 2.07. This study also reported that experiencing menarche under the age of 10 or 11 resulted in RR of 1.54 and 1.32, respectively, and being poor had a RR of 1.24 (105). Another study of 85 UF cases also failed to find an association between prenatal DES and UF risk (108). In contrast to the human epidemiological data, experimental studies have shown an unequivocal link between DES exposure and UFs.
Several genetically engineered mouse and rat models have been developed for UFs, although to date, only one, the Eker rat, has been used in experimental studies to explore the linkage between environmental exposures and UFs. The Eker rat develops spontaneous UFs at a 65% incidence, due to a germline retroviral insertion in the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene (109,110). The resulting tumors have a similar presentation as seen in women, occurring with high frequency often in multiples, and are histologically welldifferentiated and benign (111). The UFs that develop in Eker rats are hormone responsive, express ERα and PR, and as seen in women, parity is protective (112,113). Furthermore, several UF-derived cell lines were established from these tumors, the most widely used being the ELT-3 cell line (114,115). Selective estrogen receptor modulators (SERMs), specifically tamoxifen and raloxifene, have also been shown to inhibit growth of UF cells isolated from Eker rats (116) as well as incidence and size of UFs that develop in these animals (117). There is evidence that SERMs may be efficacious in women as well, as studies in both premenopausal (118) and postmenopausal (119) women demonstrate UF regression after raloxifene treatment. Aberrant expression of HMGA occurs in UFs in women and in the Eker rats (120), and both are stimulated to grow by insulin-like growth factor-I (IGF-I) (121). In women, TSC2 is expressed in normal uterus and fibroids, and although not well studied, defects in this tumor suppressor have been reported in UFs (122).
Interestingly, while heterozygous mice carrying a defective Tsc2 allele do not develop UFs, uterine-specific Tsc2 deletion driven by a PR-cre recombinase (Tsc2fl;PRcre) leads to development of aggressive myometrial tumors (123). 100% of Tsc2fl;PRcre mice develop myometrial thickening by 12 weeks of age and mesenchymal tumors, which express ER and PR, by 24 weeks of age. That tumors were driven by loss of Tsc2, which functions to suppress the mechanistic target of rapamycin (mTORC1/S6) pathway, was shown by blocking mTOR activity with rapamycin, which prevented the dramatic enlargement of the uterus. Ovariectomy also prevented uterine enlargement, which was rescued by administration of estrogen or estrogen + progesterone. The estrogen-dependence of these tumors was confirmed by treatment with the aromatase inhibitor letrozole, which abolished uterine overgrowth and S6 activation (123). Another group has designed a uterine-specific Tsc2 deleted mouse model by crossing Tsc2fl mice with anti-Mullerian hormone receptor type 2 (Amhr2)-cre mice (124). These mice also developed myometrial enlargement but the hyperplasia observed did not progress to tumors. This hyperplasia was also driven by mTORC1/S6 activation as rapamycin treatment attenuated the uterine enlargement (124).
As mentioned previously, mutations in MED12 are found in 70–80% of UFs in women. A conditional Med12 mutation mouse model expressing a Med12 missense variant (c. 131G>A), the principle mutation found in human UFs, has recently been developed (98). These animals were developed by crossing Med12 variant knock-in mice with Amhr2-cre mice. By 12 weeks of age 80% of females had developed UFs (98). Inconsistent with epidemiological and Eker rat model data, these animals developed more UFs when repeatedly bred.
Developmental exposure to DES has been shown to influence susceptibility to UFs later in life in animal models (125–128). As previously mentioned, in the Eker rat model, the Tsc2EK mutation increases susceptibility to develop spontaneous UFs with age. When exposed to DES neonatally, tumor incidence significantly increases as does multiplicity and tumor size (129). Eker rats without the Tsc2 mutation did not develop any tumors even if they were exposed to DES neonatally. These data imply that reprogramming due to DES exposure acts by increasing the penetrance of a Tsc2 mutation (129).
Experimental studies in Eker rats have identified a window of susceptibility to environmental exposures that coincides with key periods of myometrial development. Postnatal day (PND) 3–12, when the inner circular myometrium is differentiating and the uterine glands are developing, has been shown to be a critical window of susceptibility for promotion of uterine fibroids by DES (130). During this time the developing uterus is normally protected from estrogens, which are bound by circulating steroid hormone binding proteins, such as alpha-feto protein. This allows differentiation to proceed largely independent of steroid hormone exposure until much later in development, when alpha-feto protein production ceases and is cleared by the liver, which occurs around postnatal day 17 in rats (131). Since DES, and other xenoestrogens do not bind alpha-feto protein, even low dose exposures to these estrogenic chemicals can be very potent, and lead to adverse effects (132). Using the Eker rat model, the Walker group showed that exposure to DES during PND 3–5 or 10–12 increased tumor incidence from 63% in unexposed animals to 95% and 100% respectively, whereas a later exposure did not (130). Of interest, estrogen responsive genes were reprogrammed by DES exposure during this critical time period. In the myometrium of 5–6 month old rats (10 months before tumor development), Calbindin D9K and PR expression fluctuated as expected with estrus cycles in the unexposed animals but remained high during all stages of the estrus cycle in the animals that had been exposed neonatally to DES (130). Other reprogrammed genes were subsequently identified in the adult myometrium of neonata DES-exposed rats including Dio2, Gdf10, Car8, Gria2, and Mmp3, all of which exhibited an exaggerated response to estrogen as a consequence of this reprogramming (133). Exposure to the phytoestrogen genistein during PND 10–12 also reprogrammed expression of several of these genes, and like DES, increased tumor incidence and multiplicity (134).. These data suggest that developmental DES exposure may have an influence on UF risk later in life, although additional studies are needed to determine the impact of other EDCs on UF risk.
One mechanism by which early life EDC exposures may exert their effects is by reprogramming the developing epigenome (135–137). DES, genistein, and the plasticizer BPA have been shown to exhibit tissue-specific patterns of developmental reprogramming and/or promotion of UFs. All three EDCs act as ER ligands, and induce ER-mediated gene transcription. However, only DES and genistein induce non-genomic ER signaling to activate PI3K/AKT in the developing uterus. Activation of PI3K/AKT signaling has been shown to induce phosphorylation of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), which represses EZH2 activity and reduces levels of the histone 3 lysine 27 trimethyl (H3K27me3) repressive mark on chromatin. Furthermore, DES and genistein, but not BPA, caused estrogen-responsive genes in the adult myometrium to become reprogrammed, and hyper-responsive to hormone (133). Importantly, this pattern of EZH2 engagement to decrease H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by DES and genistein promoted development of UFs, increasing tumor incidence and multiplicity, whereas BPA did not (134). These data show that environmental estrogens have distinct 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 on chromatin during developmental reprogramming, and promote uterine tumorigenesis (134).
Altered DNA methylation patterns have also been observed in UFs from both rodents and humans. In two human studies global DNA methylation was assessed in paired UF and myometrial samples (138,139). One study found reduced DNA methylation in UFs while the other found that 62% of differentially methylated sites were hypermethylated. Interestingly, although the first study found the genome to be hypomethylated there was increased mRNA expression of both DNMT1 and DNMT3a (139). In both studies when interrogating individual differentially methylated regions an inverse relationship was found between DNA methylation and gene expression. Three tumor suppressors, KLF11, DLEC1, and KRT19 were hypermethylated at the promoter and displayed reduced gene expression in UFs (138). These studies indicate that DNA methylation is abnormally regulated in human UF and may play a role in UF etiology and development. An early study in rodents investigated neonatal exposures and reprogramming of DNA methylation in animals treated with DES during PND 1–5, with DNA methylation surveyed at PND 17 (pre-pubertal), and PND 21 and PND 30 (post-puberty) (140). Lactoferrin is an estrogen responsive gene that is known to be reprogrammed as a result of neonatal DES exposure. At PND 21 and 30, 2 out of 5 CpG sites in the promoter just upstream of the estrogen response element were demethylated in animals exposed to DES during PND 1–5 compared to unexposed controls. This post-pubertal DES induced demethylation was dependent on ovarian hormones: DES-exposed mice that were ovariectomized did not exhibit this demethylation (140).
This emerging field of epigenome reprogramming by EDCs and its influence on UF development is in its infancy, but clearly warrants additional investigation. While animal studies have identified EDC-induced epigenetic alterations in both histone and DNA methylation in UFs, similar studies in human UFs and translation of these findings to the human disease has been lacking. Furthermore, because most environmental exposures occur at very low EDC levels, and exposures to some EDCs are nearly ubiquitous, establishing causal linkages between environmental EDC exposures and the human disease presents a significant challenge for epidemiologists. Additional mechanistic studies to identify epigenetic biomarkers of exposure to specific EDCs holds promise in this regard, but such biomarkers are not currently available. Since the field has not focused on identifying EDC-specific epigenetic changes that could be used in such translational studies, this would be an important direction to consider in the future.
UFs are an important disease of reproductive age women, and as hormone-dependent tumors, are potentially promoted by exposure to hormone-active environmental agents such as EDCs. When EDC exposures occur during crucial times of uterine development, alterations in cell signaling pathways, including estrogen signaling, and the epigenome may increase susceptibility to develop UFs in adulthood. Despite the high prevalence and major impact of UFs on women’s health, the precise mechanism underlying EDC-dependent effects on MSCs that are the progenitors for these tumors are not adequately understood: virtually nothing is known about how EDCs impact the number or pathophysiology of these cells to promote tumorigenesis. Delineating the effects of EDC exposure and underlying mechanisms by which they, or other environmental exposures, promote MSC progression to UFs, including the role of epigenetic alterations and acquisition of mutations in genes such as MED12, will be key to the development of new interventions to prevent and treat this important disease of women.
This work was supported in part by an Augusta University Startup package, the Augusta University Intramural Grants Program (QY), the National Institutes of Health grant HD04622811 (to AA) and the National Institute of Environmental Health Sciences (RC2ES018789, P30ES023512 and ES023206), the Cancer Prevention Research Institute of Texas (RP120855) and the Welch Foundation (BE-0023, Houston, TX) to CLW.
Conflict of interest: None of the authors have a financial relationship with a commercial entity with an expressed interest in the subject-matter of this manuscript.
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Tiffany A. Katz, Texas A&M University Health Science Center, Institute of Biotechnology, Center for Translational Cancer Research, Houston TX.
Qiwei Yang, Augusta University, Medical College of Georgia, Department of Obsetetrics and Gynecology, Augusta GA.
Lindsey S. Treviño, Texas A&M University Health Science Center, Institute of Biotechnology, Center for Translational Cancer Research, Houston TX.
Cheryl L. Walker, Texas A&M University, Health Science Center, Institute of Biotechnology, Center for Translational Cancer, Research, Houston TX.
Ayman Al-Hendy, Augusta University, Medical College of Georgia, Department of Obsetetrics and Gynecology, Augusta GA.