| Introduction
Despite the numerous papers published over the last
decades, pathogenesis of this enigmatic disease,
called endometriosis, still remains obscure. Immune
alterations, disorders of the topical endometrium
and genetic disposition have all been associated
with the genesis of the disease.
At present we seem
to observe an increasing prevalence, in addition
to a greater aggressiveness of endometriosis, and
thus a probable involvement of environmental factors
has been hypothesised.
Dioxins are a group
of environmental pollutants consisting mainly of
PCDF, PCB and PCDD. Among PCDDs 2,3,7,8-tetrachorodibenzo-p-dioxin
(TCDD), usually known as dioxin, one of the most
potent pollutants, is to be noted, and there is
evidence suggesting that this compound may be related
to endometriosis (for additional information on
dioxin see www.ejnet.org/dioxin/).
Dioxin is a universal
pollutant, derived mainly from incineration of garbage
and metal processing. Because it is lipophilic it
is retained in the food chain and common foods are
the main source of dioxin exposure for humans.
TCDD, an endocrine
disruptor, may lead to endometriosis mainly through
genomic mechanisms, however, non-genomic actions
have been reported. Its action on DNA, as well as
on sexual steroid synthesis and metabolism, may
lead to alterations which formerly had already been
related to endometriosis.
Mechanisms of action of dioxin
Dioxin activity in the body is by binding to the
aryl hydrocarbon receptor after which the compound
is carried to the nucleus by the AHR nuclear translocator
(ARNT) where it will bind to the dioxin responsive
element activating the transcription of a series
of genes [1].
One of the principal
defense mechanisms of the body against the xenobiotic
is activation of genes that code for detoxification
enzymes, mainly those of the first phase with emphasis
on the Cyp family, especially Cyp 1A1 and Cyp 1B1
[2].
Numerous genes,
responsible for the transcription of pro-inflammatory
cytokines, are activated after exposure to dioxin
and among which RANTES, IL-5, IL-6, IL-7, IL-9,
IL-10 and IL-1beta, TNF-alpha should be mentioned.
The vascular endothelial growth factor (VEGF), which
is known to be involved in the pathophysiology of
endometriosis, has also its transcription activated
by dioxin. Binding of ARNT to DNA also leads to
activation of transcription of genes responsible
for oestradiol synthesis besides, possibly, altering
splicing in the transcription of the gene responsible
for coding for progesterone receptors [3,4,5].
Dioxin
and endometriosis
In view of the evidence that dioxin could be involved
in oestrogen-dependent diseases, some authors evaluated
the association of this pollutant with the disease.
Rier et al, in 1993 [6], evaluated the prevalence
of endometriosis in female rhesus monkeys exposed
to dioxin for 10 years. The authors observed a significant
and dose-dependent increase in the prevalence of
moderate and severe endometriosis in animals exposed
to the pollutant. On studying cynomolgus monkeys,
Yang et al [7] reported, in addition to persistence
of lesions, an increase in their diameter after
exposure to TCDD when compared to non-exposed animals.
In humans, population
studies in Seveso, Italy, and in Belgium, at sites
where there was exposure of the population to high
doses of the pollutant because of industrial accidents,
failed to identify the relationship between an increase
in serum dioxin concentration and the prevalence
of endometriosis. However, due to the fact that
dioxin accumulates in fatty tissues, serum measurement
would not be the ideal means to estimate dioxin
concentration present in the body.
Reviewing the literature,
Arisawa et al concluded that there is no
evidence up to now supporting the hypothesis of
a relationship between the disease and exposure
to dioxin but emphasize the need for population
studies of high statistical power in order to be
able to evaluate this association [8].
Role of
dioxin in the pathogenesis of endometriosis
Studies on the pathogenesis of endometriosis report
alterations in the topical endometrium. Disturbances
of the cell cycle, either increase in proliferation
or decrease in apoptosis, have already been reported.
Increase in matrix metalloproteinase expression,
as well as decrease in TIMP, favour implantation
of this endometrium in the peritoneal surface. After
implantation, formerly described increase in VEGF
is responsible for neo-angiogenesis.
All these alterations
favour implantation of endometrial cells in an inhospitable
environment: the peritoneum [9].
On looking for
a single alteration which leads to all these disturbances
it was discovered that progesterone regulates, either
directly or indirectly, their expression in the
topical endometrial cells, presupposing that a deficiency
in the action of this hormone could be involved
in the genesis of endometriosis.
Progesterone acts
on two different receptors coded for by the same
gene, PRA and PRB, and an adequate proportion between
both is fundamental for the correct action of progesterone
on the endometrium. The known anti-oestrogenic action
of progesterone is mediated by the type B receptor;
when there is an increase in PRA or a decrease in
PRB, we could have an oestrogen-like action, favouring
the emergence of endometriosis. Igarashi et al recently
reported a decrease in the PRB/PRA ratio in cultured
topical endometrial cells of women with endometriosis
after exposure to dioxin, suggesting that alteration
in progesterone action and consequently the previously
reported disturbances in the topical endometrium
of women with endometriosis would be due to exposure
to TCDD [10].
In addition to
the endometrial alterations, dioxin acts by increasing
the expression of detoxification enzymes. Increase
in the expression of the Cyp family enzymes, mainly
Cyp 1A1, leads to a paradoxical effect; this enzyme
metabolises oestrogens to catechol-oestrogens, generating
a strongly oestrogenic environment, contributing
to the pathophysiology of the disease. Finally,
several immune alterations in the peritoneal environment
of patients with endometriosis, either in the humeral
or in the cellular compartment, have already been
described, alterations that are necessary for the
endometrial cell which reaches the pelvic cavity
not to be removed. Dioxin acts on a series of components
of the immune system; we may point out the decrease
of NK cell action, in addition to stimulation of
secretion of pro-inflammatory cytokines such as
IL-5, IL-6, IL-9 and RANTES.
Alterations promoted
by exposure to this environmental potent pollutant
could lead to disorders of the topical endometrial
cells, a hyper-oestrogenic environment and immune
alterations which all together would lead to the
emergence of endometriosis.
Genetic
polymorphisms
In the beginning of the 1980s of the last century
some studies described that retrograde menstruation
occurred in approximately 80% of women, thus showing
that the theory of retrograde menstruation proposed
by Sampson did not explain alone the genesis of
the disease; the same occurring with the environmental
theory. Dioxin is an ubiquitous pollutant and all
women, in a same environment, are exposed to the
same dioxin concentration. What is the reason why
only a part of them develops the disease?
This fact is justified
by genetic polymorphisms which are small DNA alterations
that in the presence of an external stimulus generate
phenotypic alterations. Diverse polymorphisms have
already been studied in women with endometriosis,
among which detoxification enzymes of the first
and second phases are to be pointed out as concerns
dioxin. Up to the present the results were inconclusive.
In a review of the literature, Guo analyzed studies
on polymorphism of Cyp 1A1 and 1B1 first phase enzymes,
GSTM of the second phase and reached the conclusion
that new population studies are required to define
if there is or not alteration of the genes coding
for detoxification enzymes in women with endometriosis
[11].
Conclusion
The actual role of dioxins in the pathogenesis of
endometriosis is still being discussed and evidence
suggests that endometrial, immune alterations may
originate from exposure to this xenobiotic. Genetic
alteration, probably the polymorphisms, would be
the cause of the disease’s emergence in only
a part of the exposed women, however further studies
on these alterations in genes that code for detoxifying
proteins are still needed.
The search
for pathogenetic mechanisms of endometriosis should
be unremitting since the elucidation of the mysteries
of this enigmatic disease is mandatory for the improvement
of therapy as well as primary prevention.
REFERENCES
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