Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants

Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants View ORCID Profile Amelia Warren , View ORCID Profile Demetra Andreou , Dean Warren , Jack Wieland , View ORCID Profile Anna Mantzouratou doi: https://doi.org/10.1101/2025.04.15.25324328 Amelia Warren 1 Department of Life and environmental Sciences, Bournemouth University , Bournemouth, England, BH12 5BB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Amelia Warren Demetra Andreou 1 Department of Life and environmental Sciences, Bournemouth University , Bournemouth, England, BH12 5BB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Demetra Andreou Dean Warren 2 Independent Researcher Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jack Wieland 1 Department of Life and environmental Sciences, Bournemouth University , Bournemouth, England, BH12 5BB Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna Mantzouratou 1 Department of Life and environmental Sciences, Bournemouth University , Bournemouth, England, BH12 5BB Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Anna Mantzouratou For correspondence: amantzouratou{at}bournemouth.ac.uk Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Endometriosis is a chronic gynaecological disease characterised by inflammation and can cause infertility and severe chronic pelvic pain. It is a complex disease and potentially multifactorial and tends to affect women in the same family with heritability shown to be between 47-51%. Previous studies have identified over forty single nucleotide polymorphisms associated with advanced stages of endometriosis; however, no variants have been associated with earlier endometriosis stages to date. Due to being a multifactorial condition, it is also likely that interactions with the modern environment may lead to an altered genetic susceptibility to endometriosis. The aim of this study was to identify endometriosis risk variants in selected human populations within the Genomics England database and investigate the pathways these variants could act upon within the presence of modern environmental stressors and pollutants. This study focussed on the variants of regulatory sequences of the genome likely to be impacted by environmental and genetic influencers of endometriosis. A combination of systematic analysis and data interrogation in the Genomics England 100,000 genomes project were undertaken. Participant data was extracted from participants with a diagnosis of endometriosis at various stages. Variant frequency analysis and statistical testing identified six novel regulatory variants significantly enriched in the endometriosis cohort. The strongest association was observed for two IL-6 variants, which co-localized more frequently than expected by chance, suggesting a potential regulatory interaction. Although the sample size was limited, this study provides novel insights into how genetic regulatory variation and environmental pollutants may collectively influence endometriosis risk. The findings suggest that genetic susceptibility to endometriosis may be shaped by modern industrial exposures, with potential implications for personalised risk assessment and prevention strategies. Future research should validate these findings in larger populations and explore functional mechanisms underlying gene - environment interactions to develop targeted interventions for individuals at risk. The study introduces a unique perspective by linking ancient Neanderthal and Denisovan genetic variants to modern disease risk in the context of environmental exposure. We propose those industrial pollutants—particularly endocrine-disrupting chemicals (EDCs)—may epigenetically disrupt immune and reproductive gene regulation, thereby amplifying disease risk in genetically susceptible individuals. This is an early-stage, hypothesis-generating study and has not yet undergone peer review. Findings should not be interpreted as clinical advice or diagnostic tools. Future research with larger cohorts and functional validation is warranted. Introduction Globally, 10% of reproductive-aged women have endometriosis which is a heterogenous gynaecological disease driven by estrogen signalling ( Kanellopoulos et al., 2022 ). Estrogen dominance can cause endometrial cells to implant outside the uterus, forming scar tissue ( Angioni et al., 2020 ). Endometriosis can be difficult to diagnose, with Agarwal et al., (2019) finding up to eleven years can pass between symptom onset and diagnosis. Fifty percent of diagnosed women have medically reported severe pelvic pain during adolescence that went untreated ( Nnoaham et al., 2011 ). Additional symptoms include severe menstrual cramps, heavy bleeding, with pain located in the pelvic, back, and groin, before, during, and after periods, and during intercourse ( Shi et al., 2022 ). Infertility is also associated, as 50% of infertile women have endometriosis and 25% of endometriosis patients are infertile ( Tamura et al., 2019 ). Limited diagnostic tools contribute to misdiagnosis and delays. While internal exams, ultrasounds, and laparoscopy can be used, current imaging techniques miss superficial lesions ( Becker et al., 2022 ). The European society of human reproduction and embryology (ESHRE) also states diagnostics should not use biomarkers ( Becker et al., 2022 ). Studies have suggested endometriosis disrupts the immune system through lowered levels of check point inhibitors dampening the immune response ( Santoso et al., 2020 ). Furthermore, Garcia-Gomez et al., (2020) and Patel et al., (2018) found estrogen dominance disrupts the immune system, triggering pro-inflammatory factors and altering immune cell function (T-cells, natural killers, macrophages). This disruption to the immune system fuels chronic inflammation, preventing cell death, and promotes the growth of endometriosis lesions (Garcia-Gomez et al., 2020). Patel et al., (2018) study found endometriosis patients show increased C chemokine production, leading to higher oxidant levels and worsened inflammation in both the lesions and surrounding peritoneal fluid. Studies with twins by Treloar et al., (1999) ; Lee et al., (2013) ; Saha et al., (2015) show a heritability component, with these genome-wide association studies suggesting both genetic (47%) and environmental (53%) contributions to endometriosis predisposition ( Saha et al., 2015 ). Environmental predisposition from exposure to modern industrial pollutants and chemicals found in items like plastics, pesticides and cosmetics could potentially play a role in the development of endometriosis ( Yen et al., 2019 ). For instance, exposure to endocrine disrupting chemicals (EDCs) imitating hormones and blocking the binding of naturally occurring hormones to their receptors may interfere with physiological processes ( Hansel et al., 2024 ). This disruption may harm the reproductive system potentially contributing to the onset of endometriosis ( La Merrill et al., 2020 ). Current genome-wide studies by Sapkota et al., (2017) ; Zondervan et al., (2018) ; Rahmioglu et al., (2023) collectively identified forty-two single nucleotide polymorphisms (SNPs) linked to endometriosis. Notably, some variants were associated with pain perception and maintenance and advanced stages of endometriosis. However, none of these variants predict earlier endometriosis stages, hindering increased risk assessment accuracy and early diagnosis preventing complications such as infertility. Despite current advancements in identifying endometriosis genes, most of the research has focused on advanced stages of endometriosis and comorbidities such as migraines and infertility, rather than the disease onset, leading to diagnosis of earlier stages and prevention of endometriosis to remain elusive. Understanding genetic risk in early stages and investigating how environmental factors interact with genes is crucial for better management and treatment of endometriosis and preventing complications such as infertility and ovarian and uterine cancer. Genomics England (GE) has recruited over 85,000 National Health Service (NHS) patients and sequenced over 100,000 genomes from these NHS patients to enhance research in healthcare. This database has completed genomic sequences of patients with known diseases or disorders. This enables researchers to investigate genomic sequences and variants of genes and their potential impacts on known and rare diseases (The National Genomic Research Library v5.1, Genomics England https://doi.org/10.6084/m9.figshare.4530893.v7 ). Bournemouth University and the Department of Life and Environmental Sciences is part of the Genomics England Research Network (GERN) and has been granted access to the GE Research Environment. This enables researchers to investigate genomic sequences and variants of genes and their potential impacts on known and rare diseases. Therefore, the aim of this study was to investigate genetic factors that may have potential interactions with environmental pollutants that can result to a combined risk to developing endometriosis. This study proposes that regulatory sequence variants in genes involved in immune modulation, inflammation, and hormone signalling contribute to endometriosis susceptibility and that these variants may be influenced by environmental pollutants, particularly endocrine-disrupting chemicals (EDCs). Specifically, we predict that non-coding genetic variants affecting the regulation of key genes may be more prevalent in individuals with endometriosis and could potentially modify disease risk through interactions with environmental pollutants. To test this hypothesis, we analysed whole-genome sequencing data from the 100,000 Genomes Project, focusing on regulatory variants in selected genes, their frequency in an endometriosis cohort, and their potential functional consequences. This approach aims to bridge the gap between genetics and environmental risk factors, providing a more comprehensive model of endometriosis susceptibility and identifying potential biomarkers for early-stage disease detection. Materials and Methods Ethical Approval The study received ethical approval by the BU institutional ethical approval panel, ethics ID: 45978. Literature Searches To identify genomic areas and markers of interest in relation to endometriosis development and interaction with environmental factors, a comprehensive literature review was undertaken using Web of Science and PubMed. Selection criteria were applied to select relevant papers. Literature Selection Criteria Inclusion Criteria: Original studies focusing on genomic/genetic analysis, or genome wide association design., Only human participants (no other species)., Patients with a diagnosis of endometriosis for at least a year., Patients aged between 18 and 43 years at the time of recruitment. Exclusion Criteria: Review studies., Studies including participants with other types of female infertility., Participants without an endometriosis diagnosis., Participants with additional illnesses and disease which could affect the outcome of the results. A literature search was conducted to investigate environmental factors that are adversely associated with endometriosis development risk. A review of how these factors affect signalling pathways and the genes involved in them was conducted. The key words used for environmental factors were; “endometriosis and “exposure to endocrine disrupting chemicals”, “endocrine disrupting chemicals”, “exposure to pesticides”, “pesticides”, “personal care products”, “cosmetics”, “exposure to heavy metals”, “heavy metals”, “exposure to radiation”, “radiation”, “exposure to toxins”, “toxins”, “chemicals”, “plastics”, “exposure to pollution”, “pollution”, “exposure to air pollution”, “air pollution”, “exposure to water pollution”, “water pollution”. This search yielded sixty-four papers and 236 papers were excluded. A PRISMA flow chart presented in figure one shows the screening prosses of the primary literature search. Download figure Open in new tab Figure 1: The PRISMA flow chart used to select literature for the impact of the environment on endometriosis risk. This literature review identified EDCs as the most significant environmental factor to endometriosis. Therefore, this study focused on EDC’s exploring their properties, structure, uses, mechanisms, signalling pathways effected by exposure of EDCs and their association with genetic susceptibility to endometriosis. A secondary literature search was conducted to identify genomic areas of interest and genetic markers involved in endometriosis development. The key words used in this search were “endometriosis and “polymorphism” or “SNP” or “genetic polymorphism” or “variants” or “locus” and “GWA” or “Genome-wide” or “Genome wide” or “Genetic association study”. This yielded 166 papers to be included and 2476 papers to be excluded. A PRISMA flow chart presented in figure two shows the screening prosses of the secondary literature search. Download figure Open in new tab Figure 2: PRISMA flow chart created for the screening process to select literature on genomic areas of interest in relation to endometriosis development. This literature search identified fifty-seven genes of interest in relation to endometriosis risk susceptibility, and from this, five genes were chosen to investigate further due to published studies demonstrating these were affected by the action of EDCs. These were chosen through identifying the main function of the gene and where it is expressed using the national library of medicine (NIH) ( https://www.nlm.nih.gov/ ). The pathways of the genes and their associated variants were identified using Reactome ( Gillespie et al., 2022 ). The criteria for this selection are outlined below: Literature has shown EDCs are associated with disruption to the gene; this could be through altered expression or epigenetic alterations such as cytosine demethylation and modification of histones (Alavian-Ghavanini, and Rüegg, 2018). Literature has shown EDCs effects are within the signalling pathways that selected genes are involved in. Leading to an alteration to the pathway and disrupting the homeostasis (Lauretta et al., 2019). The pathways associated with the gene are seen to be associated or involved in endometriosis onset or progression. The selected genes are expressed within tissues associated with endometriosis implant locations. The main function of the gene when disrupted potentially leads to development of endometriosis. 100,000 Genomics England Database The GE 100,000 genome database was used in this study as a part of an ongoing larger project “Genomic and chromosomal instability sequence markers in relation to fertility, early pregnancy, and cancers of the reproductive tissues” Project ID 645 which included domains of Ovarian Cancer GERN and Endocrine and Metabolism GERN to obtain participants and analyse genomic data. Study population from the Genomics England Database Participants were chosen using the GE Rare Disease Programs GRCh38 Participant Explorer by searching for clinical diagnosis of endometriosis. Participant Selection Criteria Inclusion Criteria: Female participants aged 18–43 years at the time of recruitment., Diagnosis of endometriosis recorded in medical history., Availability of whole-genome sequencing (WGS) data., Inclusion of participants with endometriosis-related infertility and/or ovarian chocolate cysts. Exclusion Criteria: Individuals not assigned female sex at birth., Participants over the age of 43 (to minimize confounding by menopause-related genetic changes)., Presence of additional ovarian pathology, chromosomal abnormalities, haematological disorders, or other reproductive tract malignancies., Diagnosis of diabetes, immunological disorders, or hormonal conditions that could confound genetic associations., Body mass index (BMI) outside the range of 18.5–30 kg/m² to minimize the impact of metabolic confounders. The final study cohort included 19 individuals meeting these criteria. The stage of endometriosis was not stated in the Participant Explored database, so endometriosis stages were estimated according to the American Society of Reproductive medicine ( Zhang et al., 2019 ), using additional clinical information available in the patient’s profile. This included the locations of endometrial implants and/or lesions and procedures or investigations carried out in relation to endometriosis with table one depicting the study criteria to estimate the stage of endometriosis patients in this study cohort. This led to four patient cohorts for stages one to four. View this table: View inline View popup Table 1: Criteria used in this study to estimate the patient’s endometriosis stage according to the American Sociated of Reproductive medicine ( Zhang et al., 2019 ). Determining genes and variants related to endometriosis risk The GE Interactive Variant Analysis (IVA) workspace was used to identify potential genes and variants linked to the risk of developing endometriosis. This workspace allows searches for variants found in the selected genes in the participants in this study, through selecting for genes, consequences and frequency in patient IDs and family genotypes. Each of the five genes selected to investigate further were searched in each participant and single nucleotide variations (SNVs), and insertion-deletion mutations (INDEL’s) were collected. The regulatory sequences introns, upstream and downstream sequences were investigated in this study rather than the coding sequences. Investigating the regulatory sequence variants and their impact on gene expression was chosen due to environmental pollutants having a higher possibility of acting upon the expression of the targeted genes rather than the protein itself (You et al 2021). Also, modern industrial pollutants may also influence the variants which may otherwise not be disadvantageous. This highly informed and targeted approach lead an efficient and more detailed investigation of flagged genomic sequences. Statistical analysis Heatmaps were created using GraphPad Prism version 10 to visualise variants found in multiple stages and variants. These were then compared to the whole population within GE and the endometriosis cohort, which was subsequently followed with a χ 2 goodness of fit test for individual variants with Fisher’s combined probably and small sample corrections and checks relevant to data discovery which allowed some flexibility. To account for multiple hypothesis testing, a Benjamini-Hochberg (BH) false discovery rate (FDR) correction was applied to all p-values, controlling for false positives while maintaining statistical power. To confirm that the enrichment of significant variants was specific to the endometriosis cohort, a randomly selected group of 19 individuals from the Genomics England database (with no endometriosis diagnosis) was analysed using the same variant screening process. A Fisher’s combined probability test was conducted to compare the endometriosis cohort, random control sample, and Genomics England total population, providing an overall measure of statistical significance across variant frequencies. Variants identified as statistically significant were assessed for co-localization effects to determine whether they exhibited non-random clustering within the endometriosis cohort. Linkage disequilibrium analysis was conducted to assess the correlation between regulatory variants associated with endometriosis. Pairwise LD values (D’ and r²) were calculated for rs34880821 and rs2069840 in IL-6 and rs806372 in CNR1 , using data from the 1000 Genomes Project across multiple populations. LDpair and LDpop from LDlink was used to determine linkage strength, with comparisons across African, East Asian, European, South Asian, and Admixed American populations. The results were analysed to evaluate population-specific evolutionary pressures and potential functional implications for immune regulation and pain sensitivity. Regulatory Sequence analysis In order to find the impact of statistically significant variants found in this study an extensive search of the variants rsID was undertaken using ClinVar, dbSNP, ensemble, UCSC, and String, the workflow for this search is shown in figure three . Download figure Open in new tab Figure 3: Workflow of methods followed for finding the impact and regulatory sequences of statistically significant variants. An extensive analysis was conducted using UCSC and previous literature on other hominoids and conservation of the statistically significant variants, this can help to identify differences which can lead to disease predisposition ( Jayapalan et al., 2016 ). All results are reported with adjusted p-values, and statistically significant associations are discussed in the context of biological plausibility and environmental interactions. Results Genomic findings of five selected genes in study participants Through using the literature searches and consulting the criteria, the five genes chosen to be investigated further were IDO1( Indoleamine 2,3-dioxygenase 1), IL-6 ( Interleukin 6), CNR1 ( cannabinoid receptor 1), TACR3 (tachykinin receptor 3) and KISS1R ( KISS1 receptor). Significant variant findings Ten variants were found to be potential contributors of endometriosis when comparing the study population and GE total population. When comparing the variants found in Ensembl and GE total populations, 40% of the variants had 0% frequency in Ensembl general population but were present in GE general population. This is potentially due to GE participants having a higher percentage of genetic mutations and variants through recruiting participants with known rare genetic conditions or specific diseases. After conducting a χ 2 goodness of fit test for each of the ten variants found using the study cohort population frequency and GE total population frequency, variants rs806372, rs76129761, rs2069840, rs34880821, rs933717388, and rs72643906 were found to be statistically significant. A BH test was conducted from the χ 2 goodness of fit test. This test shows the variants come up as significant in the endometriosis cohort. When observing co-occurrence with other significant variants rs2069840 and rs34880821 showed the strongest co-occurrence shown in eight individuals in the endometriosis cohort. Whereas rs806372 and rs933717388 shows moderate co-occurrence in three individuals. However, rs76129761 and rs72643906 rarely occurs with other variants. When conducting a co-localisation analysis, rs2069840 and rs34880821 shows a strong co-localisation effect. The expected frequency for co-localisation for the variants is two participants in the cohort of nineteen (10.5%), based on P(co-localise) = 0.316×0.263=0.083. In the endometriosis group eight individuals had both variants (47.4%), which is significantly higher than expected at p=0.0001, showing a strong co-localisation effect. However, in the random group this was seen in six individuals (31.6%), this was also higher than expected at p=0.0110 but is less pronounced than the endometriosis group. This shows the co-localisation of rs2069840 and rs34880821 occurs much more frequently than would be expected by chance in both groups. Furthermore, both variants individually and together show significant enrichment in the endometriosis group. This suggests a potential biological interaction between these variants that may be particularly relevant to endometriosis. Table two shows the variant profiles for the significant variants found within the endometriosis cohort. View this table: View inline View popup Table 2: Variant profiles for the significant variants found within this cohort (created using UCSC (2023)). When comparing the six significant variants in the endometriosis cohort compared to the random sample cohort and the total GE population, each of the variants are shown to be significantly higher in the endometriosis group. Except rs76129761 which is shown to be higher in the random sample cohort. From the fisher’s combined probability test between the endometriosis cohort and the random sample compared to the GE total population a combined χ 2 statistic; 44.37, with a p-value of 0.000013 (p < 0.001) showed strong evidence in overall frequency difference between the endometriosis cohort and the GE total population across all endometriosis variants. This suggests that the genetic profile of the endometriosis cohort significantly deviates from the general population, potentially indicating a unique genetic signature associated with endometriosis. Furthermore, the combined χ 2 statistic for the random sample cohort; 12.23, with a p-value of 0.427, showed no significant difference between the random sample cohort and the GE total population across all endometriosis variants. This lack of significant deviation suggests that the Random Sample’s variant frequencies are representative of the GE Total Population, serving as a control group. A summary of what has been found in this results section has been provided in figure four . Download figure Open in new tab Figure 4: A visual representation of the hypothetical relationships between the identified variants and environmental pollutants, and how they could relate to endometriosis onset and progression. The red arrows represent potential increased expression levels of genes, with blue arrows represent potential decreased expression of genes and transcription factors in endometriosis patients if selected the variants were to be present and disrupt expression. Green circles represent genes, orange circles represent transcription factors, blue squares represent properties of each gene, light pink boxes represent pathways, light purple boxes represent endocrine disrupting chemicals effect on genes and transcription factors and light red boxes represent variants. LD analysis LD analysis revealed strong linkage between Neanderthal-derived IL-6 variants (rs34880821 and rs2069840) (depicted in figure 5 ), in East Asians (D’ = 1.0, r² = 0.9662), suggesting selective retention and potential immune regulation effects. Europeans showed moderate LD (D’ = 0.9234, r² = 0.5794), while Africans had weak linkage (D’ = 0.8752, r² = 0.4823), likely due to the absence of Neanderthal introgression. Download figure Open in new tab Figure 5: LD analysis of variants rs34880821 and rs2069840. The Denisovan-influenced CNR1 variant (rs806372) exhibited moderate LD in East Asians (D’ = 0.8004) but weak LD in Europeans (D’ = 0.4607) and South Asians (D’ = 0.1459), suggesting population-specific evolutionary pressures. African populations had negligible LD for both variant pairs, supporting the hypothesis that these associations arose post-migration due to archaic human introgression. This study identified six novel regulatory variants enriched in the endometriosis cohort, with IL-6 variants showing strong co-localization, suggesting a role in inflammation. Variants in CNR1 , IDO1 , and KISS1R were also significantly associated, with functional analysis indicating potential disruptions in transcription factor binding and immune regulation. Several variants overlapped with regions affected by endocrine-disrupting chemicals, highlighting potential gene-environment interactions in disease susceptibility. While limited by sample size, these findings provide new insights into how regulatory genetic variation and modern environmental exposures may collectively influence endometriosis risk, warranting further validation in larger studies. Discussion Many sufferers of endometriosis are subject to misdiagnosis and long diagnosing times, through a lack of understanding of risk factors in earlier endometriosis stages. To obtain a better understanding of genetic factors predisposing endometriosis development, two literature searches and interrogation of the GE 100,000 genome database were carried out. Using a highly targeted multilevel approach five genes have been characterised as potential targets in the developing endometriosis pathway, containing variants or having altered expression levels, with five variants found as highly significant and one as moderately significant in our cohort population when compared to the GE total population. This builds on the work conducted by Sapkota et al., (2017) , Zondervan et al., (2018) and Rahmioglu et al., (2023) who collectively found forty-two SNPs linked to endometriosis. IDO1 The downstream variant rs72643906 of IDO1 was significantly higher in the study cohort, which may potentially influence endometriosis development through altering expression levels of IDO1 . UCSC, (2023) data found rs72643906 to alter the motif of the transcription factor Zic family member 2 ( ZIC2) , which regulates tissue expression ( Luo et al., 2015 ). Although, rs72643906 is found to be very rare, UCSC, (2023) data has shown this variant to be highly conserved in mammals and to be associated with an elevated risk of COVID-19. Because of this, it can be hypothesised that rs72643906 is disadvantageous to the immune system. This can be validated through Brooks et al., (2016) study finding IDO1 expression to be increased by immune system activation. It is possible to hypothesise rs72643906 modifies ZIC2 motif preventing the transcription factor from binding increases IDO1 and ZIC2 expression levels. However, this effect is potentially reversed through exposure to BPA decreasing expression levels of IDO1 and ZIC2 when it is introduced through the environment into the pathway (figure four). Increased IDO1 expression levels have been associated with endometriosis risk in research conducted by Mei et al., (2013) and Kong et al., (2021) finding elevated expression of IDO1 in endometriosis patients. CNR1 This research showed two significant variants of CNR1, rs76129761 a deleterious variant which has not been referenced in any previous publications and rs806372, referenced in previous literature, however, the literature did not have relevance to endometriosis. These variants were found to be frequent within the study population, and rs76129761 was found to be highly conserved within mammals and rs806372 had a potential splicing site implicating three alternative transcripts within intron 1 (6q15) of CNR1 (UCSC, 2023). Due to being frequent in the study population and having a splicing site, it is possible the variants affect CNR1 expression levels potentially leading to endometriosis development. Research by Allam et al., (2022) , and Bouaziz et al., (2017) found increased levels of CNR1 in endometriosis patients when compared to controls. UCSC (2023) data showed rs806372 to be a Denisovan variant, which is prevalent in east Asian populations, who have a high prevalence of endometriosis (15.4%), compared to European (1.4%) and general (4.44%) populations ( Parazzini et al., 2020 ). This shows that the variant might be well established in populations where Denisovans and sapiens interacting being randomly selected until the onset of EDCs in our modern society ( Zhang et al., 2021 ). This impact may have been increased by DEHP, DiNP and BPA which have previously been shown in this paper to increase CNR1 expression and potentially in turn endometriosis risk ( Ernst et al., 2020 ; Forner-Piquer et al., 2018 ). The CNR1 variant rs806372 may potentially modify the SRY-box transcription factor ( SOX) 12 motif (UCSC, 2023) preventing the transcription factor from binding and causing increased expression of CNR1 and decreased SOX12 levels. If DEHP is introduced to the pathway through exposure from the environment the expression of SOX12 and CNR1 is increased an observation supported by the expression studies ( Chou et al., 2019 ; Ernst et al., 2020 ). The significant variant rs76129761 of the CNR1 gene potentially changes the motif of five potential transcription factors. All the transcription factors Zinc finger protein 701 ( ZNF701) , SOX4 , S0X6 , Forkhead box D3 ( FOXD3) and SOX11 when in the presence of rs76129761 potentially increase expression levels alongside increased CNR1 expression. Furthermore, when exposed to BPA this consequence is potentially further increased in the pathways including SOX4 , SOX6 , and SOX11 ( Lichtensteiger et al., 2021 ; Kang et al., 2014 ). However, in the presence of BPA FOXD3 was decreased ( Baba et al., 2009 ), although there was no literature available for ZNF701 and other EDCs. KISS1R The intronic variant rs933717388 of KISS1R was found to be significantly higher in the study population and potentially novel variant due to no literature or records referencing this variant. Data obtained from UCSC (2023) found rs933717388 to lie on the binding sites of Zinc finger protein 707 ( ZNF707) and Zinc finger and BTB domain-containing protein 11 ( ZTB11) and modifies the motifs, potentially preventing the transcription factors from binding. This can alter expression of KISS1R, specifically ZTB11 is a silencing transcription factor, which means potentially increased ZTB11 levels as the transcription factor might not be binding as readily resulting in increased KISS1R expression levels. Therefore, it may be hypothesised that rs933717388 causes an increased expression of KISS1R which may lead to dysregulation of the HPGA and reproductive regulation, while increasing metastasis of endometriotic cells outside of the uterus ( Xie et al., 2022 ; Gillespie et al., 2022 ). This is supported by Blasco et al., (2020) finding abnormal and heightened expression levels of KISS1R in endometriosis patient granulosa cells when compared to controls. Within both pathways, KISS1R and transcription factors expression levels are increased, with exposure to DEHP increasing KISS1R expression levels further, although there is not literature for DEHP effect on ZNF707 , or ZTB11 . IL-6 Intronic variants rs2069850 and rs34880821 of the IL-6 gene were found to be significant within the study cohort. These variants have both been referenced before in various publications, but none of which related to endometriosis, or pathways known to be involved. However, the variants have been found to colocalise in the endometriosis cohort, which suggests a potential biological interaction between these variants that are potentially relevant to endometriosis. Data from UCSC (2023) showed rs34880821 to be a Neandertal methylation site which is shown to increase susceptibility to auto-immune/inflammatory conditions ( Zhou et al., 2022 ). Therefore, the reference allele was methylated in Neandertals and Denisovan’s, but this variant abolishes the methylation site, so rs34880821 may exuberate endometriosis development due to the disease being associated with dysregulation of the immune and inflammatory system by aberrant silencing of the area and continuous expression. Specifically, this gene primary function in maturation of B cells and inflammatory pathways ( Aliyu et al., 2022 ). A study conducted by Moghaddam et al., (2022) found dysregulation of IL-6 to increase angiogenesis and cellular proliferation in the endometrium. This can lead to increased rates of endometrial cell shedding and exacerbate the immune response ( Sobstyl et al., 2023 ). This was also seen in Incognito et al., (2023) study finding increased levels of IL-6 in endometriosis patients. This probability of heightened IL-6 expression in endometriosis patients is further validated in research by Benjamin et al., (2020) and Li et al., (2021), finding an increase in IL-6 expression levels when compared to controls. The research conducted did not find any significant variants for TACR3 , but did however, find two variants (rs796412104 and rs565747925) to be consistent in the study population when compared to the GE Population. TACR3 can be considered as an involved factor in endometriosis development through altered levels of TACR3 potentially increasing adhesion of endometriotic cells outside of the uterus. This is due to being involved in the P-CSMS which regulates adhesion, vesicle trafficking and adhesion ( Verma et al., 2024 ). This could be further validated by Blasco et al., 2020 finding TACR3 expression levels to be altered in endometriosis patients’ granulosa cells when compared to controls. Furthermore, TACR3 is one of the regulators of the HPGA regulating GnRH release (Casteel and Singh, 2020). Due to Xie et al., (2022) finding DEHP exposure to alter expressions of regulators in the HPGA, it is possible that DEHP exposure may increase endometriosis risk through altering TACR3 expression levels. The Intersection of Ancient Genetic Variants, Epigenetic Regulation, and Modern Environmental Pollutants in Endometriosis Susceptibility Our findings highlight how ancient genetic variants inherited from Neanderthals and Denisovans, epigenetic regulation, and modern industrial pollutants may potentially converge to shape population-specific risks for endometriosis. The linkage disequilibrium (LD) analysis of IL-6 and CNR1 regulatory variants suggests that evolutionary pressures involving immune regulation and inflammatory responses, when combined with modern environmental exposures, may amplify disease susceptibility ( Sankararaman et al., 2014 ; Harris & Nielsen, 2016 ). Neanderthal introgression has significantly influenced IL-6 regulation, particularly in East Asian populations. The IL-6 variant rs34880821, located at a Neanderthal-derived methylation site, exhibits strong LD in East Asians (r² = 0.9662, D’ = 1.0), while showing weaker LD in Europeans (r² = 0.5794) and South Asians (r² = 0.8104) ( Sankararaman et al., 2014 ). This suggests that Neanderthal introgression may have played a role in shaping IL-6 regulatory pathways, particularly in East Asians, where it remains strongly linked. Given that East Asian populations also have the highest reported prevalence of endometriosis (∼15.4%), it is likely that these genetic variants contribute to heightened inflammatory responses, immune dysregulation, and fibrotic lesion formation ( Yamamoto et al., 2019 ; Velarde et al, 2023 ). The functionality for the Neanderthal-derived methylation at rs34880821 may indicate another subtle contributor to endometriosis risk. Methylation usually functions as a gene-silencing mechanism, regulating cytokine levels to prevent excessive inflammation ( Zeberg & Pääbo, 2020 ). If methylation is lost, IL-6 expression could become hyperactive, leading to chronic immune activation, sustaining peritoneal inflammation, fibrosis and deep-infiltrating endometriosis, as IL-6 is known to drive fibrotic remodelling in reproductive tissues ( Velarde et al, 2023 ). It also may account for heightened neuroinflammation, potentially explaining increased pain sensitivity in East Asian endometriosis patients ( Zeberg & Pääbo, 2020 ). Similarly, the Denisovan-derived rs806372 variant in CNR1 , which is involved in immune modulation and pain perception, exhibits moderate LD in East Asians (D’ = 0.8004) but weak LD in Europeans (D’ = 0.4607) and South Asians (D’ = 0.1459) ( Sankararaman et al., 2014 ). Since CNR1 plays a key role in pain signalling and inflammatory responses, this Denisovan-influenced variant may enhance pain sensitivity in individuals with endometriosis, particularly in East Asian populations ( Harris & Nielsen, 2016 ). While these ancestral variants may have once provided immune advantages in prehistoric environments, modern environmental factors may be reversing these evolutionary benefits, transforming once-adaptive immune responses into drivers of chronic disease ( Velarde et al 2023 ). Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), phthalates, and dioxins, has been shown to demethylate immune regulatory genes, including IL-6 , leading to excessive cytokine production ( Yamamoto et al., 2019 ). If Neanderthal-derived IL-6 regulatory variants are already prone to overactivation, additional EDC-induced demethylation could further escalate inflammatory signalling, worsening lesion development. This suggests a gene-environment interaction, where modern industrial chemicals exacerbate genetic predispositions inherited from archaic human ancestors. In contrast to East Asian and European populations, African populations exhibit significantly lower LD for these IL-6 and CNR1 variants (D’ < 0.02, r² < 0.001), suggesting these genetic associations arose post-migration due to Neanderthal and Denisovan introgression ( Sankararaman et al., 2014 ). There is limited available data on the prevalence of endometriosis in African populations, and estimates may vary due to underdiagnosis. This study supports a novel model for endometriosis susceptibility, in which ancestral genetic variants interact with modern environmental pollutants to modulate immune regulation, chronic inflammation, and pain perception across populations. Limitations and future directions While this study provides novel insights into the genetic and environmental factors influencing endometriosis susceptibility, several limitations must be acknowledged. The sample size was limited, particularly in younger individuals under 29 years old. Additionally, family-based cascade genetic testing was not included, preventing the evaluation of heritability patterns and potential familial aggregation of risk variants. Another limitation is the reliance on medical records to infer endometriosis staging, which introduces the potential for misclassification bias. Furthermore, while this study identified significant associations between regulatory variants and endometriosis risk, functional validation through in vitro and in vivo models is required to confirm their biological relevance. Future research should focus on expanding the study cohort to include a larger and more diverse population to improve the statistical power of genetic associations and assess whether these findings are consistent across different ethnic backgrounds. Family-based studies incorporating cascade genetic testing could help clarify inheritance patterns and the potential contribution of additional rare variants to endometriosis risk. Further, functional studies are necessary to evaluate how the identified regulatory variants influence gene expression and immune signalling pathways, particularly in response to endocrine-disrupting chemicals. Integrating environmental exposure data with genomic analysis would provide a more comprehensive understanding of how genetic and environmental factors interact in the development and progression of endometriosis. These future directions will be critical for translating genetic discoveries into practical applications for early diagnosis and personalized treatment strategies. Conclusion This study provides a novel perspective on the genetic and environmental interplay driving endometriosis susceptibility, highlighting the influence of ancient regulatory variants and modern industrial pollutants. This research identified statistically significant regulatory variants in IL-6 , CNR1 , IDO1 , and KISS1R that may contribute to endometriosis risk through interactions with endocrine-disrupting chemicals. These findings aim to bridge the gap between genetic predisposition, evolutionary selection, and environmental exposures, shedding light on how Neanderthal and Denisovan introgressed variants in immune and pain-regulatory genes may influence disease susceptibility in modern populations. This is the first study to systematically explore how ancient genetic signatures, epigenetic regulation, and contemporary environmental pollutants intersect in the pathophysiology of endometriosis. These results lay the first steps for future precision medicine approaches, where genetic screening combined with environmental risk assessment may improve early detection and personalized intervention strategies. Moving forward, functional validation of these regulatory variants and their interaction with endocrine disruptors will be crucial in understanding their mechanistic role in endometriosis onset and progression. These findings enhance our understanding of endometriosis as a multifactorial disease but also provide a framework for future research integrating evolutionary genetics, environmental health, and reproductive medicine. Data availability statement Research on the de-identified patient data used in this publication can be carried out in the Genomics England Research Environment subject to a collaborative agreement that adheres to patient led governance. All interested readers will be able to access the data in the same manner that the authors accessed the data. For more information about accessing the data, interested readers may contact research-network{at}genomicsengland.co.uk or access the relevant information on the Genomics England website: https://www.genomicsengland.co.uk/research . Author’s role A.W. contributed to the study design, collected the data and analysed the data and drafted the manuscript. D.A. contributed to the study design, provided supervision of the study and contributed to the article drafting and editing. D.W. contributed to the study design, analysed the data and editing. J.W. contributed to data gathering. A.M. leads the GE project that this study is a part of, designed the study, data analysis and interpretation, provided supervision of the study and manuscript drafting and editing. Funding Bournemouth University funded the writing of this manuscript granted to the first author of this manuscript. Conflict of interest The authors declare no conflicts of interest. Acknowledgements Posthumous acknowledgement. This work is dedicated to our beloved colleague Dr Elpida Fragkouli for her consistent support, supervision and contribution to the study design and data interpretation. This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Welcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. References 1. “c.1018delG” - ClinVar - NCBI . (n.d.). Retrieved July 17, 2024, from https://www.ncbi.nlm.nih.gov/clinvar/?term=c.1018delG 2. 100,000 Genomes Project | Genomics England. (n.d.). Retrieved July 17, 2024, from https://www.genomicsengland.co.uk/initiatives/100000-genomes-project 3. 17[chr] AND 43000000:44000000[chrpos37] - ClinVar - NCBI. (n.d.). Retrieved July 17, 2024, from https://www.ncbi.nlm.nih.gov/clinvar/?term=17[chr]+AND+43000000:44000000[chrpos37] 4. 672[geneid] - ClinVar - NCBI . (n.d.). Retrieved July 17, 2024, from https://www.ncbi.nlm.nih.gov/clinvar/?term=672[geneid] 5. ↵ Agarwal , S. K. , Chapron , C. , Giudice , L. C. , Laufer , M. R. , Leyland , N. , Missmer , S. A. , Singh , S. S. , & Taylor , H. S . ( 2019 ). Clinical diagnosis of endometriosis: a call to action . American Journal of Obstetrics and Gynecology , 220 ( 4 ). doi: 10.1016/j.ajog.2018.12.039 OpenUrl CrossRef PubMed 6. Alavian-Ghavanini , A. , & Rüegg , J. ( 2018 ). Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: From Mechanisms to Novel Test Methods . In Basic and Clinical Pharmacology and Toxicology (Vol. 122, Issue 1). doi: 10.1111/bcpt.12878 OpenUrl CrossRef 7. Al-Deresawi , M. S. , Alfaisal , A. H. M. , Al-Obaidi , S. R. , & Fahad , I. A . ( 2018 ). Hypermethylation of miR-203 and overexpression of SOX4 are new methods for prediction of endometrial adenocarcinoma . Journal of Pharmaceutical Sciences and Research , 10 ( 12 ). 8. Alexander , T. A. , & Machiela , M. J . ( 2020 ). LDpop: An interactive online tool to calculate and visualize geographic LD patterns . BMC Bioinformatics , 21 ( 1 ). doi: 10.1186/s12859-020-3340-1 OpenUrl CrossRef PubMed 9. ↵ Aliyu , M. , Zohora , F. T. , Anka , A. U. , Ali , K. , Maleknia , S. , Saffarioun , M. , & Azizi , G . ( 2022 ). Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach . In International Immunopharmacology (Vol. 111 ). doi: 10.1016/j.intimp.2022.109130 OpenUrl CrossRef PubMed 10. ↵ Allam , S. , Paris , E. , Lazcano , I. , Bitterman , P. , Basu , S. , O’Donnell , J. , & Barua , A . ( 2022 ). Detection of Cannabinoid Receptor Expression by Endometriotic Lesions in Women with Endometriosis as an Alternative to Opioid-Based Pain Medication . Journal of Immunology Research , 2022 . doi: 10.1155/2022/4323259 OpenUrl CrossRef 11. ↵ Angioni , S. , D’alterio , M. N. , Coiana , A. , Anni , F. , Gessa , S. , & Deiana , D . ( 2020 ). Genetic characterization of endometriosis patients: Review of the literature and a prospective cohort study on a mediterranean population . International Journal of Molecular Sciences , 21 ( 5 ). doi: 10.3390/ijms21051765 OpenUrl CrossRef 12. ↵ Baba , K. , Okada , K. , Kinoshita , T. , & Imaoka , S . ( 2009 ). Bisphenol A disrupts notch signaling by inhibiting gamma-secretase activity and causes eye dysplasia of Xenopus laevis . Toxicological Sciences , 108 ( 2 ). doi: 10.1093/toxsci/kfp025 OpenUrl CrossRef PubMed Web of Science 13. Beck , T. , Rowlands , T. , Shorter , T. , & Brookes , A. J . ( 2023 ). GWAS Central: an expanding resource for finding and visualising genotype and phenotype data from genome-wide association studies . Nucleic Acids Research , 51 ( D1 ), D986 – D993 . doi: 10.1093/NAR/GKAC1017 OpenUrl CrossRef PubMed 14. ↵ Becker , C. M. , Bokor , A. , Heikinheimo , O. , Horne , A. , Jansen , F. , Kiesel , L. , King , K. , Kvaskoff , M. , Nap , A. , Petersen , K. , Saridogan , E. , Tomassetti , C. , van Hanegem , N. , Vulliemoz , N. , Vermeulen , N. , Altmäe , S. , Ata , B. , Ball , E. , Barra , F. , … Yazbeck , C. ( 2022 ). ESHRE guideline: endometriosis . Human Reproduction Open , 2022 ( 2 ). doi: 10.1093/hropen/hoac009 OpenUrl CrossRef PubMed 15. ↵ Benjamin , J. J. , Koshy , T. , Kumar , K. M. , Maruthy , K. N. , & Padmavathi , R . ( 2020 ). Meta-analysis of association between il-6-174 g/c polymorphism and female infertility related disorders . In Journal of Reproductive Immunology (Vol. 140 ). doi: 10.1016/j.jri.2020.103134 OpenUrl CrossRef 16. Berman , H. M. , Westbrook , J. , Feng , Z. , Gilliland , G. , Bhat , T. N. , Weissig , H. , Shindyalov , I. N. , & Bourne , P. E . ( 2000a ). The Protein Data Bank . Nucleic Acids Research , 28 ( 1 ), 235 – 242 . doi: 10.1093/NAR/28.1.235 OpenUrl CrossRef PubMed Web of Science 17. Berman , H. M. , Westbrook , J. , Feng , Z. , Gilliland , G. , Bhat , T. N. , Weissig , H. , Shindyalov , I. N. , & Bourne , P. E . ( 2000b ). The Protein Data Bank . Nucleic Acids Research , 28 ( 1 ), 235 – 242 . doi: 10.1093/NAR/28.1.235 OpenUrl CrossRef PubMed Web of Science 18. ↵ Blasco , V. , Pinto , F. M. , Fernández-Atucha , A. , González-Ravina , C. , Fernández-Sánchez , M. , & Candenas , L . ( 2020 ). Female infertility is associated with an altered expression of the neurokinin B/neurokinin B receptor and kisspeptin/kisspeptin receptor systems in ovarian granulosa and cumulus cells . Fertility and Sterility , 114 ( 4 ). doi: 10.1016/j.fertnstert.2020.05.006 OpenUrl CrossRef 19. Bouaziz , J. , Bar On , A. , Seidman , D. S. , & Soriano , D. ( 2017 ). The Clinical Significance of Endocannabinoids in Endometriosis Pain Management . In Cannabis and cannabinoid research (Vol. 2 , Issue 1 ). doi: 10.1089/can.2016.0035 OpenUrl CrossRef 20. Bromberger , J. T. , Matthews , K. A. , Kuller , L. H. , Wing , R. R. , Meilahn , E. N. , & Plantinga , P . ( 1997 ). Prospective study of the determinants of age at menopause . American Journal of Epidemiology , 145 ( 2 ). doi: 10.1093/oxfordjournals.aje.a009083 OpenUrl CrossRef PubMed Web of Science 21. ↵ Brooks , A. K. , Lawson , M. A. , Smith , R. A. , Janda , T. M. , Kelley , K. W. , & McCusker , R. H . ( 2016 ). Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus . Journal of Neuroinflammation , 13 ( 1 ). doi: 10.1186/s12974-016-0563-1 OpenUrl CrossRef 22. Brown , J. S. ( 2009 ). Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: An endocrine-disruption theory of schizophrenia . In Schizophrenia Bulletin (Vol. 35 , Issue 1 ). doi: 10.1093/schbul/sbm147 OpenUrl CrossRef PubMed Web of Science 23. Cai , P. , Li , G. , Wu , M. , Zhang , B. , & Bai , H . ( 2021 ). ZIC2 upregulates lncRNA SNHG12 expression to promote endometrial cancer cell proliferation and migration by activating the Notch signaling pathway . Molecular Medicine Reports , 24 ( 3 ). doi: 10.3892/mmr.2021.12271 OpenUrl CrossRef 24. Casteel , C. O. , & Singh , G . ( 2022 ). Physiology, Gonadotropin-Releasing Hormone . In StatPearls . 25. Chang , L. , Yuan , Z. , Shi , H. , Bian , Y. , & Guo , R . ( 2017 ). miR-145 targets the SOX11 3’UTR to suppress endometrial cancer growth . American Journal of Cancer Research , 7 ( 11 ). OpenUrl 26. ↵ Chou , C. K. , Huang , H. W. , Yang , C. F. , Dahms , H. U. , Liang , S. S. , Wang , T. N. , Kuo , P. L. , Hsi , E. , Tsai , E. M. , & Chiu , C. C . ( 2019 ). Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes . Environmental Toxicology , 34 ( 4 ). doi: 10.1002/tox.22694 OpenUrl CrossRef 27. Ensembl genome browser 112 . (n.d.). Retrieved July 17, 2024, from https://www.ensembl.org/index.html 28. ↵ Ernst , J. , Grabiec , U. , Falk , K. , Dehghani , F. , & Schaedlich , K . ( 2020 ). The endocrine disruptor DEHP and the ECS: Analysis of a possible crosstalk . Endocrine Connections , 9 ( 2 ). doi: 10.1530/EC-19-0548 OpenUrl CrossRef 29. ↵ Forner-Piquer , I. , Santangeli , S. , Maradonna , F. , Verde , R. , Piscitelli , F. , di Marzo , V. , Habibi , H. R. , & Carnevali , O. ( 2018 ). Role of Bisphenol A on the Endocannabinoid System at central and peripheral levels: Effects on adult female zebrafish . Chemosphere , 205 . doi: 10.1016/j.chemosphere.2018.04.078 OpenUrl CrossRef 30. García-Gómez , E. , Vázquez-Martínez , E. R. , Reyes-Mayoral , C. , Cruz-Orozco , O. P. , Camacho-Arroyo , I. , & Cerbón , M . ( 2020 ). Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis . In Frontiers in Endocrinology (Vol. 10 ). doi: 10.3389/fendo.2019.00935 OpenUrl CrossRef PubMed 31. ↵ Gillespie , M. , Jassal , B. , Stephan , R. , Milacic , M. , Rothfels , K. , Senff-Ribeiro , A. , Griss , J. , Sevilla , C. , Matthews , L. , Gong , C. , Deng , C. , Varusai , T. , Ragueneau , E. , Haider , Y. , May , B. , Shamovsky , V. , Weiser , J. , Brunson , T. , Sanati , N. , … D’Eustachio , P . ( 2022 ). The reactome pathway knowledgebase 2022 . Nucleic Acids Research , 50 ( D1 ). doi: 10.1093/nar/gkab1028 . OpenUrl CrossRef PubMed 32. Graceli , J. B. , Dettogni , R. S. , Merlo , E. , Niño , O. , da Costa , C. S. , Zanol , J. F. , Ríos Morris , E. A. , Miranda-Alves , L. , & Denicol , A. C. ( 2020 ). The impact of endocrine-disrupting chemical exposure in the mammalian hypothalamic-pituitary axis . In Molecular and Cellular Endocrinology (Vol. 518 ). doi: 10.1016/j.mce.2020.110997 OpenUrl CrossRef PubMed 33. ↵ Hansel , M. C. , Rosenberg , A. M. , Kinkade , C. W. , Capurro , C. , Rivera-Núñez , Z. , & Barrett , E. S . ( 2024 ). Exposure to Synthetic Endocrine-Disrupting Chemicals in Relation to Maternal and Fetal Sex Steroid Hormones: A Scoping Review . Current Environmental Health Reports , 11 ( 3 ), 356 – 379 . doi: 10.1007/S40572-024-00455-6/FIGURES/1 OpenUrl CrossRef PubMed 34. ↵ Harris , K. , & Nielsen , R . ( 2016 ). The genetic cost of Neanderthal introgression . Genetics , 203 ( 2 ), 881 – 891 . Link OpenUrl Abstract / FREE Full Text 35. Home - GraphPad . (n.d.). Retrieved July 17, 2024, from https://www.graphpad.com/ 36. Hu , K. L. , Zhao , H. , Chang , H. M. , Yu , Y. , & Qiao , J. ( 2018 ). Kisspeptin/kisspeptin receptor system in the ovary . In Frontiers in Endocrinology (Vol. 8, Issue JAN). doi: 10.3389/fendo.2017.00365 OpenUrl CrossRef 37. Huang , P. , Deng , W. , Bao , H. , Lin , Z. , Liu , M. , Wu , J. , Zhou , X. , Qiao , M. , Yang , Y. , Cai , H. , Rao , F. , Chen , J. , Chen , D. , Lu , J. , Wang , H. , Qin , A. , & Kong , S . ( 2022 ). SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization . ELife , 11 . doi: 10.7554/eLife.72073 OpenUrl CrossRef 38. Huang , Q. F. , Jiang , B. , Yang , X. , Yu , B. , & Hu , X. P . ( 2023 ). Primary versus secondary cutaneous endometriosis: Literature review and case study . Heliyon , 9 ( 10 ). doi: 10.1016/j.heliyon.2023.e20094 OpenUrl CrossRef 39. ↵ Incognito , G. G. , di Guardo , F. , Gulino , F. A. , Genovese , F. , Benvenuto , D. , Lello , C. , & Palumbo , M. ( 2023 ). Interleukin-6 as A Useful Predictor of Endometriosis-Associated Infertility: A Systematic Review . International Journal of Fertility & Sterility , 17 ( 4 ), 226 . doi: 10.22074/IJFS.2023.557683.1329 OpenUrl CrossRef PubMed 40. ↵ Jayapalan , S. , Subramanian , D. , & Natarajan , J . ( 2016 ). Computational identification and analysis of neurodegenerative disease associated protein kinases in hominid genomes . Genes and Diseases , 3 ( 3 ). doi: 10.1016/j.gendis.2016.04.004 OpenUrl CrossRef 41. Joseph , N. , Reicher , B. , & Barda-Saad , M. ( 2014 ). The calcium feedback loop and T cell activation: How cytoskeleton networks control intracellular calcium flux . In Biochimica et Biophysica Acta - Biomembranes (Vol. 1838 , Issue 2 ). doi: 10.1016/j.bbamem.2013.07.009 OpenUrl CrossRef PubMed Web of Science 42. ↵ Kanellopoulos , D. , Karagianni , D. , Pergialiotis , V. , Patsouras , G. , Patsouras , K. , Nikiteas , N. , Lazaris , A. C. , & Iliopoulos , D . ( 2022 ). The interplay between endometriosis and fertility in rats: a systematic review . In Journal of Medicine and Life (Vol. 15 , Issue 6 ). doi: 10.25122/jml-2021-0329 OpenUrl CrossRef 43. ↵ Kang , S. Y. , Song , J. Y. , & Cho , H. H . ( 2014 ). Gene expression analysis of uterine smooth muscle cells exposed to bisphenol A . Toxicology and Environmental Health Sciences , 6 ( 4 ). doi: 10.1007/s13530-014-0215-8 OpenUrl CrossRef 44. Kao , L. C. , Germeyer , A. , Tulac , S. , Lobo , S. , Yang , J. P. , Taylor , R. N. , Osteen , K. , Lessey , B. A. , & Giudice , L. C . ( 2003 ). Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease. Based implantation failure and infertility . Endocrinology , 144 ( 7 ). doi: 10.1210/en.2003-0043 OpenUrl CrossRef PubMed Web of Science 45. Kim , J. , Chung , J. Y. , Hwang , J. R. , Lee , Y. Y. , Kim , T. J. , Lee , J. W. , Kim , B. G. , Bae , D. S. , Choi , C. H. , & Hewitt , S. M . ( 2020 ). Identification of candidate genes associated with susceptibility to ovarian clear cell adenocarcinoma using cis-eQTL analysis . Journal of Clinical Medicine , 9 ( 4 ). doi: 10.3390/jcm9041137 OpenUrl CrossRef 46. Kong , Y. , Shao , Y. , Ren , C. , & Yang , G. ( 2021 ). Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis . In Stem Cell Research and Therapy (Vol. 12 , Issue 1 ). doi: 10.1186/s13287-021-02526-z OpenUrl CrossRef 47. ↵ la Merrill , M. A. , Vandenberg , L. N. , Smith , M. T. , Goodson , W. , Browne , P. , Patisaul , H. B. , Guyton , K. Z. , Kortenkamp , A. , Cogliano , V. J. , Woodruff , T. J. , Rieswijk , L. , Sone , H. , Korach , K. S. , Gore , A. C. , Zeise , L. , & Zoeller , R. T. ( 2020 ). Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification . Nature Reviews Endocrinology , 16 ( 1 ). doi: 10.1038/s41574-019-0273-8 OpenUrl CrossRef PubMed 48. ↵ Lee , S. H. , Harold , D. , Nyholt , D. R. , Goddard , M. E. , Zondervan , K. T. , Williams , J. , Montgomery , G. W. , Wray , N. R. , & Visscher , P. M . ( 2013 ). Estimation and partitioning of polygenic variation captured by common snps for alzheimer’s disease, multiple sclerosis and endometriosis . Human Molecular Genetics , 22 ( 4 ). doi: 10.1093/hmg/dds491 OpenUrl CrossRef PubMed Web of Science 49. Li , C. , Zhao , H. L. , Li , Y. J. , Zhang , Y. Y. , Liu , H. Y. , Feng , F. Z. , & Yan , H . ( 2021 ). The expression and significance of leukemia inhibitory factor, interleukin-6 and vascular endothelial growth factor in Chinese patients with endometriosis . Archives of Gynecology and Obstetrics , 304 ( 1 ), 163 – 170 . doi: 10.1007/S00404-021-05980-5/TABLES/5 OpenUrl CrossRef PubMed 50. ↵ Lichtensteiger , W. , Bassetti-Gaille , C. , Rehrauer , H. , Georgijevic , J. K. , Tresguerres , J. A. F. , & Schlumpf , M . ( 2021 ). Converging Effects of Three Different Endocrine Disrupters on Sox and Pou Gene Expression in Developing Rat Hippocampus: Possible Role of microRNA in Sex Differences . Frontiers in Genetics , 12 . doi: 10.3389/fgene.2021.718796 OpenUrl CrossRef 51. Lingegowda , H. , Williams , B. J. , Spiess , K. G. , Sisnett , D. J. , Lomax , A. E. , Koti , M. , & Tayade , C . ( 2022 ). Role of the endocannabinoid system in the pathophysiology of endometriosis and therapeutic implications . In Journal of Cannabis Research (Vol. 4 , Issue 1 ). doi: 10.1186/s42238-022-00163-8 OpenUrl CrossRef 52. Liu , C. F. , & Lefebvre , V . ( 2015 ). The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis . Nucleic Acids Research , 43 ( 17 ). doi: 10.1093/nar/gkv688 OpenUrl CrossRef PubMed 53. Liu , Z. , Lu , Y. , Zhong , K. , Wang , C. , & Xu , X. ( 2022 ). The associations between endocrine disrupting chemicals and markers of inflammation and immune responses: A systematic review and meta-analysis . In Ecotoxicology and Environmental Safety (Vol. 234 ). doi: 10.1016/j.ecoenv.2022.113382 OpenUrl CrossRef 54. ↵ Luo , Z. , Gao , X. , Lin , C. , Smith , E. R. , Marshall , S. A. , Swanson , S. K. , Florens , L. , Washburn , M. P. , & Shilatifard , A . ( 2015 ). Zic2 is an enhancer-binding factor required for embryonic stem cell specification . Molecular Cell , 57 ( 4 ). doi: 10.1016/j.molcel.2015.01.007 OpenUrl CrossRef PubMed 55. Machiela , M. J. , & Chanock , S. J . ( 2015 ). LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants . Bioinformatics , 31 ( 21 ). doi: 10.1093/bioinformatics/btv402 OpenUrl CrossRef PubMed 56. Machiela , M. J. , & Chanock , S. J . ( 2018 ). LDassoc: An online tool for interactively exploring genome-wide association study results and prioritizing variants for functional investigation . Bioinformatics , 34 ( 5 ). doi: 10.1093/bioinformatics/btx561 OpenUrl CrossRef PubMed 57. Mathew , D. , Drury , J. A. , Valentijn , A. J. , Vasieva , O. , & Hapangama , D. K . ( 2016 ). In silico, in vitro and in vivo analysis identifies a potential role for steroid hormone regulation of FOXD3 in endometriosis-associated genes . Human Reproduction , 31 ( 2 ). doi: 10.1093/humrep/dev307 OpenUrl CrossRef PubMed 58. Matta , K. , Koual , M. , Ploteau , S. , Coumoul , X. , Audouze , K. , Bizec , B. le , Antignac , J. P. , & Cano-Sancho , G . ( 2021 ). Associations between exposure to organochlorine chemicals and endometriosis: A systematic review of experimental studies and integration of epidemiological evidence . In Environmental Health Perspectives (Vol. 129, Issue 7). doi: 10.1289/EHP8421 OpenUrl CrossRef 59. Mei , J. , Jin , L. P. , Ding , D. , Li , M. Q. , Li , D. J. , & Zhu , X. Y . ( 2012 ). Inhibition of IDO1 suppresses cyclooxygenase-2 and matrix metalloproteinase-9 expression and decreases proliferation, adhesion and invasion of endometrial stromal cells . Molecular Human Reproduction , 18 ( 10 ). doi: 10.1093/molehr/gas021 OpenUrl CrossRef PubMed Web of Science 60. ↵ Mei , J. , Li , M. Q. , Ding , D. , Li , D. J. , Jin , L. P. , Hu , W. G. , & Zhu , X. Y . ( 2013 ). Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway . International Journal of Clinical and Experimental Pathology , 6 ( 3 ), 431 . /pmc/articles/PMC3563200/ OpenUrl 61. Merrill , A. K. , Sobolewski , M. , & Susiarjo , M . ( 2023 ). Exposure to endocrine disrupting chemicals impacts immunological and metabolic status of women during pregnancy . Molecular and Cellular Endocrinology , 577 . doi: 10.1016/j.mce.2023.112031 OpenUrl CrossRef 62. ↵ Moghaddam , M. Z. , Ansariniya , H. , Seifati , S. M. , Zare , F. , & Fesahat , F . ( 2022 ). Immunopathogenesis of endometriosis: An overview of the role of innate and adaptive immune cells and their mediators . In American Journal of Reproductive Immunology (Vol. 87 , Issue 5 ). doi: 10.1111/aji.13537 OpenUrl CrossRef 63. Moise-Silverman , J. , & Silverman , L. A. ( 2022 ). A review of the genetics and epigenetics of central precocious puberty . In Frontiers in Endocrinology (Vol. 13 ). doi: 10.3389/fendo.2022.1029137 OpenUrl CrossRef 64. Moreno , C. S. ( 2020 ). SOX4: The unappreciated oncogene . In Seminars in Cancer Biology (Vol. 67 ). doi: 10.1016/j.semcancer.2019.08.027 OpenUrl CrossRef PubMed 65. Myers , T. A. , Chanock , S. J. , & Machiela , M. J . ( 2020 ). LDlinkR: An R Package for Rapidly Calculating Linkage Disequilibrium Statistics in Diverse Populations . Frontiers in Genetics , 11 . doi: 10.3389/fgene.2020.00157 OpenUrl CrossRef PubMed 66. Nassar , L. R. , Barber , G. P. , Benet-Pagès , A. , Casper , J. , Clawson , H. , Diekhans , M. , Fischer , C. , Gonzalez , J. N. , Hinrichs , A. S. , Lee , B. T. , Lee , C. M. , Muthuraman , P. , Nguy , B. , Pereira , T. , Nejad , P. , Perez , G. , Raney , B. J. , Schmelter , D. , Speir , M. L. , … Kent , W. J . ( 2023a ). The UCSC Genome Browser database: 2023 update . Nucleic Acids Research , 51 ( D1 ), D1188 – D1195 . doi: 10.1093/NAR/GKAC1072 OpenUrl CrossRef PubMed 67. Nassar , L. R. , Barber , G. P. , Benet-Pagès , A. , Casper , J. , Clawson , H. , Diekhans , M. , Fischer , C. , Gonzalez , J. N. , Hinrichs , A. S. , Lee , B. T. , Lee , C. M. , Muthuraman , P. , Nguy , B. , Pereira , T. , Nejad , P. , Perez , G. , Raney , B. J. , Schmelter , D. , Speir , M. L. , … Kent , W. J . ( 2023b ). The UCSC Genome Browser database: 2023 update . Nucleic Acids Research , 51 ( D1 ), D1188 – D1195 . doi: 10.1093/NAR/GKAC1072 OpenUrl CrossRef PubMed 68. National Library of Medicine - National Institutes of Health. (n.d.). 69. ↵ Nnoaham , K. E. , Hummelshoj , L. , Webster , P. , D’Hooghe , T ., de Cicco Nardone , F ., de Cicco Nardone , C ., Jenkinson , C. , Kennedy , S. H. , & Zondervan , K. T. ( 2011 ). World Endometriosis Research Foundation Global Study of Women’s Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries . Fertility and Sterility , 96 ( 2 ). OpenUrl PubMed 70. ↵ Parazzini , F. , Roncella , E. , Cipriani , S. , Trojano , G. , Barbera , V. , Herranz , B. , & Colli , E . ( 2020 ). The frequency of endometriosis in the general and selected populations: A systematic review . In Journal of Endometriosis and Pelvic Pain Disorders (Vol. 12 , Issues 3–4). doi: 10.1177/2284026520933141 OpenUrl CrossRef 71. ↵ Patel , B. G. , Lenk , E. E. , Lebovic , D. I. , Shu , Y. , Yu , J. , & Taylor , R. N. ( 2018 ). Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways . In Best Practice and Research: Clinical Obstetrics and Gynaecology (Vol. 50 ). doi: 10.1016/j.bpobgyn.2018.01.006 OpenUrl CrossRef PubMed 72. Qin , W. , Yuan , Q. , Liu , Y. , Zeng , Y. , ke , D ., Dai , X. , Shuai , Y. , Hu , J. , & Shi , H . ( 2021 ). Identification of key molecular markers in epithelial ovarian cancer by integrated bioinformatics analysis . Taiwanese Journal of Obstetrics and Gynecology , 60 ( 6 ). doi: 10.1016/j.tjog.2021.09.007 OpenUrl CrossRef 73. Qu , M. , Zhu , Y. , & Jin , M . ( 2018 ). MicroRNA-138 inhibits SOX12 expression and the proliferation, invasion and migration of ovarian cancer cells . Experimental and Therapeutic Medicine , 16 ( 3 ). doi: 10.3892/etm.2018.6375 OpenUrl CrossRef 74. Rahaman , O. , & Ganguly , D. ( 2021 ). Endocannabinoids in immune regulation and immunopathologies . In Immunology (Vol. 164 , Issue 2 ). doi: 10.1111/imm.13378 OpenUrl CrossRef 75. ↵ Rahmioglu , N. , Mortlock , S. , Ghiasi , M. , Møller , P. L. , Stefansdottir , L. , Galarneau , G. , Turman , C. , Danning , R. , Law , M. H. , Sapkota , Y. , Christofidou , P. , Skarp , S. , Giri , A. , Banasik , K. , Krassowski , M. , Lepamets , M. , Marciniak , B. , Nõukas , M. , Perro , D. , … Zondervan , K. T . ( 2023 ). The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions . Nature Genetics , 55 ( 3 ). doi: 10.1038/s41588-023-01323-z OpenUrl CrossRef PubMed 76. Ruiz , T. F. R. , Taboga , S. R. , & Leonel , E. C. R. ( 2021 ). Molecular mechanisms of mammary gland remodeling: A review of the homeostatic versus bisphenol a disrupted microenvironment . In Reproductive Toxicology (Vol. 105 ). doi: 10.1016/j.reprotox.2021.07.011 OpenUrl CrossRef 77. ↵ Saha , R. , Pettersson , H. J. , Svedberg , P. , Olovsson , M. , Bergqvist , A. , Marions , L. , Tornvall , P. , & Kuja-Halkola , R . ( 2015 ). Heritability of endometriosis . Fertility and Sterility , 104 ( 4 ). doi: 10.1016/j.fertnstert.2015.06.035 OpenUrl CrossRef PubMed 78. ↵ Sankararaman , S. , Mallick , S. , Patterson , N. , & Reich , D . ( 2014 ). The genomic landscape of Neanderthal ancestry in present-day humans . Nature , 507 ( 7492 ), 354 – 357 . Link OpenUrl CrossRef PubMed Web of Science 79. ↵ Santoso , B. , Sa’adi , A. , Dwiningsih , S. R. , Tunjungseto , A. , Widyanugraha , M. Y. A. , Mufid , A. F. , Rahmawati , N. Y. , & Ahsan , F . ( 2020 ). Soluble immune checkpoints CTLA-4, HLA-G, PD-1, and PD-L1 are associated with endometriosis-related infertility . American Journal of Reproductive Immunology , 84 ( 4 ). doi: 10.1111/aji.13296 OpenUrl CrossRef 80. ↵ Sapkota , Y. , Steinthorsdottir , V. , Morris , A. P. , Fassbender , A. , Rahmioglu , N. , de Vivo , I. , Buring , J. E. , Zhang , F. , Edwards , T. L. , Jones , S. , Dorien , O. , Peterse , D. , Rexrode , K. M. , Ridker , P. M. , Schork , A. J. , MacGregor , S. , Martin , N. G. , Becker , C. M. , Adachi , S. , … Nyholt , D. R. ( 2017 ). Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism . Nature Communications , 8 . doi: 10.1038/ncomms15539 OpenUrl CrossRef PubMed 81. Schock , E. N. , & LaBonne , C. ( 2020 ). Sorting Sox: Diverse Roles for Sox Transcription Factors During Neural Crest and Craniofacial Development . In Frontiers in Physiology (Vol. 11 ). doi: 10.3389/fphys.2020.606889 OpenUrl CrossRef PubMed 82. Shan , T. , Uyar , D. S. , Wang , L. S. , Mutch , D. G. , Huang , T. H. M. , Rader , J. S. , Sheng , X. , & Huang , Y. W . ( 2019 ). SOX11 hypermethylation as a tumor biomarker in endometrial cancer . Biochimie , 162 . doi: 10.1016/j.biochi.2019.03.019 OpenUrl CrossRef PubMed 83. Sherry , S. T. , Ward , M. , & Sirotkin , K. ( 1999 ). dbSNP - database for single nucleotide polymorphisms and other classes of minor genetic variation . In Genome Research (Vol. 9 , Issue 8 ). doi: 10.1101/gr.9.8.677 OpenUrl FREE Full Text 84. ↵ Shi , J. Y. , Paredes Mogica , J. A. , & De , E. J. B. ( 2022 ). Non-Surgical Management of Chronic Pelvic Pain in Females . In Current Urology Reports (Vol. 23 , Issue 10 ). doi: 10.1007/s11934-022-01110-z OpenUrl CrossRef 85. SNPedia . (n.d.). Retrieved July 17, 2024, from https://www.snpedia.com/ 86. ↵ Sobstyl , A. , Chałupnik , A. , Mertowska , P. , & Grywalska , E . ( 2023 ). How Do Microorganisms Influence the Development of Endometriosis? Participation of Genital, Intestinal and Oral Microbiota in Metabolic Regulation and Immunopathogenesis of Endometriosis . In International Journal of Molecular Sciences (Vol. 24 , Issue 13 ). doi: 10.3390/ijms241310920 OpenUrl CrossRef 87. Song , Y. , Fu , J. , Zhou , M. , Xiao , L. , Feng , X. , Chen , H. , & Huang , W . ( 2016 ). Activated Hippo/Yes-associated protein pathway promotes cell proliferation and anti-apoptosis in endometrial stromal cells of endometriosis . Journal of Clinical Endocrinology and Metabolism , 101 ( 4 ). doi: 10.1210/jc.2016-1120 OpenUrl CrossRef PubMed 88. Szklarczyk , D. , Kirsch , R. , Koutrouli , M. , Nastou , K. , Mehryary , F. , Hachilif , R. , Gable , A. L. , Fang , T. , Doncheva , N. T. , Pyysalo , S. , Bork , P. , Jensen , L. J. , & von Mering , C. ( 2023 ). The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest . Nucleic Acids Research , 51 ( 1 D ), D638 – D646 . doi: 10.1093/NAR/GKAC1000 OpenUrl CrossRef PubMed 89. ↵ Tamura , H. , Yoshida , H. , Kikuchi , H. , Josaki , M. , Mihara , Y. , Shirafuta , Y. , Shinagawa , M. , Tamura , I. , Taketani , T. , Takasaki , A. , & Sugino , N . ( 2019 ). The clinical outcome of Dienogest treatment followed by in vitro fertilization and embryo transfer in infertile women with endometriosis . Journal of Ovarian Research , 12 ( 1 ). doi: 10.1186/s13048-019-0597-y OpenUrl CrossRef 90. Tanha , M. , Bozorgmehr , M. , Shokri , M. R. , Edalatkhah , H. , Tanha , M. , Zarnani , A. H. , & Nikoo , S . ( 2022 ). 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin potential impacts on peripheral blood mononuclear cells of endometriosis women . Journal of Reproductive Immunology , 149 . doi: 10.1016/j.jri.2021.103439 OpenUrl CrossRef 91. The National Genomic Research Library v5.1, Genomics England . doi: 10.6084/m9.figshare.4530893.v7 OpenUrl CrossRef 92. ↵ Treloar , S. A. , O’Connor , D. T. , O’Connor , V. M. , & Martin , N. G . ( 1999 ). Genetic influences on endometriosis in an Australian twin sample . Fertility and Sterility , 71 ( 4 ). doi: 10.1016/S0015-0282(98)00540-8 OpenUrl CrossRef PubMed Web of Science 93. ↵ Velarde MC , Bucu MEM , Habana MAE . Endometriosis as a highly relevant yet neglected gynecologic condition in Asian women . Endocr Connect . 2023 Oct 5; 12 ( 11 ): e230169 . doi: 10.1530/EC-23-0169 . PMID: 37676242 ; PMCID: PMC10563646 OpenUrl CrossRef PubMed 94. ↵ Verma , H. , Kaur , S. , Kaur , S. , Gangwar , P. , Dhiman , M. , & Mantha , A. K. ( 2024 ). Role of Cytoskeletal Elements in Regulation of Synaptic Functions: Implications Toward Alzheimer’s Disease and Phytochemicals-Based Interventions . In Molecular Neurobiology . doi: 10.1007/s12035-024-04053-3 OpenUrl CrossRef 95. Wasik , A. M. , Nygren , L. , Almestrand , S. , Zong , F. , Flygare , J. , Wennerholm , S. B. , Saft , L. , Andersson , P. , Kimby , E. , Wahlin , B. E. , Christensson , B. , & Sander , B . ( 2014 ). Perturbations of the endocannabinoid system in mantle cell lymphoma: Correlations to clinical and pathological features . Oncoscience , 1 ( 8 ). doi: 10.18632/oncoscience.77 OpenUrl CrossRef 96. ↵ Xie , Q. , Kang , Y. , Zhang , C. , Xie , Y. , Wang , C. , Liu , J. , Yu , C. , Zhao , H. , & Huang , D. ( 2022 ). The Role of Kisspeptin in the Control of the Hypothalamic-Pituitary-Gonadal Axis and Reproduction . In Frontiers in Endocrinology (Vol. 13 ). doi: 10.3389/fendo.2022.925206 OpenUrl CrossRef 97. ↵ Yamamoto , A. , Harris , H. R. , Vitonis , A. F. , Chavarro , J. E. , & Missmer , S. A . ( 2019 ). Epidemiologic factors associated with endometriosis in East Asia . Global Medical Discovery , 8 ( 1 ), 1 – 10 . OpenUrl 98. ↵ Yen , C. F. , Kim , M. R. , & Lee , C. L. ( 2019 ). Epidemiologic factors associated with endometriosis in East Asia . In Gynecology and Minimally Invasive Therapy (Vol. 8 , Issue 1 ). doi: 10.4103/GMIT.GMIT_83_18 OpenUrl CrossRef 99. You , H. H. , & Song , G. ( 2021 ). Review of endocrine disruptors on male and female reproductive systems . In Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology (Vol. 244 ). doi: 10.1016/j.cbpc.2021.109002 OpenUrl CrossRef 100. ↵ Zeberg , H. , & Pääbo , S . ( 2020 ). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals . Nature , 587 ( 7835 ), 610 – 612 . Link OpenUrl CrossRef PubMed 101. Zhang , D. , Li , Y. , Tian , J. , Zhang , H. , & Wang , S . ( 2015 ). MiR-202 promotes endometriosis by regulating SOX6 expression . International Journal of Clinical and Experimental Medicine , 8 ( 10 ). OpenUrl 102. Zhang , J. , Liu , Y. , Zhi , X. , Xu , L. , Tao , J. , Cui , D. , & Liu , T. F . ( 2024 ). Tryptophan catabolism via the kynurenine pathway regulates infection and inflammation: from mechanisms to biomarkers and therapies . Inflammation Research 2024 73:6, 73 ( 6 ), 979 – 996 . doi: 10.1007/S00011-024-01878-5 OpenUrl CrossRef PubMed 103. ↵ Zhang , X. , Witt , K. E. , Bañuelos , M. M. , Ko , A. , Yuan , K. , Xu , S. , Nielsen , R. , & Huerta-Sanchez , E . ( 2021 ). The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans . Proceedings of the National Academy of Sciences of the United States of America , 118 ( 22 ). doi: 10.1073/pnas.2020803118 OpenUrl Abstract / FREE Full Text 104. ↵ Zhang , Y. , Xiao , X. , Xu , F. , Lin , Q. , Xu , J. , & Du , B . ( 2019 ). Evaluation of uterosacral ligament involvement in deep endometriosis by transvaginal ultrasonography . Frontiers in Pharmacology , 10 ( APR ). doi: 10.3389/fphar.2019.00374 OpenUrl CrossRef 105. Zhao , H. , Liu , S. , Ma , C. , Ma , S. , Chen , G. , Yuan , L. , Chen , L. , & Zhao , H . ( 2019 ). Estrogen-related receptor γ induces angiogenesis and extracellular matrix degradation of temporomandibular joint osteoarthritis in rats . Frontiers in Pharmacology , 10 . doi: 10.3389/fphar.2019.01290 OpenUrl CrossRef 106. ↵ Zhou , Z. , Swagemakers , S. M. A. , Lourens , M. S. , Suratannon , N. , der Spek , P. J. V. , Dalm , V. A. S. H. , Dik , W. A. , Ijspeert , H. , & Hagen , P. M. van . ( 2022 ). Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals? Asian Pacific Journal of Allergy and Immunology , 40 ( 4 ). doi: 10.12932/ap-251022-1489 OpenUrl CrossRef 107. Ziarniak , K. , Yang , T. , Boycott , C. , Beetch , M. , Sassek , M. , Grzeda , E. , Ma , Y. , Sliwowska , J. H. , & Stefanska , B . ( 2022 ). DNA hypermethylation of Kiss1r promoter and reduction of hepatic Kiss1r in female rats with type 2 diabetes . Epigenetics , 17 ( 13 ). doi: 10.1080/15592294.2022.2119120 OpenUrl CrossRef 108. ↵ Zondervan , K. T. , Becker , C. M. , Koga , K. , Missmer , S. A. , Taylor , R. N. , & Viganò , P . ( 2018 ). Endometriosis . Nature Reviews. Disease Primers , 4 ( 1 ). doi: 10.1038/S41572-018-0008-5 OpenUrl CrossRef 109. Zou , G. , Wang , J. , Xu , X. , Xu , P. , Zhu , L. , Yu , Q. , Peng , Y. , Guo , X. , Li , T. , & Zhang , X . ( 2020 ). A comprehensive cell profiling reveals new cell subtypes and immune dysfunction in peritoneal fluid of endometriosis . doi: 10.21203/RS.3.RS-89810/V1 . OpenUrl CrossRef View the discussion thread. Back to top Previous Next Posted April 19, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants Amelia Warren , Demetra Andreou , Dean Warren , Jack Wieland , Anna Mantzouratou medRxiv 2025.04.15.25324328; doi: https://doi.org/10.1101/2025.04.15.25324328 Share This Article: Copy Citation Tools Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants Amelia Warren , Demetra Andreou , Dean Warren , Jack Wieland , Anna Mantzouratou medRxiv 2025.04.15.25324328; doi: https://doi.org/10.1101/2025.04.15.25324328 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Sexual and Reproductive Health Subject Areas All Articles Addiction Medicine (578) Allergy and Immunology (869) Anesthesia (306) Cardiovascular Medicine (4498) Dentistry and Oral Medicine (450) Dermatology (385) Emergency Medicine (616) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1532) Epidemiology (15310) Forensic Medicine (31) Gastroenterology (1136) Genetic and Genomic Medicine (6665) Geriatric Medicine (674) Health Economics (1007) Health Informatics (4628) Health Policy (1381) Health Systems and Quality Improvement (1632) Hematology (546) HIV/AIDS (1279) Infectious Diseases (except HIV/AIDS) (15974) Intensive Care and Critical Care Medicine (1114) Medical Education (627) Medical Ethics (147) Nephrology (679) Neurology (6724) Nursing (347) Nutrition (1008) Obstetrics and Gynecology (1154) Occupational and Environmental Health (962) Oncology (3376) Ophthalmology (989) Orthopedics (370) Otolaryngology (423) Pain Medicine (440) Palliative Medicine (131) Pathology (672) Pediatrics (1708) Pharmacology and Therapeutics (701) Primary Care Research (720) Psychiatry and Clinical Psychology (5509) Public and Global Health (9307) Radiology and Imaging (2235) Rehabilitation Medicine and Physical Therapy (1378) Respiratory Medicine (1202) Rheumatology (598) Sexual and Reproductive Health (724) Sports Medicine (537) Surgery (725) Toxicology (101) Transplantation (291) Urology (268) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a094a6b1fba6c89d',t:'MTc4MTA1NTQ0OQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();