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

Endometriosis is defined as the ectopic growth of endometrium-like tissue. It brings pain and infertility to approximately 6–10% of women who are in reproductive age. The pathogenesis of endometriosis is still unclear, which also leads to underdiagnosis and delay in clinical diagnosis. Growing evidence suggests that endometriosis is associated with genetic, environmental, and epigenetic factors. It is valuable to discuss the potential impact of environmental factors in the development of endometriosis. Drug intervention can target the enzymes responsible for epigenetic alterations based on the controllability and reversibility of these features. Additionally, particular epigenetic biomarkers can be employed to diagnose illnesses and determine prognoses. This article discusses the relationship between endometriosis, environmental risk factors and epigenetics and looks forward to how epigenetic technology can be used in the diagnosis and treatment of endometriosis.

- endometriosis - epigenetics - DNA methylation - histone modification - noncoding RNA - environmental exposure - endocrine disruptors 1. Introduction Endometriosis is a multifaceted condition marked by enduring pelvic pain and difficulties in conception. It involves a persistent inflammation triggered by estrogen, impacting mainly the pelvic organs such as the ovaries. This is a result of the endometrial tissue traveling backward and taking root in the lower abdominal area [1]. It exhibits diverse macroscopic features and possesses an intricate natural progression that remains incompletely understood. This condition, marked by hereditary factors and considerable biochemical alterations within the lesions, underscores the complexity of its etiology. Regarding the pathophysiology of endometriosis, multiple hypotheses exist, such as retrograde implantation, body cavity metaplasia, and eutopic endometrial determinism [2]. Numerous investigations have demonstrated the critical role that environmental factors play in the development of endometriosis, but conclusions from different experiments are often not uniform. Female fetuses are often exposed to some drug stimulation A trivial environmental exposure may not be immediately presented in an individual, but it can be magnified under the effect of period; this is just what the hot topic epigenetics targets. We must gain more insight into the processes underlying harmful environmental exposures so that we can prepare prevention strategies in advance. In addition to educating the populace, other measures include limiting exposure, phasing out harmful technologies, and optimizing the application of available natural resources. The article is divided into two aspects of natural environment and social environment, from the physical, chemical, and biological factors and lifestyle, to clarify the environmental exposure risk of endometriosis. Recent research has revealed that endometriosis development and prevalence are regulated by epigenetics. Waddington proposed the word “epigenetic” to identify the molecular mechanisms converting genetic traits into observable phenotypes [9]. Epigenetics is a scientific field exploring hereditary alterations in gene expression. It aims to elucidate how genes’ activity can be modulated despite the organism’s unchanged genome sequence. This burgeoning discipline, often referred to as the study beyond genes, is witnessing significant attention within the scientific community. Unlike genetic alterations, epigenetics operates through diverse avenues, including regulation of DNA methylation, histone modification, and miRNA, which control gene activation or suppression, thereby influencing susceptibility to diseases [10]. These changes have a significant connection with environment, and epigenetic changes caused by early-life exposure can lead to subsequent phenotypic variation. Studies of epigenetic mechanisms in endometriosis can map out associated risk factors and estimate risk factors for essential populations. It is also possible to search for biomarkers and drug targets that create potential therapeutic interventions. Understanding and harnessing epigenetic mechanisms, pivotal for disease management and prevention, are facilitated by ongoing research endeavors in this domain [11]. The interplay of genetic and epigenetic events inherited at birth offers insights into the hereditary predisposition and the manifold alterations in endometrial physiology, immunology, and placental development associated with endometriosis [12]. Recent advancements in understanding epigenetic mechanisms, alongside investigations into environmental influences and intrinsic abnormalities within the endometrium of affected individuals, have supported unraveling the biological basis of this disorder. These insights serve as a basis for developing novel therapeutic interventions targeting disease-related pain and infertility [13]. 2. Association between environmental exposure factors and endometriosis 2.1 Physical Environmental factors could induce endometriosis to a certain extent in many aspects. Among the physical factors, sun exposure and ultraviolet radiation have attracted more attention. A study examining the habits of adults suggests that using tanning beds, wearing sunscreen, and having a history of sunburns can contribute to a higher likelihood of developing endometriosis. In particular, the usage of tanning beds during early adulthood may raise the risk of endometriosis due to the potentially damaging impact of ultraviolet A rays [14]. Additionally, a separate study found that women with endometriosis tend to have a heightened sensitivity to environmental factors and less exposure to sunlight or ultraviolet radiation [15]. There is no definitive answer to the positive or negative effects of UV radiation and sun exposure, but it is clear that this is strongly associated with endometriosis. 2.2 Chemical 2.2.1 EDCs EDCs are a category of external chemical compounds that impact the functioning of the endocrine system. EDCs can interfere with the activity of many physiological processes; their effect depends on the exposure duration and exposure dose and duration. An Italian research project involving 80 reproductive-age women discovered elevated levels of PCBs in the blood serum of individuals with endometriosis [16]. The study’s participants were women who had not given birth. The accumulation of lipophilic environmental toxins in the body may be reduced by the process of childbirth or breastfeeding. Another study, which examined 30 individuals with deep infiltrating endometriosis, revealed higher concentrations of dioxin and PCBs in adipose tissue in comparison to the control group without endometriosis [17]. The link between dioxins and endometriosis is definitely important, but there is still not enough solid evidence from epidemiological studies. Right now, there is a lot of debate and no clear answers. Future research needs to be more thorough, with better strategies for selecting study participants and more accurate statistical methods. Prospective case-control studies with analysis of human samples have shown that women with endometriosis have considerably higher urinary phthalate concentrations than women without the disease [18]. Phthalates may adversely affect fertility by affecting folliculogenesis, oocyte maturation, and embryonic development. Diethylhexyl phthalate (DEHP) is frequently applied in the flexible polyvinyl chloride formula of the plasticizer. This is a ubiquitous environmental contaminant that may have detrimental effects on fertility. Samples of blood and peritoneal fluid were obtained from 24 women without endometriosis and 55 endometriosis-afflicted women. Women with endometriosis had plasma DEHP levels that were substantially higher compared to the control group [19]. The primary application of bisphenol A (BPA) is as a substance in the manufacture of polymers, particularly polycarbonate resins. Plastic bags, bottles, and packaging are made of polycarbonate, which means that BPA exposure tends to occur through diet [20]. As a result, BPA interferes with GnRH’s pulsatile production; the hypothalamic-pituitary-ovarian axis is impacted negatively. Prenatal, perinatal, and postnatal exposure to BPA can damage the steps of the development of ovarian induced functional impairment and may injure the female adult animals and future generations of uterus shape and function [7]. In addition to being responsible for the physiological causes of endometriosis, BPA, phthalates, and perfluoroalkyl substances (PFAS) found in food and water raise the danger in infertility and repeated miscarriage in humans [21]. 2.2.2 Heavy metals Heavy metals are a high-emission pollutant mainly due to the presence of human industrial production. One of the key elements that can lead to human exposure to heavy metals is the overall condition of the surrounding environment [22]. It is well-known that environmental heavy metal exposure will inevitably have a serious impact on female fertility. Cadmium (Cd) is responsible for of both spontaneous abortion and endometriosis. When lead (Pb) quantity rises above a particular point, teratogenic consequences and spontaneous abortion may result. The menstrual cycle is impacted by toxic mercury levels, which may result in infertility [23]. These metals affect the natural regulation of female reproduction at various levels. Studies have been done on the role of Cd, which has potent estrogen-like activity 2.3 Biological factors 2.3.1 Abnormal gut microbiota in patients with EMS The most researched internally region in endometriosis study of the microbiome focuses on the gut microbiota. Many kinds of bacteria make up the gut microbiome, including cyanobacteria, spirochetes, anaerobic microbes, and the gastrointestinal microbiota. By influencing alterations in the metabolome, the gut microbiota can affect the health of the host. Microorganisms help absorb and metabolize nutrients from the intestines, preserve a steady equilibrium in the gut, and support the body’s proper immune system. On the other hand, immune system damage results from upset intestinal flora balance, which lowers the amount of good bacteria and increases the amount of harmful bacteria, eventually triggering an inflammatory reaction. The gut’s abundance and diversification of bacteria produces a range of enzymes that support equilibrium in health. A number of investigations have looked into endometriosis patients’ aberrant gut microbiome. In the condition of disease, the gut microbiome can be transformed into other bacteria [26]. Numerous microbiological abnormalities, including elevated levels of 2.3.2 Persistent inflammation control is influenced by the gut microbiota in EMS Because of an imbalance of immune cell groups and changed cytokines, either systemic or specific immunological systems contribute to the formation and maintenance of endometriotic infections. Immunologic alterations included increased numbers of peritoneal macrophages, decreased T-cell reactivity, and decreased natural killer cell cytotoxicity. In contrast to normal endometrium, several key inflammatory mediators are altered in endometriosis, including elevated COX-2, IL-1β, IL-8, TNF-α, PGE2, and E2. Clear research evidence suggests that immunological factors contribute to the pathophysiology of endometriosis and the resulting infertility. Reduced cytotoxicity of natural killer cells increases the likelihood associated with endometriosis tissue implant [29]. An increasing amount of research has demonstrated that the gut microbiota is centrally regulated in different types of inflammation in addition to being necessary to maintain normal GI tract function. Increased degrees of systemic inflammation are intimately linked to endometriosis development as well as progression [30]. Thus, the gut microbiome has the potential to contribute to endometriosis by promoting or inhibiting inflammatory feedback. Discussions in the context of endometriosis commonly revolve around the theme of inflammation [31]. The presence of lesions triggers an inflammatory reaction, characterized by the early recruitment of activated peritoneal macrophages [32]. While inflammation may contribute to scarring or adhesion formation, milder forms of the disease are often linked to infertility, indicating a secondary endometrial effect arising from this inflammatory cascade [31]. Endometriosis’s pathophysiology hinges significantly on inflammation, characterized by local and systemic symptoms and clinical manifestations. Consequently, inflammatory mediators hold potential as diagnostic biomarkers or therapeutic targets [33]. A specific inflammatory cascade that includes the synthesis of several inflammatory mediators such prostaglandins, chemokines, and cytokines takes place within the endometrium. Chemokines are essential for recruiting T cells, eosinophils, neutrophils, macrophages, and monocytes to the area throughout inflammation [34]. The intricate interplay regulates the acute and chronic stages of the inflammatory procedure, underscoring the complexity of regulatory mechanisms in endometriosis [35]. 2.3.3 Gut microbiota involve in hormonal regulation It has been speculated that normal circulatory estrogen levels in the human system are frequently regulated by the ecological balance in the gut bacteria, but ecological imbalance will disturb this balance and have a negative impact on estrogen [36]. Endometriosis is an estrogen-related disease, and gut can serve as a reservoir for estrogen metabolites capable of acting locally and distally in disease development [37]. The estrogen-gut microbiome axis is formed by the participation of intestinal flora in the estrogen period. The gut microbiota comprises genes linked to glucuronidase activity, such as 3. The social environment factors: potential effects of lifestyle 3.1 Night work and rotating shifts In addition to natural environmental factors, the population is also exposed to a variety of unstable social environments; different lifestyles and eating habits are also predisposing factors affecting endometriosis. An unhealthy lifestyle for professional women, such as irregular night work and rotating shifts, is strongly associated with the chance of developing endometriosis. In case-control research, 235 endometriosis-affected women were questioned about every paid night shift they had worked between the age of 18 and the reference date. Research has indicated that working at night is linked to a 50% increased chance of endometriosis. About twice as many people are in danger of developing the disease if they work in excess of half their night hours [39]. A study of 68 nurses under the age of 40 assessed sleep, menstrual function, and pregnancy outcomes. Sleep time decreased by about 1 hour during night work and time to fall asleep increased. Sleep disturbances may lead to irregular menstruation, which in turn affects hormonal stability, and may be associated with risk factors for endometriosis [40]. To sum up, the gynecological health of women who work and rotate shifts at night needs to be paid more attention. Adopting a reasonable work system and regular working hours may reduce the incidence of endometriosis. Nurses and other staff who have to be engaged in night work can try the flow work system of phased night work and phased normal work to let the body recover. 3.2 Diet: red meat consumption, caffeine intake, trans fatty acids The association between dietary variations and the occurrence of endometriosis has attracted significant attention, mostly because of the discovery that consumption of red meat, caffeine, and trans fatty acids can impact the disease’s biological process. A study published in 2013 evaluated the association between food intake and endometriosis, analyzing the nutrients and food groups involved. The women with endometriosis had diets that included more red meat, coffee, and trans fats, and fewer vegetables than the control group [41]. In contrast to trans fats, intake of omega-3 polyunsaturated fatty acids has been shown to have the efficacy of relieving pain in people suffering from endometriosis, with anti-inflammatory effects [42]. A higher prevalence of endometriosis was shown to be correlated to eating habits containing excessive red meat, whether processed or unprocessed, in the Nurses’ Health Study II, a long-term follow-up of over 82,000 U.S. nurses. The release of heme from red meat, which has a pro-oxidation effect, could be the reason behind this detrimental effect. Patients with endometriosis who drank above 7 g of caffeine monthly had a greater related probability of developing endometriosis, according to a case-control study involving 180 infertile patients (Figure 1) [43]. 4. Epigenetic pathophysiological mechanisms and effects of endometriosis 4.1 DNA methylation DNA methylation refers to the reaction in which some biological molecules increase methyl groups catalyzed by specific enzymes. Although the phenomenon of DNA methylation has long been recognized [44], its specific role was not elucidated until Griffith and Mahler proposed that it could be related to the memory of genes in 1969 [45]. The so-called gene memory in today’s view actually refers to gene regulation without changing the original DNA sequence. DNA methylation is catalyzed by DNA deoxyribonucleic acid methyltransferase (DNMT). In humans, the targets of DNMTs are mainly cytosine in CpG islands. About 70% of gene promoters are located in CpG islands [46], which are highly conserved in evolution, which suggests that CpG islands are important in both gene initiation and transcription. In fact, the methyl group that binds to the CpG island in the promoter region of the gene can make the relevant regions of DNA tightly structured and the expression of the corresponding gene silenced [47]. Thus, hypomethylation is associated with gene expression, while hypermethylation is associated with gene silencing. DNMTS can be classified into three classes: DNMT1, DNMT3A, and DNMT3B. DNMT1 is supposed to have a role in maintaining DNA methylation status; however, DNMT3A and DNMT3B are involved in Endometriosis cannot develop itself without the help of estrogen; at the site of the lesion, high levels of estrogen can be detected [49]. Estrogen acts by binding to the nuclear estrogen receptor, which has two major isoforms: estrogen receptor α (ERα) and receptor β (ERβ), encoded by gene ESR1 and gene ESR2 [50]. The two receptors share 96% similarity in the DNA-binding domain. However, their ligand-binding domains are only 58% in similarity, which implies that the two receptors have very different ligands and very different pathways. It was found that in human gene, ESR1 has three different promoters: promoter A, promoter B, and promoter C; the mRNA generated by these promoters was detected in three different isoforms in endometriosis stromal cells [51]. Through research and comparison, the expression level of ERβ in ectopic endometrium was found abnormally increased; at the same time, the value of ERα: ERβ was significantly lower than what it used to be in normal tissue [52]. Additionally, the study also found that c - MYC, cyclin1, and GREB1 mRNA expression levels were increased [53]. The hypomethylation of the ESR2 promoter region of the ERβ gene may be the best reason to explain the upregulation of ERβ [54]. A large body of evidence suggests that steroid metabolism and related pathways have a close relationship with the developing period of endometriosis [51]. Among them, estradiol (E2) is considered to be the main hormone for the persistence and ectopic growth of endometrial tissue. It was strongly supported by For a long time, progesterone has been considered to have the effect of anti-estrogen, thus applying in the contain of endometrial growth. However, scientists found that many patients are not sensitive to the treatment of progesterone, in other words, the phenomenon of progesterone resistance [57]. In cells, progesterone receptors have two isoforms, PRA and PRB; they are encoded by the same gene located at 11q22-q23, expressing progesterone receptor (PGR). In an Advanced technology allows people to explore more abnormal methylation sites. In addition to the genes above, research also identified TMEM184A, GREM2, SFN, KIR3DX1, HPGD, ESR1, BST2, PIK3CG, and RNASE1 as significant candidate genes associated with ovarian endometriosis [61]. 4.2 Histone modification DNA swirls around histones to form the basic building blocks of chromatin. Histone modification can change the tightness of DNA to inhibit or activate gene expression. The types of histone modification include acetylation, methylation, phosphorylation, ubiquitination, and so forth. Among them, the most in-depth research is based on acetylation and methylation [62]. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) play major roles in histone acetylation. It was found histone acetylation can promote gene expression [63]. Compared with normal endometrium, the histones (H3, H4) in the promoter region of the ESR1 gene in ectopic endometrium tissue showed a low acetylation state, which decreased the expression level of ERα, thus allowing ERβ to be the dominant receptor [64]. In addition, increased acetylation of H3 and H4 was found in SF-1 promoter of endometriosis patients. The function of ERβ and SF-1 in endometriosis has been detailed in the section on methylation, both of which contribute to the development of the disease. Histone methylation mainly acts on lysine and arginine in the tails of H3 and H4 proteins. H3K9 and H3K27 inhibit gene expression, while H3K4 can promote gene expression [65]. The function of histone methylation modification in endometriosis has been widely discussed. For example, H3K4, H3K9, and H3K27 were highly methylated in ectopic lesions, and H3K27me3 was highly expressed in the promoter region of the isodistal frame gene [64]. 4.3 Noncoding RNA RNA can be divided into mRNA, rRNA, tRNA, and noncoding RNA. When it comes to noncoding RNA, we considered it does not participate in specific protein synthesis but achieves gene regulation at the posttranscriptional level [66]. Research on noncoding RNAs is often focused on microRNA (miRNA) and lncRNA. miRNAs are about 22 nucleotides in length, which are genetically highly conserved and are mainly responsible for maintaining the regulation of the body’s own genes. When miRNA and mRNA complement successfully, it can promote the degradation of mRNA, thus achieving the purpose of blocking protein synthesis. The significance of miRNAs in endometriosis has been demonstrated by numerous studies, like mediating cell proliferation, apoptosis, epithelial-mesenchymal transformation, and so on [65]. The microarray analysis revealed the presence of 66 species of microRNAs in endometriosis along with 357 distinct mRNA expression differences when compared to normal samples [67]. Elevated miR-196a can be observed in endometrial stromal cells (ESCs), and through the mechanism of complementary pairing, the increase of this RNA leads to the low expression of progesterone receptor mRNA, thus inhibiting the expression of PR and producing progesterone resistance. Interestingly, small extracellular vesicles (SEVs) (< 200 nm) are better biomarkers of endometriosis than free miRNAs. sEV-miRNAs can carry microRNAs (miRNAs), and they are less likely to be degraded [68]. Long noncoding RNA (LncRNA) are more than 200 nucleotides in length. In 2015, Wang compared normal and abnormal endometrium through microarray analysis and found 488 upregulated and 789 downregulated lncRNA types. H19 is a lncRNA, which is similar to molecular sponge, so if we reduce the bioavailability of miRNAlet-7, we could inhibit the development of heterosomia since its activity is reduced in heterosomia [69]. MALAT1 lncRNA, which is highly conserved throughout evolution, emerges as another significant lncRNA in the context of endometriosis. It is so significantly increased in endometriosis that there is a good choice to use it as a biomarker [70]. However, the role of estrogen and progesterone receptors has not been clarified, which provides a reference direction for future research. 4.4 Epigenetic implications on disease development 4.4.1 Progesterone resistance Epigenetics is increasingly recognized as playing a pivotal role in both the normal functioning and dysregulation of the endometrium [71]. Variability in lesion size, location, and characteristics correlates with changes in endometrial physiology and gene expression patterns [72]. These alterations, often attributed to progesterone resistance, encompass a wide array of proteins and pathways, with emerging evidence implicating epigenetic mechanisms [73]. At that time, Brosens and associates proposed that epigenetic processes controlling endometrial cells’ reactivity to different stimuli influence the pathways causing endometrial progesterone resistance [74]. In normal endometrium, the downregulation of epithelial PGR is a characteristic feature during implantation [75]. This tightly regulated decrease in PGR expression is crucial for successful implantation in both mice and humans. However, in the context of endometriosis, there appears to be persistent expression of PGR instead of its expected disappearance [76]. Progesterone acts 4.4.2 Infertility One prevalent endometriosis-related issue is infertility, which is defined as a failure to become pregnant even after engaging in frequent, unprotected sexual activity for a period of 12 months or more. The risk of developing infertility due to endometriosis primarily affects individuals under the age of 35 [78]. Endometriosis occurs in 5% of women of reproductive age, but is worth distinguishing from endometriosis lesions, which occur in not a small proportion of women with infertility. Endometriosis lesions is found in 25–50% of infertile women, and in those who have the disease, infertility is thought to affect 30–50% of them [79]. Complexly disrupted hormone signaling and an increased inflammatory the micro environment are the fundamental features shared by all the theories. Dysregulated gene expression impedes implantation, leading to infertility and miscarriages, and perpetuates the pathogenesis of endometriosis [80]. 5. Links between environmental exposures and epigenetics Let us start with an example. Norbotton is located within the Arctic Circle, and because of its geography, the grain harvest is extremely volatile. If the crop fails, people will starve, and when the harvest comes, people will feast. Statistics show that grandfathers who binge eat between the ages of 9 and 12 years are associated with shorter lifespans and an increased risk of diabetes in their grandchildren, and vice versa [81]. Two seemingly unrelated things are closely linked. What bridges the gap between environment and phenotype in the absence of genetic change? Epigenetics dose. Epigenetics overrides the genome and regulates gene expression. It does not involve changes in DNA sequence; it is heritable, controllable, and multilayered [82]. More and more research suggest that the environment can alter epigenetic inheritance. On the basis of no changes in the genome, by changing the DNA methylation level, histone modification sites, and the expression of noncoding RNA, the regulation of gene expression can be realized, thus affecting the protein synthesis and the character. Viral infections, starvation, and high temperatures have been shown to modify the epigenetic components of 6. Application of environmental factors and epigenetics in the diagnosis and treatment of endometriosis At present, surgical method is still the first choice to diagnose endometriosis. Despite the irreplaceable accuracy of surgical diagnosis, patients often miss the prime of treatment, which highlights the advantages of epigenetic diagnosis. Epigenetic changes are reversible, which means that the right biomarkers along with appropriate drug treatment can intervene in diseases. Here, we list some epigenetics-related molecules used in diagnosis and treatment. In the serum of patients with endometriosis, the levels of miR-125b-5p, miR-150-5p, miR-342-3p, and miR-451a were significantly increased, while the levels of miR-3613-5p and let-7b were significantly decreased [87]. In addition, significant lncRNA abnormalities can also be confirmed in the serum of patients concerned. Wang et al. screened 5 lncRNAs and found that the sensitivity of diagnosis of EMS could be as high as 89.7% [88]. Interestingly, some scholars have suggested that small extracellular vesicles carrying noncoding RNA are less susceptible to degradation; they are more accurate markers [63]. DNA methylation and histone modification are important in epigenetic changes, both of whose reactions are catalyzed by enzymes. Therefore, DNMT inhibitors and HADC inhibitors play an important role. In experiments, Hirakawa observed that treating ATM genes with DNMT inhibitors could halt the cell cycle [89]. ATM is associated with capillary mutation and hypermethylation in ectopic endometrial tissue. The familiar tumor suppressor gene P53 can mediate apoptosis when cells are damaged, preventing the delivery of altered genes, and ATM can activate P53, which means that the high-grade ATM gene makes it difficult for abnormally expressed endometrial cells to be cleared. Gut flora is also important in endometriosis. Gut microbiota can produce butyrate, which increases the expression of Rap1GAP protein In summary, epigenetic changes can help restore normal gene expression in endometriosis by acting as a molecular marker. More targeted drugs are yet to be developed, which may open up new frontiers for the treatment of endometriosis (Figure 2). 7. Conclusion The origin of endometriosis is an intricate issue with incompletely understood etiology, which calls for more sophisticated study designs and standardized methods due to its complications. Environmental exposures may not initially change specifically in an individual over a short period of time, but as toxicity accumulates over time, adverse outcomes through epigenetic mechanisms are increasingly likely. Reducing exposure to environmental risk factors is the primary control pathway, by avoiding exposure to harmful chemicals and choosing natural and organic products. Dietary modifications are also necessary for people at high risk of endometriosis, such as increasing the intake of antioxidant foods, which can help reduce oxidative stress and inflammation in the body. A better understanding of the magnitude, duration, and targets of adverse environmental exposures is needed in order to advance prevention and control strategies. The future research direction is to recognize relevant pathways and investigate the impact of epigenetic factors in the pathophysiology in EMS. More research is being done to elucidate the effects of environmental pollutants, such as endocrine disruptors, on the disease and how these risks can be reduced. Future research is necessary to emphasize population studies that integrate environmental, genetic, and epigenetic data. Considering the expected applicability of particular epigenetic biomarkers in illness diagnosis and prognosis assessment, translating epigenetic research into clinical practice is a very promising therapeutic approach.

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