Environmental Exposure to Persistent Organic Pollutants and Its Association with Endometriosis Risk: Implications in the Epithelial-Mesenchymal Transition Process.

We aimed to explore the relationship of adipose tissue concentrations of some persistent organic pollutants (POPs) with the risk of endometriosis and the endometriotic tissue expression profile of genes related to the endometriosis-related epithelial-mesenchymal transition (EMT) process. This case-control study enrolled 109 women (34 cases and 75 controls) between January 2018 and March 2020. Adipose tissue samples and endometriotic tissues were intraoperatively collected to determine concentrations of nine POPs and the gene expression profiles of 36 EMT-related genes, respectively. Associations of POPs with endometriosis risk were explored with multivariate logistic regression, while the relationship between exposure and gene expression profiles was assessed through Spearman correlation or Mann-Whitney U tests. After adjustment, increased endometriosis risk was associated with p,p'-DDT, PCB-180, and ΣPCBs. POP exposure was also associated with reduced gene expression levels of the CLDN7 epithelial marker and increased levels of the ITGB2 mesenchymal marker and a variety of EMT promoters (HMGA1, HOXA10, FOXM1, DKK1, CCR1, TNFRSF1B, RRM2, ANG, ANGPT1, and ESR1). Our findings indicate that exposure to POPs may increase the risk of endometriosis and might have a role in the endometriosis-related EMT development, contributing to the disease onset and progression. Further studies are warranted to corroborate these findings.

Expression Profiles of Genes Related to Development and Progression of Endometriosis and Their Association with Paraben and Benzophenone Exposure.

Increasing evidence has been published over recent years on the implication of endocrine-disrupting chemicals (EDCs), including parabens and benzophenones in the pathogenesis and pathophysiology of endometriosis. However, to the best of our knowledge, no study has been published on the ways in which exposure to EDCs might affect cell-signaling pathways related to endometriosis. We aimed to describe the endometriotic tissue expression profile of a panel of 23 genes related to crucial cell-signaling pathways for the development and progression of endometriosis (cell adhesion, invasion/migration, inflammation, angiogenesis, and cell proliferation/hormone stimulation) and explore its relationship with the exposure of patients to parabens (PBs) and benzophenones (BPs). This cross-sectional study included a subsample of 33 women with endometriosis from the EndEA study, measuring their endometriotic tissue expressions of 23 genes, while urinary concentrations of methyl-, ethyl-, propyl-, butyl-paraben, benzophenone-1, benzophenone-3, and 4-hydroxybenzophenone were determined in 22 women. Spearman's correlations test and linear and logistic regression analyses were performed. The expression of 52.2% of studied genes was observed in >75% of endometriotic tissue samples and the expression of 17.4% (n = 4) of them in 50-75%. Exposure to certain PB and BP congeners was positively associated with the expression of key genes for the development and proliferation of endometriosis. Genes related to the development and progression of endometriosis were expressed in most endometriotic tissue samples studied, suggesting that exposure of women to PBs and BPs may be associated with the altered expression profile of genes related to cellular pathways involved in the development of endometriosis.

Erythema nodosum caused by goserelin acetate sustained-release: Case report and literature review.

Goserelin acetate is a gonadotropin-releasing hormone analog that is commonly used in patients with prostate cancer, endometriosis, and precocious puberty. The side effects of the drug include allergic rash, flushing, excessive sweating, skin swelling at the injection site, sexual dysfunction, erectile dysfunction, and menopausal symptoms. However, erythema nodosum has so far not been reported. In this paper, we have presented the case of erythema nodosum caused by goserelin acetate and a review of the literature on its adverse effects, thus providing useful insights into clinical management and medication safety.

Polychlorinated biphenyls and the risk of endometriosis: Systematic review and meta-analysis.

OBJECTIVE: We aimed to collect recent findings for a deeper understanding of the association between human exposure to polychlorinated biphenyls (PCBs) and endometriosis development. METHODS: Web of Science, PubMed, Scopus, Google Scholar, and Embase were searched based on inclusion criteria from 2000 to the end of 2020. No filter was exerted to limit the language of publications and geographical restriction. Odds ratios (OR) using the random-effects model and the corresponding 95% confidence interval (CI) were calculated for each included study. RESULTS: Fourteen studies were included in our analyses. The pooled OR and 95% CI for PCB was 1.96 (1.31 to 2.93). Despite being statistically significant, there was evidence of moderate heterogeneity (I2 = 63%, P = 0.001, τ2 = 0.32). Findings from our subgroup analyses showed a significant association between PCB exposure and endometriosis among European population (OR = 3.66, 95% CI: 2.08-6.44). Also a positive association was detected between PCB exposure and an increased odds of endometriosis in studies with laparoscopy (OR = 2.32, 95% CI: 1.16-4.63) or surgery confirm of controls (OR = 1.39, 95% CI: 1.02-1.89). Moreover, according to matched-pairs design, a significant association between PCB exposure and endometriosis development was detected (OR = 1.51, 95% CI: 1.04-2.18), also heterogeneity decreased in studies with matched-pairs design (I2 = 30.4%). CONCLUSIONS: Findings of this study confirm an association between endometriosis and exposure to PCB. However, more primary studies using proper methodology are needed to confirm this association.

Endocrine disruptors and endometriosis.

Endometriosis is a hormone-dependent inflammatory gynecological disease of reproductive-age women. It is clinically and pathologically characterized by the presence of functional endometrium as heterogeneous lesions outside the uterine cavity. The two major symptoms are chronic pelvic pain and infertility, which profoundly affect women's reproductive health and quality of life. This significant individual and public health concerns underscore the importance of understanding the pathogenesis of endometriosis. The environmental endocrine-disrupting chemicals (EDCs) are exogenous agents that interfere with the synthesis, secretion, transport, signaling, or metabolism of hormones responsible for homeostasis, reproduction, and developmental processes. Endometriosis has been potentially linked to exposure to EDCs. In this review, based on the robust literature search, we have selected four endocrine disruptors (i) polychlorinated biphenyls (PCB)s (ii) dioxins (TCDD) (iii) bisphenol A (BPA) and its analogs and (iv) phthalates to elucidate their critical role in the etiopathogenesis of endometriosis. The epidemiological and experimental data discussed in this review indicate that these four EDCs activate multiple intracellular signaling pathways associated with proinflammation, estrogen, progesterone, prostaglandins, cell survival, apoptosis, migration, invasion, and growth of endometriosis. The available information strongly indicates that environmental exposure to EDCs such as PCBs, dioxins, BPA, and phthalates individually or collectively contribute to the pathophysiology of endometriosis. Further understanding of the molecular mechanisms of how these EDCs establish endometriosis and therapeutic strategies to mitigate the effects of these EDCs in the pathogenesis of endometriosis are timely needed. Moreover, understanding the interactive roles of these EDCs in the pathogenesis of endometriosis will help regulate the exposure to these EDCs in reproductive age women.

Therapeutic effects of green tea on endometriosis.

Endometriosis is a chronic disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity. It affects 8%-10% of women in their reproductive years, and represents a major clinical problem with deleterious social, sexual and reproductive consequences. Current treatment options include pain relief, hormonal intervention and surgical removal. However, these treatments are deemed unsatisfactory owing to varying success, significant side effects and high recurrence rates. Green tea and its major bioactive component, (-)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly anti-angiogenic, anti-proliferation, anti-metastasis, and apoptosis induction. In recent years, preclinical studies have proposed the use of green tea to inhibit the growth of endometriosis. Herein, the aim of this review is to summarize the potential therapeutic effects of green tea on molecular and cellular mechanism through inflammation, oxidative stress, invasion and adhesion, apoptosis and angiogenesis in endometriosis.

Endometrial Cells Acutely Exposed to Phthalates In Vitro Do Not Phenocopy Endometriosis.

Environmental factors that have been linked to an increased endometriosis risk include exposure to di-(2-ethylhexyl)-phthalate (DEHP), an endocrine disruptor. This study aims to investigate whether DEHP in vitro exposure in primary endometrial stromal cells (EnSC), primary endometrial epithelial cells (EnEC), and the human endometrial adenocarcinoma cell line Ishikawa properly mimics alterations described in the eutopic endometrium of women with endometriosis. Primary EnSC and EnEC, isolated from six fertile egg donors, and Ishikawa cells were exposed to DEHP (0.1, 1, and 10 µM) and were assessed for viability, endometriosis markers (IL-6, VEGF-A, HOXA10, EZH2, and LSD1), steroid receptor gene expressions (ER-1, ER-2, PR-T, PR-B, and PGRMC1), and invasive capacity. Viability after 72 h of DEHP exposure was not significantly affected. None of the endometriosis markers studied were altered after acute DEHP exposure, nor was the expression of steroid receptors. The invasive capacity of EnSC was significantly increased after 10 µM of DEHP exposure. In conclusion, acute DEHP exposure in primary endometrial cells does not fully phenocopy the changes in the viability, expression of markers, or steroidal receptors described in endometriosis. However, the significant increase in EnSC invasiveness observed after DEHP exposure could be a link between DEHP exposure and increased endometriosis likelihood.

Effects of risk factors for ovarian cancer in women with and without endometriosis.

OBJECTIVE: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. DESIGN: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. SETTING: Population-based. PATIENT(S): We included 8,500 women with ovarian cancer, 13,592 control women. INTERVENTION(S): Ten well-established ovarian cancer risk factors. MAIN OUTCOME MEASURE(S): Risk of ovarian cancer for women with and without endometriosis. RESULT(S): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). CONCLUSION(S): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

Association of environmental phenols with endometriosis and uterine leiomyoma: An analysis of NHANES, 2003-2006.

Exposure to phenols is widespread since they are found in many everyday products. Given that phenols are considered endocrine disrupting chemicals with the potential to interfere with hormonal activities, they could have adverse effects on female reproductive health. We analyzed cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), 2003-2006 to examine the association between phenols and endometriosis and uterine leiomyoma (fibroids). Levels of bisphenol A (BPA), benzophenone-3, and triclosan were measured using urine samples, and information on endometriosis and fibroids diagnoses as well as other relevant characteristics were ascertained using self-reported questionnaires. Multivariate logistic regression with odds ratios (ORs) and 95 % confidence intervals (CIs) were used to quantify the association between each phenol and female gynecologic condition. Our study included 700 women, of which 53 women had endometriosis and 107 women had fibroids. We found exposure to BPA to be statistically significantly positively associated with endometriosis (p = 0.05); women in the highest exposure quartile had over the three times the odds of having endometriosis relative to women in the lowest quartile (OR=3.58, 95 % CI 1.00-12.89). None of the phenols considered were significantly associated with fibroids. Overall, exposure to BPA increased the odds of having endometriosis, and there appeared to be a dose-response relationship. This suggests that BPA may play a role in the pathogenesis of endometriosis although the cross-sectional nature of NHANES data is a methodological limitation. Additional research on the impact of endocrine disrupting chemicals, like phenols, on female reproductive health should be conducted.

Evaluation of the potential role of diethylstilbestrol on the induction of endometriosis in a rat model - An alternative approach.

Endometriosis is known to be a gynaecological condition characterised by persistent inflammation and abnormal development of endometrial stroma and glands. Researchers require a rodent model to analyse the disease environment. Animal models are the best option for investigating the etiology and effective treatment of debilitating illnesses in women since rodents, like humans, menstruate. In order to develop the model system, diethylstilbestrol (DES) was examined for its ability to induce endometriosis in rats by investigating its effect on the estrus cycle, hormones, and key markers. The results demonstrated that animals given DES had an erratic estrus cycle and aberrant hormone levels. Histomorphology revealed the development of an endometriosis environment with degenerative epithelium and enlarged glandular cells after DES induction. The higher levels of estrogen, progesterone, and MCP-1 were shown in the endometriosis induced animals. Endometriosis-induced groups had decreased levels of HOXA10 and HOXA11 and increased levels of VEGF and COX-2. Finally, the DES demonstrated endometriosis induction efficacy, implying that it might be a viable replacement for endometriosis induction.

Combined Exposure to Multiple Endocrine Disruptors and Uterine Leiomyomata and Endometriosis in US Women.

Background: Uterine leiomyomata (UL) and endometriosis (EM) are common gynecological diseases damaging the reproductive health of fertile women. Among all the potential factors, environmental endocrine-disrupting chemicals are insufficiently addressed considering the multiple pollutants and mixture exposure. Methods: Women aged 20 to 54 years old in the National Health and Nutrition Examination Survey (NHANES) 2001-2006, having a complete measurement of ten commonly exposed endocrine-disrupting chemicals (including urinary phthalate metabolites, equol, and whole blood heavy metals) and answered questions about UL and EM were included (N=1204). Multivariable logistic regression model, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models were implemented to analyze the combined effect of chemicals on the overall association with UL and EM. Results: In single chemical analysis, equol (OR: 1.90, 95% CI: 1.11, 3.27) and mercury (Hg) (OR: 1.91, 95% CI: 1.14, 3.25) were found positively associated with UL in tertile 3 vs. tertile 1. In WQS regression and BKMR models, the significant positive association between WQS index and UL (OR: 2.54, 95% CI: 1.52, 4.29) was identified and the positive relationship between equol and Hg exposure and UL were further verified. Besides, the mixture evaluation models (WQS and BKMR) also found MEHP negatively associated with UL. Although none of the single chemicals in tertile 3 were significantly associated with EM, the WQS index had a marginally positive association with EM (OR: 2.01, 95% CI: 0.98, 4.15), and a significant positive association was identified in subanalysis with participants restricted to premenopausal women (OR: 2.18, 95% CI: 1.03, 4.70). MIBP and MBzP weighted high in model of EM and MEHP weighted the lowest. Conclusion: Comparing results from these three statistical models, the associations between equol, Hg, and MEHP exposure with UL as well as the associations of MIBP, MBzP, and MEHP exposure with EM warrant further research.

Does Exposure of Lead and Cadmium Affect the Endometriosis?

This study aimed to investigate the effects of blood lead levels (BLLs) and lead and cadmium exposure on endometriosis (EM). The study cohort consisted of female workers who underwent a lead-associated special medical examination between 1 January 2000 and 31 December 2004 (n = 26,542). The standard admission rate (SAR) and admission odds ratio (OR) for EM were calculated using the general population and noise-exposed groups, respectively, for the same period as the reference standards. The SAR for EM was 1.24 (95% confidence interval (CI): 1.03-1.48) in lead-exposed workers and 1.44 (95% CI: 1.11-1.85) in workers with BLLs < 5 µg/dL when compared with that of the general population. Admission ORs of EM in lead-exposed workers and those with BLLs < 5 µg/dL were statistically higher than those of noise-exposed workers (OR, 1.40; 95% CI, 1.15-1.70 and OR, 1.48; 95% CI, 1.11-1.98, respectively). The relative excess risk due to interaction of lead and cadmium was 0.33. Lead exposure was associated with EM admission. EM admission in lead-exposed workers with BLLs < 5 µg/dL was statistically higher than that of the general population and noise-exposed workers. Co-exposure to lead and cadmium has a synergistic effect with EM.

Perfluoroalkyl substances (PFAS) in drinking water and risk for polycystic ovarian syndrome, uterine leiomyoma, and endometriosis: A Swedish cohort study.

BACKGROUND: Perfluorinated substances (PFAS) are chemicals with endocrine disruptive properties that may interfere with the female reproductive system. However, few studies have explored the association between benign gynecological diseases and high PFAS exposure. OBJECTIVES: The aim of this study was to investigate the possible associations between PFAS exposure and subsequent diagnosis of polycystic ovarian syndrome (PCOS), uterine leiomyoma (fibroids), and endometriosis in a cohort exposed to PFAS through drinking water. MATERIAL AND METHODS: In 2013, high levels (with sum of PFAS above 10,000 ng/L), dominated by perfluorooctanesulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS), were found in the drinking water from one of the two waterworks in Ronneby, Sweden. The contamination came from firefighting foams used at a nearby airfield. Females of all ages (n = 29,106) who had ever resided in the municipality between 1985 and 2013 formed a cohort. Individual exposure was assessed based on municipality waterworks distribution data linked to annual residential address data; 27% of the females had ever lived at an address with PFAS-contaminated water. Gynecological health outcomes were retrieved from the Swedish National Patient Register. The Cox proportional hazards model was used to estimate the association between exposure and each diagnosis. RESULTS: There were in all 161 cases of PCOS, 1,122 cases of uterine leiomyoma, and 373 cases of endometriosis. In women aged 20-50 years (n = 18,503), those with the highest estimated PFAS exposure had increased hazard ratios (HR) for PCOS (HR = 2.18; 95% confidence interval (CI) 1.43, 3.34) and uterine leiomyoma (HR = 1.28; 95% CI 0.95, 1.74). No increased HR for endometriosis was found (HR = 0.74; 95% CI 0.42, 1.29). CONCLUSIONS: Exposure to high levels of PFAS in drinking water was associated with increased risk of PCOS and possibly uterine leiomyoma, but not endometriosis. The findings for PCOS are consistent with prior studies reporting positive associations between PCOS and PFAS exposure at background levels.

Associations between Exposure to Organochlorine Chemicals and Endometriosis: A Systematic Review of Experimental Studies and Integration of Epidemiological Evidence.

BACKGROUND: Growing epidemiological evidence suggests that organochlorine chemicals (OCCs), including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play a role in the pathogenesis of endometriosis. OBJECTIVES: We aimed to systematically review the experimental evidence (in vivo and in vitro) on the associations between exposure to OCCs and endometriosis-related end points. METHODS: A systematic review protocol was developed following the National Toxicology Program /Office of Health Assessment and Translation (NTP/OHAT) framework and managed within a web-based interface. In vivo studies designed to evaluate the impact of OCCs on the onset or progression of endometriosis and proliferation of induced endometriotic lesions were eligible. Eligible in vitro studies included single-cell and co-culture models to evaluate the proliferation, migration, and/or invasion of endometrial cells. We applied the search strings to PubMed, Web of Science, and Scopus®. A final search was performed on 24 June 2020. Assessment of risk of bias and the level of evidence and integration of preevaluated epidemiological evidence was conducted using NTP/OHAT framework Results: Out of 812 total studies, 39 met the predetermined eligibility criteria (15 in vivo, 23 in vitro, and 1 both). Most studies (n=27) tested TCDD and other dioxin-like chemicals. In vivo evidence supported TCDD's promotion of endometriosis onset and lesion growth. In vitro evidence supported TCDD's promotion of cell migration and invasion, but there was insufficient evidence for cell proliferation. In vitro evidence further supported the roles of the aryl hydrocarbon receptor and matrix metalloproteinases in mediating steroidogenic disruption and inflammatory responses. Estrogen interactions were found across studies and end points. CONCLUSION: Based on the integration of a high level of animal evidence with a moderate level of epidemiological evidence, we concluded that TCDD was a known hazard for endometriosis in humans and the conclusion is supported by mechanistic in vitro evidence. Nonetheless, there is need for further research to fill in our gaps in understanding of the relationship between OCCs and their mixtures and endometriosis, beyond the prototypical TCDD. https://doi.org/10.1289/EHP8421.

From Environmental to Possible Occupational Exposure to Risk Factors: What Role Do They Play in the Etiology of Endometriosis?

Endometriosis is a gynecological disorder characterized by the presence of endometrial stroma and glands outside the uterine cavity. A systematic review of the literature was conducted to clarify, starting from environmental exposure data, whether possible occupational risk factors may correlate with the onset of the disease. The guidelines for reporting systematic reviews of the "PRISMA" statement were followed and two databases, Scopus and PubMed, were used. Of the 422 studies selected with specific keywords, 32 publications were eligible, 28 of which referred to chemical agents and 4 related to night work. Conflicting data emerged among these studies. Although some compounds seemed to be more involved than others in the onset of endometriosis. Association with exposure to organochlorine compounds is the most supported by the epidemiological data, while other pesticide exposure did not show any clear correlation. Likewise, the hypothesis of a correlation with perfluoroalkyls exposure is not currently supported by data. The involvement of metals as risk factors has not been confirmed, while the role of night work, in the case of long service, seems to play an etiological role. In order to clarify the potential occupational risk of endometriosis development, well-designed studies are needed to evaluate the potential association between chemical compounds and disease etiology.

Cosmetic and personal care product use, urinary levels of parabens and benzophenones, and risk of endometriosis: results from the EndEA study.

AIM: To explore the relationship of urinary concentrations of different congeners of benzophenones and parabens with the utilization of cosmetics and personal care products (PCPs) and their impact on the risk of endometriosis, and to evaluate the influence of oxidative stress on associations found. METHODS: This case-control study comprised a subsample of 124 women (35 cases; 89 controls). Endometriosis was confirmed (cases) or ruled out (controls) by laparoscopy, with visual inspection of the pelvis and biopsy of suspected lesions (histological diagnosis). Urinary concentrations of benzophenone-1 (BP-1), benzophenone-3 (BP-3), 4-hydroxibenzophenone (4-OH-BP), methyl- (MeP), ethyl- (EtP), propyl- (PrP), and butyl-paraben (BuP), and biomarkers of oxidative stress [lipid peroxidation (TBARS) and total antioxidant power (TAP)] were quantified. Information was gathered on the frequency of use of cosmetics and PCPs. Associations between the frequency of cosmetics/PCP use, urinary concentrations of benzophenones and parabens, oxidative stress, and endometriosis risk were explored in logistic and linear multivariable regression analyses. RESULTS: The frequency of utilization of certain cosmetics and PCPs was significantly associated with urinary concentrations of benzophenones and parabens. After adjustment for potential confounders, the risk of endometriosis was increased in women in the second versus first terciles of MeP (OR = 5.63; p-value<0.001), BP-1 (OR = 5.12; p-value = 0.011), BP-3 (OR = 4.98; p-value = 0.008), and Æ©BPs (OR = 3.34; p-value = 0.032). A close-to-significant relationship was observed between TBARS concentrations and increased endometriosis risk (OR = 1.60, p-value = 0.070) and an inverse association between TAP concentrations and this risk (OR = 0.15; p-value = 0.048). Oxidative stress results did not modify associations observed between benzophenone/paraben exposure and endometriosis risk. CONCLUSIONS: Our findings indicate that the frequency of cosmetics and PCP utilization is a strong predictor of exposure to certain benzophenone and paraben congeners. These compounds may increase the risk of endometriosis in an oxidative stress-independent manner. Further studies are warranted to corroborate these findings.

BPA modulates the WDR5/TET2 complex to regulate ERß expression in eutopic endometrium and drives the development of endometriosis.

Overexpression of estrogen receptor ß (ERß) in endometrium contributes to endometriosis (EM) pathogenesis. Trimethylation of the H3 lysine (K) 4 (H3K4me3) in promoters is strongly correlated with gene expression. This study aimed to explore the effects of bisphenol A (BPA) exposure on EM development from the perspective of the regulation of ERß expression in eutopic endometrium via the H3K4me3-related epigenetic pathway. A mouse EM model was established to investigate the effects of BPA. Immortalized human normal endometrial stromal cells (iESCs) were cultured and treated with BPA to explore the underlying mechanism. Eutopic endometria from patients with or without EM were collected and analyzed. Results showed that BPA elevated ERß expression in mouse eutopic endometrium and promoted lesion growth. BPA also promoted WD repeat domain 5 (WDR5) expression and upregulated H3K4me3 levels in the ERß promoter and Exon 1. Further research indicated that WDR5 interacted with tet methylcytosine dioxygenase 2 (TET2), while BPA exposure enhanced the interaction between these two proteins, promoted the recruitment of the WDR5/TET2 complex to the ERß promoter and Exon 1, and inhibited DNA methylation of CpG islands. The WDR5/TET2 interaction was essential for BPA-induced ERß overexpression. Enhanced WDR5/TET2 interaction was also observed in eutopic endometria from EM patients. Further results showed that BPA upregulated WDR5 expression through the G protein-coupled estrogen receptor (GPER)-mediated PI3K/mTOR signaling pathway. In conclusion, our study suggests that BPA exposure promotes EM development by upregulating ERß expression in eutopic endometrium via the WDR5/TET2-mediated epigenetic pathway.

Asymptomatic Atypical Hyperplasia and Endometriosis Following Treatment with Tamoxifen: A Case Report and Review of the Literature.

BACKGROUND: Tamoxifen may cause proliferative effects in the endometrium. Patients on tamoxifen have an increased risk for endometriosis, but are not routinely screened for this. CASE: A 49-year-old postmenopausal patient presented for a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy several years after initiating tamoxifen for breast cancer. She had no clinical history to suggest endometriosis, but was found to have extensive pelvic endometriosis intraoperatively with polypoid hyperplasia found on the pathology of the uterine and the ovarian tissue. CONCLUSION: This is the first case reported of an asymptomatic patient on tamoxifen with a new diagnosis of endometriosis along with atypical hyperplasia in the ectopic tissue. The potential for pre-malignant/malignant transformation may alter the treatment course if identified following tamoxifen exposure.

Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis.

PURPOSE: Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). METHODS: Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the ß value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. RESULTS: In total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort. CONCLUSION: We found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).

Bisphenol A Exposure Enhances Endometrial Stromal Cell Invasion and Has a Positive Association with Peritoneal Endometriosis.

Results of previous epidemiology studies on BPA exposure and endometriosis (EMs) risk were inconsistent, and were limited by inappropriate control selection, incorrect BPA detection method, and the generalization of different subtypes of EMs. Upregulated matrix metalloproteinase (MMP) 2 and MMP9 are involved in the development of EMs. We conducted a case-control study among 120 EMs patients and 100 healthy women to evaluate the relationships between BPA exposure and MMP2, MMP9 expressions, and the risk of EMs subtypes. Besides, we used human endometrial stromal cell lines (HESCs) to investigate the underlying mechanisms. Creatinine-adjusted urinary BPA concentrations were positively correlated with serum MMP2, MMP9 levels, and the risk of peritoneal EMs (third vs lowest quartile: OR 4.92, 95% CI 1.47, 16.50; fourth versus lowest quartile: OR 3.70, 95% CI 1.07, 12.74, Ptrend = 0.030). The risk of peritoneal EMs increased approximately tenfold when creatinine-adjusted urinary BPA concentration was 2 µg/g. In vitro study found that BPA exposure increased MMP2, MMP9 expressions in a dose-dependent manner. The effects of BPA on HESCs could be blocked by G protein-coupled estrogen receptor (GPER) inhibitor or mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) inhibitor. This study provides evidence that BPA exposure promotes peritoneal EMs, and raises a concern about the potential toxicity of BPA on the female reproductive system.