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Endocrine Disruptors in Endometriosis

Authors:

Abstract

Endometriosis is an estrogen-dependent disease, which involves the growth of endometrial tissue outside the uterine cavity, commonly in the pelvic region. The etiology of the disease is unclear, but multiple factors may contribute to its prognosis. Toxicological studies indicate that many chemicals are able to interfere with endocrine homeostasis, called endocrine disrupting chemicals (EDC) like Bisphenol A, Phtalate, Polychlorinated Biphenyls and Dioxins. As well documented, endometriosis is an estrogen-dependent disease; therefore, environmental toxicants that either mimic estrogen or enhance estrogenic exposure in the endometrium are thought to increase the risk of endometriosis. The purpose of this mini-review is to provide an overview of epidemiological studies, which have evaluated the relationship between endometriosis and exposure to endocrine disruptors.
Endocrine Disruptors in Endometriosis
Mariana Antunes Ribeiro α & Wellerson Rodrigo Scarano σ
Abstract-
Endometriosis is an estrogen-dependent disease,
which involves the growth of endometrial tissue outside the
uterine cavity, commonly in the pelvic region. The etiology of
the disease is unclear, but multiple factors may contribute to
its prognosis. Toxicological studies indicate that many
chemicals are able to interfere with endocrine homeostasis,
called endocrine disrupting chemicals (EDC) like Bisphenol A,
Phtalate, Polychlorinated Biphenyls and Dioxins. As well
documented, endometriosis is an estrogen-dependent
disease; therefore, environmental toxicants that either mimic
estrogen or enhance estrogenic exposure in the endometrium
are thought to increase the risk of endometriosis. The purpose
of this mini-review is to provide an overview of epidemiological
studies, which have evaluated the relationship between
endometriosis and exposure to endocrine disruptors.
Keywords:
endometriosis, endocrine disruptors, infertility,
bisphenol-A, phthalate, PCBs, TCDD.
I. Endometriosis
ndometriosis is an estrogen-dependent disease
defined as the growth of endometrial glands and
stroma at extra-uterine sites. Reports on the
incidence of endometriosis vary widely, from
approximately 10% of reproductive-aged women
(Barbieri 1990) up to 30% of women with chronic pelvic
pain (Howard 1993). These reports may underestimate
the true prevalence of this disease, which may approach
45% of women in their reproductive years(Rawson
1991). Although retrograde menstruation occurs in 70-
80% of women of reproductive age, not all develop
endometriosis (Halme et al. 1984). Therefore, other
factors must play a role in the pathogenesis of
endometriosis, like genetic background, malfunctioning
inflammatory/immunological mechanisms and
potentially environmental factors (Bischoff & Leigh
2004).
Endometriosis is intimately associated with
steroid metabolism and associated pathways,
corresponding to the dominant roles estrogen receptors
(ESRs) and progesterone receptors (PGRs) play in
uterine biology. Both human and animal model studies
show endometriosis is estrogen (E2) dependent and is
regulated through the ESRs alpha and beta (ESR1 and
ESR2) (Burns et al. 2012; Han et al. 2015; Zhao et al.
2015). Toxicological studies indicate that many
chemicals are able to interfere with endocrine
Author α: Department of Morphology, Institute of Biosciences of
Botucatu, Sao Paulo State University UNESP, Botucatu, SP, Brazil.
Author σ: PhD, Department of Morphology, Institute of Biosciences of
Botucatu, São Paulo StateUniversity UNESP, Rua Professor Doutor
Antonio Celso Wagner Zanin s/nº, Distrito de Rubião Júnior, Botucatu -
SP, Brazil. e-mail: scarano@ibb.unesp.br
homeostasis, called endocrine disrupting chemicals
(EDC), may directly or indirectly impair female
reproduction (Mantovani 2006). The definition of
endocrine disruptor by European Union is an exogenous
substance able to mime the hormones that can interfere
with the production, release, transportation, metabolism,
link, action or elimination of natural hormones, which are
responsible of maintenance of homeostasis and
regulation on development processes (Caserta et al.
2008). The main targets EDC are bisphenol A (BPA), di-
(2-ethylhexyl) phthalate (DEHP), mono-ethyl-hexyl
phthalate (MEHP) and polyhalogenated aromatic
hydrocarbons that consists of dioxins, mainly, 2,3,7,8-
Tetrachlorodibenzo-p-dioxin (TCDD) and poly-
chlorinated biphenyls (PCB). Recently, they have gained
special attention as emerged chemicals because of their
persistence in the environment, potential for
bioaccumulation and toxicity. Nuclear receptors
pathways are the main cellular targets of the EDC under
study, thus they are considered meaningful biomarkers
of effective dose. The panel of nuclear receptors
includes estrogen receptor alpha (ERα) and beta (ERβ),
androgen receptor (AR) and aryl hydrocarbon receptor
(AhR), it of these act in different pathways (Caserta et al.
2013).
As well documented, endometriosis is an
estrogen-dependent disease; therefore, environmental
toxicants that either mimic estrogen or enhance
estrogenic exposure in the endometrium are thought to
increase the risk of endometriosis. Therefore, this article
aims to review the main endocrine disrupters that may
be involved with endometriosis.
II. Bisphenol a (bpa)
BPA is a compound used in the production of
polycarbonate plastics and epoxy resins. Given its
similarity to endogenous estrogen, BPA has the ability to
interact with estrogen receptors and stimulate estrogen
production and also alter gonadotrophin hormone
secretion (Buck Louis et al. 2013). Cobellis and co-
workers correlated BPA and endometriosis (Cobellis et
al. 2009). In this study, they found detectable BPA
serum levels in more than half of patients with
endometriosis, whereas it was absent in women without
the disease. This data is still controversial once other
studies could not observe a relation between BPA and
endometriosis (Buck Louis et al. 2013; Itoh et al. 2007).
More studies should be performed once it was reported
that BPA causes subfertility in male rats that neonatally
exposed to 2.4 µg of the compound per day for five
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days, by subcutaneous injection. This subfertility is
manifested as embryo resorption, also known as post-
implantation loss. In these resorbed embryos, the
expression levels of three types of DNA methyl-
transferases involved in CpG methylation were
significantly decreased compared to viable embryos of
neonatally BPA exposed males or control embryos. The
authors suggested that BPA might have altered the
epigenome. As suggested by Guo (2009), there is
accumulating evidence supporting a concept that
endometriosis is an epigenetic disease, therefore further
studies should be performed to demonstrate the
correlation between the epigenetics changes and BPA
in endometriosis.
III. Phthalates
Phthalates are chemicals used in numerous
industrial and consumer products and also exhibit
endocrine disruptive properties or to mimic or alter
endogenous hormone activity. Adult human exposure to
phthalates is primarily through ingestion of
contaminated food from food processing machines and
packaging materials and dermal application of personal
care and cosmetic products. Exposure is also possible
through inhalation of indoor air contaminated from
building materials, and parenteral exposure through
medical equipment such as IV tubing and blood bags
(Upson et al. 2013). Di-(2-ethylhexyl) phthalate (DEHP)
is the most commonly used chemical additive to provide
flexibility to polyvinylchloride and in humans, it is likely
that the stomach acid lipases hydrolyze DEHP into
mono-(2-ethylhexyl) phthalate (MEHP))(Albert & Jégou
2013). This compound is metabolized quickly and
excreted in urine without evidence of accumulation
within the body. Phthalates produce antiandrogenic
effects largely through the reduction in testosterone
production and, possibly, reduced estrogen production
at high doses (Buck Louis et al. 2013). Results of
investigations into the pathophysiology of endometriosis
have suggested that disease onset and progression
involve steroid-related mechanisms, including hormone-
related changes of the endometrium and peritoneal
cavity, excess estrogen production by ectopic
endometriotic lesions, and alterations in ovarian
steroidogenesis. Thus, it is plausible that endocrine-
disrupting chemicals such as phthalates may affect
endometriosis risk(Ulukus et al. 2006).
The in utero and neonatal exposure to low
doses of bisphenol A (BPA) and/or phthalates
(DEHP/MEHP and BBP/DBP/MBP) may cause DNA
hypermethylation/hypomethylation at CpG islands near
gene promoter regions, histone modifications
(acetylation, methylation, phosphorylation, ubiquity-
nation, sumoylation and ADP ribosylation), and
expression of non-coding RNAs, including micro RNAs.
These epigenetic marks can induce up/down alterations
in gene expression that may persist throughout a lifetime
(Singh & Li 2012).
IV. PCBS and TCDD
The main group of environmental pollutants that
have been proposed to play a role in the pathogenesis
of endometriosis includes polyhalogenated aromatic
hydrocarbons, a class of widespread environmental
contaminants consisting of polychlorinated dibenzo-p-
dioxins (PCDD), dibenzofurans and 12 polychlorinated
biphenyls (PCB) (Schecter et al. 2006).
Dioxins are byproducts of industrial processes
such as bleaching of paper pulp and the manufacture of
certain pesticides and incineration of plastic and
medical waste (Foster et al. 2010). Dioxins are lipophilic
substances that resist biological and environmental
degradation, remaining in the environment. Studies in
animals have shown that 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) is considered the environmental
contaminant, within dioxin group, with the greatest
toxicity and thus is also significant to human health
(Schecter et al. 2006).
Seventy-five dioxin congeners and 135 furan
congeners comprise the complex mixture of dioxins,
7:10 congeners which are respectively capable of
binding to and activating the aryl hydrocarbon receptor
(AhR) (Van den Berg et al. 2006). This binding induces
the proliferation, differentiation and apoptosis, although
the mechanism for this stimulation is not completely
understood (Kogevinas 2001). Of the 209 congeners of
polychlorinated biphenyls (PCBs), twelve have the
potential to activate the AhR (Van den Berg et al. 2006).
In normal physiological conditions, AhR resides in an
inactive state in the cytoplasm. After association with
TCDD, the AhR is activated by a change in conformation
and translocates to the nucleus where it forms a
heterodimer with ARNT (Aryl hydrocarbon receptor
nuclear translocator). The heterodimer binds to the XRE
(Xenobiotic Response Element) and alters the
expression of genes controlled by the enhancer XRES.
XRES, with the conserved sequences " GCGTG " are
found in the promoter regions of various genes involved
in the metabolism of xenobiotics, including CYP1A1
(Cytochrome P450 Family, subfamily a polypeptide 1a -
1), CYP1A2 (Cytochrome P450 Family, 1, subfamily a
polypeptide -2) CYP1B1 (Cytochrome P450 family,
subfamily B, polypeptide 1 -1) and NAD(P)H quinone
Oxidoreductase (Mimura & Fujii-Kuriyama 2003). In
addition to the expression of various genes to CYP
connection with TCDD because several toxicological
effects such as teratogenesis, tumor promotion and
immunosuppression (Shimizu et al. 2000).
Furthermore, it is reported that, in somatic cells,
the gene expression of DNA methyltransferase 1
(Dnmt1) is controlled by the transcription factor Sp1
(Bigey et al. 2000) and the promoter region Dnmt 3B
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also contains an Sp1 binding site (Ishida et al. 2003).
The Sp1 is important for a number of physiological
processes, including angiogenesis, cell cycle
progression, inflammation and senescence (Chang &
Hung 2012). Taking into account the involvement of Sp1
with DNMTs, the change of the activity of Sp1 may affect
the level of expression of DNA methyltransferases and
their activity. Lee et al (Lee et al. 2011) showed that
exposure to TCDD causes Sp1 phosphorylation. Based
on this evidence, the phosphorylated Sp1 would bind to
receptors of DNMTs, thereby increasing its activity.
Thus, changes in methylation status in the promoter
region of some genes can cause alterations in gene
expression and consequently contribute to
endometriosis development.
Dioxins have also been postulated to stimulate
the development of endometriosis via their immune-
suppressive effects and their interference with the
estrogensignaling pathway. The immunosuppressive
effect of high doses of dioxins is well documented(Oh et
al. 2005). Firstly, dioxin exposure may lead to inhibition
of leukocyte phagocytic function, which is possibly
important in the prevention of endometriosis by the
elimination of menstrual debris (Levin et al. 2005).
Additionally, dioxins can decrease immunological
memory induce apoptosis in both T cells and B cells),
inhibit T-lymphocyte function and decrease natural killer
cell activity in plasma and peritoneal fluid (Puebla-
Osorio et al. 2004; Ahmed et al. 2005). Furthermore,
dioxin may stimulate the activity of peritoneal fluid
macrophages and their local production of pro-
angiogenic factors, cytokines (e.g. interleukin-1) and
growth factors. The combined effect of immune
dysfunction and peritoneal inflammation could favor the
development of endometriosis. Furthermore, cellular
changes or genetic predisposition may predestine an
individual to the immunological modulation caused by
dioxin exposure (Simsa et al. 2010).
Local estrogen production can be increased
following dioxin exposure and facilitate development of
endometriotic lesions by elevating mRNA expression of
aromatase, the key catalytic enzyme in estrogen
synthesis (Attar & Bulun 2006). Dioxins and PCB are
known to interfere with estrogen concentrations. Both
agonistic and antagonistic effects have been ascribed to
dioxins and PCB by direct interference with the estrogen
receptor or by the interaction between the activated aryl
hydrocarbon receptor (AHR)/aryl hydrocarbon receptor
nuclear translocator heterodimer and the estrogen
receptor a and b, leading to estrogen-dependent gene
activation (Mimura & Fujii-Kuriyama 2003).
V. Conclusion
Developing a better understanding the basic
mechanisms that may allow environmental toxicants to
promote endometriosis, will enable us to develop better
strategies to reduce the potential toxic impact of these
compounds to the future generation.
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Alterations in estrogen-mediated cellular signaling play an essential role in the pathogenesis of endometriosis. In addition to higher estrogen receptor (ER) β levels, enhanced ERβ activity was detected in endometriotic tissues, and the inhibition of enhanced ERβ activity by an ERβ-selective antagonist suppressed mouse ectopic lesion growth. Notably, gain of ERβ function stimulated the progression of endometriosis. As a mechanism to evade endogenous immune surveillance for cell survival, ERβ interacts with cellular apoptotic machinery in the cytoplasm to inhibit TNF-α-induced apoptosis. ERβ also interacts with components of the cytoplasmic inflammasome to increase interleukin-1β and thus enhance its cellular adhesion and proliferation properties. Furthermore, this gain of ERβ function enhances epithelial-mesenchymal transition signaling, thereby increasing the invasion activity of endometriotic tissues for establishment of ectopic lesions. Collectively, we reveal how endometrial tissue generated by retrograde menstruation can escape immune surveillance and develop into sustained ectopic lesions via gain of ERβ function.
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Background: A very large proportion of the literature on the endocrine disruptors categorized as anti-androgens deals with phthalates, which are produced in large amounts for use as plastic emollients and additives. In this review, we bring together and analyse work on the effects of phthalates in animals and humans at different stages of their development to assess whether or not their possible anti-androgenic properties represent a significant threat to human health. Methods: The database PubMed was systematically searched for all English language articles until July 2013 in each subject area discussed. Results: We provide an up-to-date exhaustive, comparative and critical assessment of both in vivo and in vitro studies undertaken to explore the effects of phthalates on the human testis from fetal life to adulthood. These results are compared and discussed in the light of the key data reported in the literature for mice and rats. Conclusions: The current literature highlights the fact that (i) there is a huge difference between the number of studies performed in animals and in humans, with many fewer for humans; (ii) there are differences in the way rats, mice, primates and humans respond to phthalates, for reasons that need to be further explored; (iii) more work is required to clarify the contradictions, in the few existing human epidemiological studies at all stages of development, which may be partly explained by varying methods of exposure assessment; (iv) in accordance with recent findings in rodents, it cannot be excluded that transgenerational effects of phthalates and/or epigenetic changes exist in humans; (v) a number of methodological limitations need to be solved for the in vitro and xenografting models using human fetal testis to fulfil their 'missing link' role between epidemiological studies in humans and rodent models; and (vi) epidemiological and in vitro studies generally converge sufficiently to conclude that phthalate anti-androgenicity is plausible in adult men.
Article
Phthalates are ubiquitous environmental chemicals with endocrine disruptive properties. The impact of these chemicals on endocrine-related disease in reproductive-age women is not well understood. To investigate the relationship between urinary phthalate metabolite concentrations and the risk of a hormonally-driven disease, endometriosis, in reproductive-age women. We used data from a population-based case-control study of endometriosis, conducted among female enrollees of a large healthcare system in the U.S. Pacific Northwest. We measured urinary phthalate metabolite concentrations on incident, surgically-confirmed cases (n=92) diagnosed between 1996 and 2001 and population-based controls (n=195). Odds ratios (OR), and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusting for urinary creatinine concentrations, age, and reference year. The majority of women in our study had detectable concentrations of phthalate metabolites. We observed a strong inverse association between urinary mono-(2-ethyl-5-hexyl) phthalate (MEHP) concentration and endometriosis risk, particularly when comparing the fourth and first MEHP quartiles (aOR 0.3, 95% CI: 0.1-0.7). Our data suggested an inverse association between endometriosis and urinary concentrations of other di-2-ethylhexyl phthalate (DEHP) metabolites (mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP)) and ∑DEHP, however, the confidence intervals include the null. Our data also suggested increased endometriosis risk with greater urinary concentrations of mono-benzyl phthalate (MBzP) and mono-ethyl phthalate (MEP), although the associations were not statistically significant. Exposure to select phthalates is ubiquitous among female enrollees of a large healthcare system in the U.S. Pacific Northwest. The findings from our study suggest that phthalates may alter the risk of a hormonally-mediated disease among reproductive-age women.
Article
Objective: To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis. Design: Matched cohort design. Setting: Fourteen clinical centers. Patient(s): The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131 women matched on age and residence. Intervention(s): None. Main outcome measure(s): Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts, respectively. Result(s): Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index, and creatinine. In the population cohort, six phthalate metabolites-mono-n-butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate-were significantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (monooctyl phthalate; OR 1.38; 95% CI 1.10-1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03-1.78]. Conclusion(s): Select phthalates were associated with higher odds of an endometriosis diagnosis for women with magnetic resonance imaging-diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings.