REVIEW

Correlation between dioxin and endometriosis: an epigeneticroute to unravel the pathogenesis of the disease

Vincenza Sofo1• Martin Gotte2

• Antonio Simone Lagana3• Francesca Maria Salmeri1 •

Onofrio Triolo3• Emanuele Sturlese3

• Giovanni Retto3• Maria Alfa1

•

Roberta Granese3• Mauricio Simoes Abrao4

Received: 17 February 2015 / Accepted: 23 April 2015 / Published online: 29 April 2015

� Springer-Verlag Berlin Heidelberg 2015

Abstract

Introduction Environmental toxicants can act as en-

docrine disrupters on the female reproductive system.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is resistant to

degradation and due to its lipophilic nature, accumulates in

the fat tissue and in the food chain. Human and animal

exposure to TCDD affects levels of the steroid receptors

and steroid-responsive gene expression and has an impact

on metabolism and serum transport of steroids. Gene ex-

pression is commonly altered in endometriosis and in the

eutopic endometrium of women with the disease. Aber-

rantly expressed genes include those associated with the

regulation of transcription, proliferation, sex steroid meta-

bolism, apoptosis, cell cycle, the immune response and cell

adhesion.

Methods In this paper, we review the evidence about

TCDD’s effect on eutopic and ectopic endometrium, in

order to unravel the machinery behind the dysregulation of

immune and hormonal homeostasis caused by this envi-

ronmental toxicant.

Conclusion The evidence collected in this review sug-

gests that TCDD could modulate transcription at multiple

levels, including the epigenetic level, and via microRNAs,

thus disturbing the physiologic processes mediated through

the aryl hydrocarbon receptor pathways. Exposure to

TCDD also modulates the immune response by influencing

the production and action of endometrial cytokines and

chemokines, destroying mucosal immunity of the repro-

ductive tract and re-directing the tissue distribution and

behavior of leukocytes. Despite this large body of evi-

dence, current human-based epidemiological studies on the

association between TCDD and endometriosis remain

controversial.

Keywords 2,3,7,8-Tetrachlorodibenzo-p-dioxin �Aryl hydrocarbon receptor � Endometriosis �Sex hormone receptors � Epigenetics

Animal models and epidemiological dataabout the exposure to environmental toxicantsand the development of endometriosis

Endometriosis is an estrogen-dependent disease defined by

the ectopic presence and growth of functional endometrial

tissue, glands and stroma, outside the uterine cavity [1].

The disease affects 2–10 % of women of reproductive age

and 50 % of those infertile [2] and may cause pelvic pain

[3], abnormal bleeding, infertility/sterility and, conse-

quently, important psychological problems [4]. En-

dometriosis is classified depending on the number, size,

and superficial and/or deep location of endometrial im-

plants, plaques, endometriomas, and/or adhesions. The

most used classification of endometriosis was developed by

the American Society for Reproductive Medicine [5],

& Antonio Simone Lagana

antlagana@unime.it

1 Department of Environmental Sciences, Safety, Territory,

Food and Health, University of Messina, Via C. Valeria 1,

98125 Messina, Italy

2 Department of Gynecology and Obstetrics, Munster

University Hospital, 48149 Munster, Germany

3 Department of Pediatric, Gynecological, Microbiological and

Biomedical Sciences, University of Messina, Via C. Valeria

1, 98125 Messina, Italy

4 Department of Obstetrics and Gynecology, Sao Paulo

University (USP), Sao Paulo, Brazil

123

Arch Gynecol Obstet (2015) 292:973–986

DOI 10.1007/s00404-015-3739-5

although other classification can be used for deep infil-

trating endometriosis [6] or to correlate endometriosis and

infertility [7]. The etiopathogenesis of endometriosis still

remains controversial: immunological, hormonal, genetic,

and environmental factors may be all involved. Accumu-

lating evidence revealed that the peritoneal microenviron-

ment of endometriotic women undergoes a number of local

inflammatory–reparative phenomena, with the involvement

of resident macrophages, and the attraction and recruitment

of peripheral mononuclear cells (monocytes and lympho-

cytes) from the blood into the peritoneal cavity [8]: during

endometriosis a breakdown occurs in endometrial and

peritoneal homeostasis caused by cytokine-addressed cell

proliferation and dysregulation of apoptosis [9].

Numerous natural and synthetic chemicals can interfere

with the female reproductive system in mammals, leading

to a decreased fertility including anovulation, reduced

conception rates, abortion, menstrual abnormalities, devel-

opmental defects of reproductive tissues and increased in-

cidence of reproductive tract diseases [10]. Among these

chemicals, polyhalogenated aromatic hydrocarbons

(PHAHs) are a family of persistent environmental pollu-

tants, identified as endocrine disrupting chemicals (EDCs)

by several authors [11–13], particularly of reproductive

function in several animal species, including humans [14].

The family of PHAHs includes polychlorinated-dibenzo-

p-dioxins (PCDDs), commonly called dioxins, and dioxin-

like chemicals as several polychlorinated-dibenzofurans

(PCDFs) and polychlorinated-biphenyls (PCBs). Over the

past 15 years, particular attention has been paid to the as-

sociation between pathogenesis of endometriosis and these

EDCs, particularly 29 dioxin and dioxin-like chemicals,

namely: 7 PCDDs, 10 PCDFs, 4 non-ortho and 8 mono-

ortho coplanar PCBs [15–17]. These chemical agents may

mimic, increase (agonists) or inhibit (antagonists) the hor-

mone actions. In this way, they may interfere with the

synthesis, secretion, transport, binding, action or elimina-

tion of hormones, which are responsible for the mainte-

nance of the homeostasis, reproduction, development and

behavior. Under certain circumstances, these toxicants may

also act as tumor promoters and enhancers in mice [18] and

humans [19]. In fact, studies have shown that these envi-

ronmental chemicals act as ligands of nuclear receptors and

therefore affect the transcriptional regulation. Dose, weight,

time, and duration of exposure in critical periods of life are

important factors in determining adverse effects of EDCs.

The effects may be reversible or irreversible, immediate

(acute) or latent and not apparent for a period of time

[15–17]. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the

most toxic member of the PHAH family, is accidentally

produced as an unwanted byproduct of manufacturing

processes and incineration, whereas PCBs have had wide-

spread commercial application until being banned in the

United States in 1979. These chemical compounds are re-

sistant to degradation and due to their lipophilic nature,

accumulate in the fat tissue of animals and in the food chain

and consequently in human adipose tissue [14, 18, 20].

Thus, among humans and animals, the ingestion of con-

taminated food or water is the main source of exposure to

members of the toxic PHAH family [21, 22]. Studies on

TCDD effects revealed that the experimental exposure of

animals, as well as accidental exposure of humans, pro-

voked wasting, chloracne, induction of xenobiotic me-

tabolizing enzymes, and altered reproductive development

[23]. Some studies [24–26] suggested a possible role of

TCDD exposure in the pathogenesis of endometriosis. The

mechanism by which dioxin acts changing the endometrial

physiology remains uncertain and is speculative due to the

difficulty in assessing the exposure over intrauterine life,

childhood and adulthood and its actual consequences, in

addition to the limitations to its in vitro reproducibility.

Rier et al. [27] reported for the first time that exposure to

TCDD is associated with a dose-dependent increase in the

incidence and severity of endometriosis in rhesus monkeys.

These authors demonstrated that TCDD exposure and en-

dometriosis may be associated with increased serum con-

centrations of PHAH congeners in the same animals

[16, 28, 29]. Several studies on mouse models, in which the

disease was surgically induced, have shown that treatment

with dioxins or dioxin-like substances caused a dose-de-

pendent increase in the size of endometriotic lesions

[30, 31].

Several human-based epidemiological studies evaluated

the incidence of endometriosis after environmental expo-

sure to TCDD or correlated the incidence of disease to

TCDD or PCBs body burden [26, 32–34]. Although the

link between TCDD-like compounds and endometriosis is

controversial [35], it is widely accepted that these toxicants

are present and become concentrated in the biological

fluids such as plasma, breast milk and follicular fluids

[36–39]. One study [32] showed that 18 % of sera of en-

dometriotic women were positive for TCDD compared to

3 % of controls. Other studies demonstrated that serum

concentrations of dioxin-like and non-dioxin-like PCBs

were significantly elevated in women with endometriosis

[40], both peritoneal or deep infiltrating [41]. Conversely,

other authors [36, 37] did not show any statistically sig-

nificant correlation between exposure and disease. These

contradictory results could be due on one hand to different

methods of analysis, and on the other hand to small number

of samples. Several studies [36, 42] suggested that the

highest levels of dioxins and PCBs were present in infertile

women and that the bio-accumulation of dioxins is differ-

ent depending on geographical areas studied. It was already

shown by Heilier’s group [25] that increases of PCDD/

PCDF and dioxin-like PCBs in the sera are associated with

974 Arch Gynecol Obstet (2015) 292:973–986

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peritoneal endometriosis and deep nodules of adenomyosis.

In addition, in endometriotic women there are higher levels

of PCDDs and PCDFs in peritoneal fluid than in serum:

Cai’s work [40] was the first to demonstrate that PCDDs

and PCDFs in PF are linked with endometriosis. So, their

results suggest that some dioxins in PF likely play a role in

the pathogenesis of endometriosis and reflect the changes

of peritoneal microenvironment.

Despite this large body of evidence, current human-

based epidemiological studies on the association between

environmental pollutants and endometriosis remain con-

troversial. In this paper, we review the effect of TCDD on

eutopic and ectopic endometrium, in order to unravel the

machinery behind the dysregulation of immune and hor-

monal homeostasis. This paper conforms with the Uniform

Requirements for Manuscripts Submitted to Biomedical

Journals [43] drawn up by the International Committee of

Medical Journal Editors (ICMJE), the COMET (Core

Outcome Measures in Effectiveness Trials) Initiative

(http://www.comet-initiative.org/) by the MRC North West

Hub for Trials Methodology (NWHTMR) and the

CROWN (CoRe Outcomes in WomeN’s health) Initiative.

TCDD’s action on ectopic endometrium

It was postulated that the correlation between en-

dometriosis and TCDD exposure may depend, at least in

part, on polymorphisms of the xenobiotic metabolizing

enzymes. These polymorphisms could lead to variation in

the level of enzyme expression in vivo, including enzymes

such as cytochrome P450 CYP1A1 and CYP2E1, micro-

somal epoxide hydrolase (EPHX1), glutathione S-trans-

ferase (GST) M1 (GSTM1) and T1 (GSTT1) and arylamine

N-acetyltransferase 2 (NAT2). As extensively reviewed by

Guo [44], despite the plausibility that the lack of, or di-

minished, dioxin detoxification enzyme levels may be

correlated with endometriosis risk, there have been con-

flicting reports on the association of endometriosis and

genetic polymorphisms involving dioxin detoxification

enzymes. For example, a comprehensive reappraisal of all

published primate data [45] evidenced several method-

ological deficiencies in the previous reports. Moreover,

three additional papers [34, 46, 47] come to a similar

conclusion. Finally, also a meta-analysis which suggested a

positive correlation between GSTM1/GSTT1 polymor-

phisms and endometriosis [48] seems to be biased and so

there is little evidence that supports it. Guo’s report [44]

concluded that all genetic variants involving CYP1A1,

CYP2E1, EPHX1, AHR, ARNT, AHRR, and NAT1 that

have been investigated by single studies show no asso-

ciation with endometriosis. However, for CYP1A1 MspI

polymorphisms, women with a ?/- and ?/? genotype

have an about 40 % increased risk of endometriosis as

compared with women of a -/- genotype. For NAT2

polymorphisms, there is no evidence that they are associ-

ated with endometriosis. In contrast, accumulating clear

evidence from several recent studies shows that environ-

mental toxicants negatively affect ovarian function and

fertility [49–51]. Some papers have shown that all of the

dioxins and dioxin-like substances have a high binding

affinity with a nuclear receptor, the cytosolic aryl hydro-

carbon receptor (AhR) [52–54] and that their actions are

mediated by AhR [17, 52, 55, 56]. In fact, in AhR-/-

mice the absence of this protein eliminates the develop-

mental toxicity of TCDD [13]. This further supports the

hypothesis that the reproductive alterations involve an

AhR-mediated mechanism. AhR and its nuclear partner,

AhR nuclear translocator (ARNT), are two founding

members of the bHLH-PAS family and their dimerization

to form an active transcription factor complex has become

a paradigm in studying mechanisms of bHLH-PAS protein

function. Unliganded AhR is located in the cytosol asso-

ciated with Hsp-90 [57, 58] and a 38 kDa, immunophilin-

related protein (XAP2) [59–61]. Ligand binding to the AhR

is thought to produce conformational changes in the AhR

protein which result in the exposure of an AhR nuclear

localization signal and the translocation of the whole

complex into the nucleus [62]. Upon ligand binding, the

AhR translocates into the nucleus, releases the chaperones

and interacts with ARNT [63]. This interaction reconsti-

tutes an active transcription factor which binds a specific

DNA recognition site, called ‘‘xenobiotic responsive ele-

ment’’ (XRE), within the promoter region of AhR-

regulated genes and results in their increased transcription

[64–67]. AhR acts via multiple signaling pathways [68]:

among these, one of the most important and widely studied

is the interaction between AhR/ARNT complex and XREs

in the regulatory region of target genes, including genes

coding for Phases I and II biotransformation enzymes and

genes involved in regulation of development, proliferation

and differentiation. Another pathway involves the interac-

tion of the AhR with the retinoblastoma protein (Rb) [69,

70] and NF-jB [71], and last but not least, it was recently

shown that AhR signaling also includes cross-talk with a

number of protein kinases and that it is possible a ligand-

independent activation of this receptor by phosphorylation.

The activated AhR is quickly exported to the cytosol where

it is degraded by the 26S proteasome, hence preventing

constitutive receptor activity [72]. Currently, recent find-

ings [68] seem to suggest that AhR/ARNT enhancer

complex with promoters of target genes strictly depends on

the interaction with coactivators/corepressors. In particular,

the binding between AhR/ARNT complexes with XREs

provokes the recruitment of coregulators, such as histone

acetyltransferases (HATs). This last enzymes cause

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acetylation of core histones, which allows the release of the

tightly packed DNA strands, the bending of AhR/ARNT

enhancer and the interaction with other coregulators and

transcription factors. An assembly of coactivators and

general transcription factors, including p300, SRC-1, p/CIP

and transcription factor IIB, then interacts with gene pro-

moters and potentiates the expression of target loci [73].

The most well studied of these responsive genes include

the Cyp1a1, Cyp1a2 and Cyp1b1 loci that encode the

xenobiotic metabolizing monooxygenases central to the

adaptive metabolic response [74]. Even if the molecular

pathways of AhR signaling are slowly determined, in the

past year very little was known about its endogenous

ligands. As it was well summarized by Nguyen and

Bradfield [75] and recently by Endler et al. [76], several

candidate endogenous ligands have been isolated from

mammalian tissues: indigoids (indigo and indirubin),

2-(10H-indole-30-carbonyl)-thiazole-4-carboxylic acid

methyl ester (ITE), equilenin [3-hydroxy-1,3,5(10),6,8-es-

trapentaen-17-one], arachidonic acid metabolites, heme

metabolites, tryptophan metabolites, ultraviolet photo-

products of tryptophan and even dietary products, such as

indole-3-carbinol derivatives and natural flavonoids. Con-

sidered together, all these recent findings suggest that the

AhR can induce proliferation, differentiation or apoptosis

by mechanisms dependent on xenobiotic ligands or on

endogenous activities that may be ligand-mediated or

completely ligand-independent. Animal studies showed

that in utero, developmental or prepubertal exposure to

environmental toxics may reduce uterine sensitivity to

progesterone and have an impact on menstrual process

[27]. Additionally, adult exposure to TCDD may promote

chronic inflammation [18, 77]. Considering the robust anti-

inflammatory effects of progesterone [78–80], the reduced

sensitivity to this steroid might also account for several

specific alterations in local and systemic behavior of im-

mune cells, reported in endometriotic patients [81–89].

TCDD has, also, antiestrogenic activity both in vitro and

in vivo [90]: normally, estrogen stimulates increases in PR

levels in rodent uteri, while TCDD inhibits these responses

in vitro [91]. Antiestrogenic effects of dioxins, such as the

inhibition of estrogen-induced uterine enlargement, MCF-7

cell growth, and target-gene induction are well described

[92, 93]. Dioxins may also have estrogenic effects in-

cluding the stimulation of uterine enlargement [94] and the

induction of estrogen-responsive genes [95]. In addition,

AhR-deficient mice exhibit impaired ovarian follicle

maturation [96]. Similarly, dioxins are reported to exert

both androgenic and anti-androgenic effects on prostate

development in an age-specific manner [97]. Despite the

fact that some EDCs target estrogen receptor (EsR) or

androgen receptor (AR) as agonists or antagonists, dioxins

do not serve as their direct ligand [98]. Moreover, the

activation of AhR by TCDD and other toxicants inhibits

estrogen-dependent uterus development and upregulates

the expression of key cytochrome P450 genes, that promote

the clearance of the EsR ligands, estradiol (E2) and estrone

(E1) [99, 100]. Activated AhR can also function as an

ubiquitin ligase that degrades EsR via the proteasome in

breast cancer cells [101] or titrates down the cellular pool

of common transcription cofactors required for EsR func-

tion [100, 102]. The action of TCDD on AhR inhibits the

effects of E2 on uterine stroma interfering with the re-

sponse of the stromal cells themselves and/or with the E2-

induced stromal–epithelial communications [103]. The

antiestrogenic epithelial effects of TCDD occur indirectly

through stromal AhR and may involve disruption of normal

E2-induced stromal–epithelial communications. Moreover,

TCDD alters the production and/or response to a number of

growth factors in uterus, so exerting its antiestrogenic ef-

fect. Buchanan et al. [103] have previously demonstrated

that the E2-induced uterine epithelial proliferative response

is mediated by stromal EsR1. Subsequently, they have

shown that TCDD inhibits E2-induced uterine epithelial

mitogenic activity and secretory protein mRNA produc-

tion, and have established that both effects require AhR

[90]. AhR-mediated effects seem to be cell-type dependent:

TCDD inhibits uterine epithelial mitogenic activity through

AhR in the stroma, while epithelial AhR is not involved in

this effect. Thus, the antiestrogenic effect of TCDD on

uterine epithelium may result from TCDD actions in the

stroma. These effects may be due to suppression of EsR1

transactivation mediated by binding of TCDD to AhR and/

or limited transcriptional co-activator availability. Con-

versely, AhR may also be pro-estrogenic in some contexts.

Activation of AhR by ligands upregulates Cyp19a1 gene

expression, which encodes the enzyme aromatase, that is

essential for estrogen biosynthesis [104, 105]. The local

estrogen content of endometriotic lesions is highly corre-

lated with the levels of aromatase [106–108]. High levels

of aromatase mRNA have been found in extra-ovarian

endometriotic lesions and endometriomas when compared

to normal endometrium [109]. Androstenedione of adrenal

and ovarian origin serves as the primary substrate for

aromatase activity in endometriotic tissue, catalyzing the

reaction to give rise to E1, which is further converted to the

more active E2 [104, 105, 108–112]. Moreover, peritoneal

and ovarian endometriotic tissues express the complete set

of genes, required for converting cholesterol to E2 [109]. In

endometriosis, aromatase is regulated at several steps:

transcriptional expression, protein expression, and enzyme

activity [113]. It is involved in a positive feedback loop

that favors expression of the key steroidogenic genes [106].

Estrogen stimulates expression of the COX-2 enzyme, re-

sulting in elevated levels of PGE2, which is a potent

stimulator of aromatase activity in endometriosis. This

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leads to continuous local production of E2 and PGE2 in

endometriotic tissue. So, in endometriosis, estrogens pro-

mote the growth and invasion of endometriotic tissue and

prostaglandins mediate pain, inflammation and infertility

[114].

Cross-talk of dioxins with estrogen signals

In many cellular regulatory networks, distinct binding

modules help to integrate different input and transduction

signaling pathways to converge on central platforms. In-

deed, cross-talk between different signaling cascades has

emerged as a paradigm of cell biology [115]. Ohtake et al.

[98] investigated molecular mechanism of AhR–ER cross-

talk, speculating that it mediates functional interactions

that regulate transcription. They found that ligand-activat-

ed AhR/ARNT associates with EsR1 and EsR2 through the

N-terminal A/B region within EsRs. By means of this as-

sociation, liganded AhR potentiates the transactivation

function of E2-unbound EsR1, while it represses E2-bound

EsR1-mediated transcription upon the binding to EREs.

Importantly, cross-talk of AhR and EsR1 signaling path-

ways through direct association of AhR with EsR1 was

retained in the presence of a partial EsR1-antagonist, ta-

moxifen, but was abolished by a full antagonist, ICI

182,780, which induces degradation of EsR1. This con-

firmed that this cross-talk required EsR1 protein, but not

the active conformation of EsR1 for co-activator recruit-

ment [98]. Ligand-activated AhR forms a complex with ER

and the co-activator p300/CBP. Moreover, AhR/EsR1

cross-talk in the transcriptional regulation of EsR1-

responsive genes was abolished in AhR-deficient mice

[116, 117] confirming the specificity of the molecular

pathway in vivo [54]. Reciprocally, E2-bound EsR1 asso-

ciates with XRE-bound AhR either to potentiate [118, 119]

or repress [120] AhR-mediated transcription. Considered

together, the AhR/EsR1 complex may be able to bind to

either XRE or ERE through the attachment functions of

AhR or EsR1, respectively. Alternatively, different com-

plex subtypes that contain AhR/EsR1 may control pro-

moter selectivity. Recent genome-wide analysis showed

that the AhR/ER complex appears to regulate both XRE

and ERE-driven transcription in a manner dependent on the

AhR-ligand [119], confirming Ohtake’s model of cross-talk

complex formation.

TCDD and endometrial inflammatory processes

Since TCDD is able to specifically inhibit the expression of

PRs and TGF-b in the endometrium [17, 121, 122], the ex-

perimental exposure to this toxicant will probably trigger an

inflammatory-like endometrial microenvironment [17, 123].

Although the well-known suppressive effect of TCDD on the

acquired immunity, it is unclear the impact of this toxicant on

endometrial chronic inflammation, typical of the disease. In

regard to this, several studies suggest that nuclear transcrip-

tion factor NF-jB can play a critical role in the inflammatory

processes associated with the development of endometriosis

[123–126]. Similar to neoplastic disease, NF-jB is consti-

tutively activated in peritoneal endometriotic implants

[126–128] and promotes the expression of a number of genes

that control cellular processes such as proliferation, adhesion,

apoptosis, angiogenesis and immune response [62, 128].

Several studies showed cyclic changes in endometrial ac-

tivity of NF-kB, reflecting phase-specific inflammatory-like

processes that occur during normal menstrual cycle [129–

131]. These phase-specific changes are clearly evident also in

ultrastructural features of the ectopic endometrium [132].

Although NF-kB becomes activated in response to a variety

of stimuli, the effect of toxic environmental exposure on the

expression and activity of NF-kB was not well established.

Studies on isolated cell types suggested that the AhR and NF-

kB expression could be mutually co-repressive [71, 133–

135]. TCCD exposure shows the ability to destroy the pro-

gesterone-dependent epithelial–stromal communications and,

in this way, may possibly affect inflammatory-related NF-kB

signaling. The high concentrations of NF-kB found in en-

dometrial tissue and cells isolated from endometriotic pa-

tients [71, 128, 131, 134–142] are decreased after progestinic

treatments [38, 143].

Epigenetics: closing the loop about TCCD actionin the pathogenesis of endometriosis?

Currently, more efforts are made to unravel the strict

connection between epigenetic modifications and the oc-

currence of reproductive diseases. As reviewed by Calic-

chio et al. [144], imprinted genes control regions (ICRs)

are a prominent and frequent target of methylation

anomalies in reproductive disorders, but such alterations

also affect non-imprinted genes. Additionally, it is be-

coming ever clearer that gene expression is commonly al-

tered in endometriosis and in the eutopic endometrium of

women with the disease. Aberrantly expressed genes in-

clude those associated with regulation of transcription,

proliferation, sex steroid metabolism, apoptosis, cell cycle,

immune response and cell adhesion [1, 145]. In light of

these, epigenetics is likely to be involved in maintaining

cellular identity in ectopic endometrial cells [146]. The

aberrant expression of several genes could depend by

epigenetic modifications, which include stable inheritable

changes of phenotypes of cells and organisms, without

Arch Gynecol Obstet (2015) 292:973–986 977

123

changes in DNA sequence or DNA content [141]. Over the

last decade, the epigenetic approach has ushered in many

new perspectives. Inheritance of the phenotypes of cells

and entire organisms without any alterations in their DNA

content or DNA sequence is, in fact, the basis of epige-

netics [147]. The epigenetic information of any organism,

animal, or human being is transferred to the next gen-

eration in one of two ways: at the cellular level or at the

whole-organism level. The epigenetic information is not

encoded into a DNA sequence. The epigenetic phenotypes

are conferred via nuclear processes such as DNA methy-

lation and chromatin modifications (acetylation, methyla-

tion, phosphorylation, ubiquitination, sumoylation,

biotinylation, ribosylation and isomerization of histones),

which are interconnected and may work together to

establish and maintain specific gene activity states in nor-

mal cells. Epigenetic marking underlies the regulation of

all genome functions, including gene expression, DNA

replication and genome stability [148]. To maintain cellu-

lar identity, the gene expression program must be iterated

through cell divisions in a heritable fashion by these epi-

genetic processes. According to most recent evidence, en-

vironmental factors, including environmental EDCs, may

affect the epigenome leading to the onset of endometriosis

in utero since there might be epigenetic changes during

ontogenic development [149, 150]. Moreover, epigenetics

may better explain what genetics cannot: it was already

reported (see ‘‘TCDD’s action on ectopic endometrium’’)

that even accurate meta-analysis failed to show robust

evidence of a possible correlation between gene polymor-

phisms (CYP1A1, CYP2E1, EPHX1, AHR, ARNT,

AHRR, NAT1 and NAT2) and endometriosis. Conversely,

several lines of evidence suggest that epigenetics plays a

definite role in the pathogenesis and pathophysiology of

endometriosis. Nevertheless, it is still unclear as how much

nutritional factors, stress and exposure to certain chemicals

in early life and thus aberrant epigenetic changes that they

may cause contribute to the risk of endometriosis [151];

moreover, there is still lack of robust evidence which can

clearly demonstrate if epigenetic modifications could be

considered causes or effects of the pro-inflammatory mi-

croenvironment and progesterone resistance, typical of the

disease. In this regard, there is also the possibility that

epigenome and hormonal/immune status influence each

other, contributing to the development of the disease:

certain phenotypic changes in endometriosis, such as in-

creased production of pro-inflammatory cytokines, may

also cause epigenetic aberrations, which in turn result in

changes in gene expression and subsequently other phe-

notypic changes such as increased cellular proliferation and

perhaps some phenotypic changes [152].

Chromatin remodeling

Currently, many efforts are made trying to unravel the

correct processes behind the epigenetic machinery. Dy-

namic changes in chromatin structure mediated by DNA-

methyltransferases (DNMTs), methyl-CpG-binding pro-

teins, histone acetyltransferases (HATs), histone deacety-

lases (HDACs), histone methyltransferases (HMTs),

histone demethylases (HDMs) seem to affect chromatin

topology and accessibility and so influence gene

expression.

DNA methylation

DNA methylation occurs at the cytosine bases adjacent to

the guanine nucleotide. This process is mediated by

DNMTs: the addition of a methyl group to specific dinu-

cleotide sites along the genome, i.e., cytosines 50 of gua-

nines [153]. If a certain sequence contains a large number

of CpG dinucleotide repeats, this region is referred to as the

CpG island. CpG islands are short (100–200 bp to several

kb in size) sequences found in nearly 60 % of all genes

[148]. DNA methylation regulates gene expression and

transcription by altering the chromatin structure: in gen-

eral, promoter hypo- and hyper-methylation is associated

with gene expression and silencing, respectively [154,

155]. It is unknown whether global alterations in DNA

methylation patterns occur in endometriosis and to what

extent they are involved in its pathogenesis. A whole-

genome scanning of methylation status in more than 25,000

promoters, using methylated DNA immunoprecipitation

with hybridization to promoter microarrays has been con-

ducted for the first time [156]. The results showed that, in

line with the current theory of the endometrial origin of

endometriosis, the overall methylation profile was highly

similar between the endometrium and the endometriotic

lesions. In addition to promoter CpGs, a number of pro-

moter distal CpG sequences are known [157]. A recent

monozygotic (MZ) twins study [158] showed a line of

evidence that epigenetic variants accumulate during aging

independently of the genetic sequence. The study tested the

epigenetic contribution to twin discordance and elucidated

the effect of environmental characteristics on gene func-

tion. The results revealed that epigenetic difference be-

tween siblings is associated with phenotypic discordance,

which might be attributed to an unshared environment.

Taylor et al. [159] demonstrated the expression of

HOXA10 to be significantly reduced in the eutopic en-

dometrium of patients with endometriosis during the se-

cretory phase, indicating the presence of some functional

defects in uterine receptivity. Those authors also observed

978 Arch Gynecol Obstet (2015) 292:973–986

123

a decreased expression of HOXA10 in endometriotic le-

sions. Wu et al. [152] reported that the promoter region of

the HOXA10 gene was hypermethylated in the eutopic

endometrium of women with endometriosis compared with

unaffected women. As promoter hypermethylation is gen-

erally associated with gene silencing, the observed

HOXA10 promoter hypermethylation provides a plausible

explanation for the reduced expression of HOXA10 in the

eutopic endometrium of women with endometriosis [159].

In endometriosis, the altered expression of the progesterone

receptor or its diminished activity may lead to an at-

tenuated response to progesterone and the decreased ex-

pression of progesterone-responsive genes, including the

HOXA10 gene, in the eutopic endometrium. The long-term

suppression of HOXA10 expression in endometriosis may

further induce the epigenetic alteration by hypermethyla-

tion at the promoter region. Based on the unique steroid

hormone receptor expression profile observed in en-

dometriotic lesions as compared to eutopic endometrium,

Meyer et al. [160] demonstrated that epigenetic changes

occur in both promoter regions of the PR gene in intestinal

endometriosis.

Histone modifications

Histone covalent modifications are acquiring ever growing

attention, because they orchestrate chromatin structure

through acetylation of lysines, methylation of lysine and

arginine residues, phosphorylation of serine and threonines,

ubiquitinization of lysines, sumoylation of lysines, proline

isomerization, biotinylation, carbonylation, deimination, gly-

cosylation, and ADP-ribosylation [161]. In particular, histone

acetylation levels are controlled by a balance between the

actions of HDACs and HATs [162]. HAT transfers acetyl

groups from acetyl-coenzyme A to lysine residues on the

N-terminal region of the histones to activate genetic tran-

scription. HDACs, on the other hand, are large multiprotein

complexes that target promoter sites through their interaction

with the sequence-specific transcription process [162].

They remove the acetyl groups, restoring the positive

charge on lysine residues and thus preventing transcription.

It is becoming apparent that HDAC inhibitors (HDACIs),

which show antiproliferative activity, including cell-cycle

arrest, and apoptosis stimulation [163] may be effective for

the treatment of this disease [164, 165]. Some of the

HDACIs are already FDA-approved and used in clinical

practice for other diseases [166–168]. Using chromatin

immunoprecipitation (ChIP) analysis, Monteiro et al. [169]

recently showed, in endometriotic lesions, the hypoacety-

lation of H3/H4 within the promoter regions of the ERa

gene and the hypoacetylation of H3/H4 within the pro-

moter regions of the HOXA10 gene.

MicroRNAs

Apart from epigenetic modifications, environmental tox-

icants may also affect additional modes of regulating gene

expression. Notably, the eutopic endometrium of women

with endometriosis compared with disease-free individuals,

contains certain molecular alterations, including the dif-

ferential expression of the most relevant microRNAs

(miRNAs) [170]. miRNAs are endogenous small (18–22

nucleotides in length), highly conserved, single noncoding

RNAs synthesized in the nucleus, which mature in the

cytoplasm. They regulate gene expression by binding to

complementary sequences on target mRNAs resulting in

translational repression or target degradation and gene si-

lencing [171]. Functional analysis of miRNAs has revealed

their significant regulatory influence on the expression of

target genes involved in both physiologic and pathologic

conditions. Cell-cycle progression, proliferation and dif-

ferentiation are among the biologic processes regulated by

miRNAs via altered expression of target genes [172]. Ac-

cumulating evidence shows an association between

deregulation of miRNAs and exposure to environmental

chemicals; miRNAs play a unique regulatory role in gene

expression. Among environmental pollutants, dioxins are a

family of compounds that are known to have multiple

hazardous effects [173]. It is also relevant to understand

‘‘the fetal basis of adult disease’’ hypothesis, which pro-

poses that prenatal exposure to certain forms of nutritional

and environmental stress can cause increased susceptibility

to clinical disorders later in life. TCDD-mediated alter-

ations in miR expression may be involved in the regulation

of its toxicity including cancer, hepatic injury, apoptosis,

and cellular development [174]. Emerging evidence sug-

gested that the dysregulation of miRNA expression is in-

volved in endometriosis. Previously, Ohlsson-Teague et al.

[175] screened miRNA expression by microarray analysis

in paired ectopic and eutopic endometrial tissues and

identified 14 upregulated (miR-145, miR-143, miR-99a,

miR-99b, miR-126, miR-100, miR-125b, miR-150, miR-

125a, miR-223, miR-194, miR-365, miR-29c and miR-1)

and 8 downregulated (miR-200a, miR-141, miR-200b,

miR-142-3p, miR-424, miR-34c, miR-20a and miR-196b)

miRNAs. More recently, Hawkins et al. [176] also found

10 upregulated (miR-202, 193a-3p, 29c, 708, 509-3-5p,

574-3p, 193a-5p, 485-3p, 100 and 720) and 12 down-

regulated (miR-504, 141, 429, 203, 10a, 200b, 873, 200c,

200a, 449b, 375 and 34c-5p) miRNAs in endometriomas

compared with the normal endometrium using next-gen-

eration sequencing technology. Changes in the expression

of select miRNAs might lead to or be a consequence of an

early defect in the physiological activity of the proliferative

endometrium, ultimately resulting in the overgrowth of this

Arch Gynecol Obstet (2015) 292:973–986 979

123

tissue outside the uterus [177]. Previously, Burney et al.

[177] reported differences in the global gene expression

profile of endometrium from women with versus without

surgically confirmed moderate–severe endometriosis. They

demonstrated maintenance of a proliferative fingerprint in

the transcriptome of early secretory endometrium (ESE)

from women with endometriosis, consistent with at-

tenuated progesterone action or progesterone resistance on

the part of the endometrium in the setting of endometriosis.

Functional genomic analysis of ESE revealed a signature of

enhanced cellular survival and persistent expression of

genes involved in DNA synthesis and cellular mitosis in

women with this disorder. In a recent work [178], the same

authors reported distinct miRNA expression profiles in the

early secretory endometrium (ESE) of women with versus

without endometriosis in a subset of samples previously

used in global gene expression analysis. Specifically, the

miR-9 and miR-34 miRNA families evidenced dysregula-

tion. Integration of the miRNA and gene expression pro-

files provides unique insights into the molecular basis of

this enigmatic disorder and, possibly, the regulation of the

proliferative phenotype during the early secretory phase of

the menstrual cycle in affected women. These authors

identified potential miRNA mediators in the delayed pro-

liferative to secretory transition of endometrium observed

in women with advanced endometriosis, showing an al-

tered miRNA expression profile and providing candidates

within a novel layer of genetic regulation in the patho-

genesis of this enigmatic disorder. Adammek et al. [179]

recently studied function of miR-145, known to be dys-

regulated in endometriosis and identified its target genes in

an in vitro endometriosis model. In this work, miR-145

inhibits endometriotic cell proliferation, invasiveness and

stemness by targeting multiple pluripotency factors, cy-

toskeletal elements and protease inhibitors. More recently,

Shi et al. [180] suggested that the downregulation of miR-

183 expression is involved in the development and pro-

gression of endometriosis. Moreover, miRNAs have been

shown, also, to play important roles in modulating innate

and adaptive immune responses, including T cell differ-

entiation and activation, and B cell differentiation [181,

182].

Transcription factors

Apart from an influence of TCDD on epigenetic and non-

coding RNA-mediated modes of regulating gene expres-

sion, there is apparently also an influence on more

traditional modes of regulating transcription. Accumulating

evidence suggests that endometrial cell gene expression is

regulated in a phase-dependent fashion. Physiologically,

the menstrual cycle-specific protein expression is under the

control of steroid hormones: the proliferative phase is

characterized by the upregulation of putative genes for

angiogenesis, inflammation and immune function [183],

whereas the secretory phase is characterized by upregula-

tion of genes which induce endometrial decidualization

(stromal cell proliferation and differentiation into decidual

cells). In particular, gene expression is regulated by the

acetylation–deacetylation switch, which depends on the

menstrual cycle through the action of HATs and HDACs

[184]. Reflecting the clinical facts, progesterone-regulated

genes are necessary for adequate decidualization process

and successful implantation; conversely, abnormal pheno-

types in decidualization can be due to changes in (epi)ge-

netic modifications at specific loci, which may be

associated with endometrial pathologies, including im-

plantation failure, pregnancy loss, preeclampsia and en-

dometriosis. As recently reviewed by Kobayashi and co-

workers [185], during endometriosis, 47 genes are highly

expressed, including cell-cycle regulators (cyclins and

CDKs), angiogenesis factors (VEGF, ANGPTs and Tie2),

immuno-inflammatory factors (COX2 and PGs), matrix

metalloproteinases and integrins. On the other hand, there

is a reduced expression of 30 decidualization susceptibility

genes, whose expression is regulated by the transcription

factors (HOXA10, FOXO1 and C/EBPbeta), growth factor

(the IGF and IGFBP family), cell cycle (the CDKN family)

and cytokines/chemokines (LIF, IL11 and TGF-beta). In-

terestingly, the expression pattern of the endometriosis

susceptibility genes resembles that of the decidualization

process: for this reason, it is possible to argue that the

epigenetic modifications observed during endometriosis

may account for the well-known progesterone resistance

both in eutopic and ectopic endometrium, typical of the

disease. SRs could be considered as hormonal-dependent

transcription factors, and upon activation with the specific

hormone they can interact with HREs in the promoter of

target genes. Nevertheless, they can also activate genes

lacking specific HREs by interacting with other sequence-

specific transcription factors bound to their target se-

quences [186]. Several members of SRs family, such as

EsR1, AR, and PRs could be epigenetically regulated by

kinases, HATs, and small ubiquitin-like modifiers

(SUMOs) and these changes modify SRs’ DNA binding

and, consequently, their transcriptional activity and hor-

mone-regulated gene expression. Even in this tightly

regulated process, coactivators and corepressors seem to

play a key role in controlling the histones’ modification and

the related transcriptional activity [161]. As extensively

reviewed by Bruner-Tran et al. [187], in vitro TCDD ex-

posure is associated with the development of a proges-

terone-resistant endometrial cell phenotype which

promoted establishment of an endometriotic-like ex-

perimental disease [122, 133]. Furthermore, acute TCDD

980 Arch Gynecol Obstet (2015) 292:973–986

123

exposure of human endometrial tissues disrupts the anti-

inflammatory action of progesterone and led to an increase

in endometrial tissue sensitivity to inflammatory cytokines,

a toxicant-mediated response that increased the secretion of

MMPs and promoted the invasive potential of endometrial

tissue in an experimental endometriosis model [133, 188].

Finally, Bruner-Tran’s group reported that early life/in

utero exposure of female mice to TCDD led to an adult

uterine phenotype in animals which mimics the reduced

uterine progesterone responsiveness observed in women

with endometriosis [189]. Interestingly, they also reported

reduced fertility in both sexes and increased risks of pre-

term birth in female mice across multiple generations fol-

lowing a single, developmental exposure to TCDD strongly

suggests toxicant-mediated epigenetic modifications have

occurred [187]. Shedding light on this partially unexplored

landscape, in utero exposure to environmental factors, such

as EDCs or shortage/excess of nutrients, during early life

could irreversibly affect fetal programming (the so-called

‘‘imprinting’’) and may account for abnormal reproductive

processes, including endometriosis.

Conclusions

Since most of the previous studies reporting epigenetic

aberrations in endometriosis were carried out cross-sec-

tionally, the question of how the epigenetic changes occur

in endometriosis is currently unknown. Further research is

necessary to fully answer this question. Nevertheless, the

evidence collected in this review seems to suggest that

TCDD could act in an epigenetic fashion, disturbing the

physiologic processes mediated through the AhR path-

ways. This may cause a breaking in the regulated repro-

ductive machinery, altering the homeostasis of the

peritoneal microenvironment on one hand, and provoking

the widely studied progesterone resistance on the other

hand. Since these epigenetic modifications occur both on

ectopic and eutopic endometrium, the resulting events will

be the marked lack of decidualization, proliferation and

immunoescaping of endometriotic cells and the infertility/

sterility, respectively. Accumulating evidence suggests that

TCDD-AhR binding triggers signals which lead to im-

pairment of endometrial function addressing toward infer-

tility and other reproductive tract diseases. Although an

impressive number of articles have been published, this

research field still remains to be clarified. Several factors

could have influenced the contradictory results shared by

different research groups: first of all, TCDD is usually

found as a component of a mixture with other environ-

mental toxicants, and this situation is very far from the

laboratory setting; moreover, in vitro studies seems not to

reflect the in vivo condition; finally, the evidence from

human-based epidemiological observation could not be

directly related to the results obtained from the animal

models. Considering these assumptions, more efforts are

needed to try to clarify the TCDD’s multiple actions on the

hormonal as well as immune regulating systems.

Conflict of interest The authors have no proprietary, financial,

professional or other personal interest of any nature in any product,

service or company. The authors alone are responsible for the content

and writing of the paper.

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