> Research revealed startling link between dioxin (TCDD) exposure
> and the development of endometriosis.
Below are a few of the abstracts relating endometriosis to dioxin at
www.pubmed.com . Search for "TCDD endometriosis" for more.
Endocrine toxicants including 2,3,7,8-terachlorodibenzo-p-dioxin
(TCDD) and dioxin-like chemicals and endometriosis: is there a link?
Endometriosis is a common gynecologic disease of unknown etiology
affecting approximately 10-15% of women of reproductive age and 50% of
infertile women. Estrogen dependence and immune modulation are
established features of endometriosis but do not adequately explain
the cause of this disorder. In recent years evidence indicated that
exposure to environmental toxicants possessing estrogenic activity
resulted in endometriosis. However, scant hospital-based case-control
studies yielded inconsistent findings and thus did not provide a
compelling argument for or against an association between
environmental toxicant exposure and endometriosis. Results of animal
studies and cell culture experiments, however, suggested that it is
biologically plausible for environmental toxicants to affect the
pathobiology of endometriosis. In this article, the literature linking
environmental toxicants with endometriosis was reviewed and the link
with endocrine toxicants discussed. PMID: 18368552
Combination of estrogen and dioxin is involved in the pathogenesis of
endometriosis by promoting chemokine secretion and invasion of
endometrial stromal cells.
BACKGROUND: The CC chemokines, regulated on activation, normal T-cell
expressed and secreted (RANTES) and macrophage-inflammatory
protein-1alpha (MIP-1alpha), have been identified as potential
contributors to the pathogenesis and the progression of endometriosis.
Dioxin, an air pollutant, and estrogen also appear to be involved in
endometriosis. The aim of this study was to probe into the effect of
dioxin and estrogen on expression of the chemokines in endometriosis-
associated cells, and to explore the pathogenesis of endometriosis.
METHODS: Co-culture models were established to evaluate the secretion
of human RANTES and MIP-1alpha. The effects of a dioxin (2,3,7,8-
tetrachlorodibenzo-p-dioxin, TCDD) and estrogen on the invasion of
endometrial stromal cells (ESC) were also examined by using an
invasion assay, and the translation and proteolytic activity of matrix
metalloproteinase (MMP)-9 and MMP-2 in ESC were determined by western
blot and zymography, respectively. RESULTS: Our results showed that
the combination of 17beta-estradiol and TCDD increased the secretion
of RANTES and MIP-1alpha, promoted the invasiveness of ESC and
increased the expression of MMP-2 and MMP-9 in ESC. Anti-RANTES, anti-
MIP-1alpha neutralizing antibody or antibody against their receptors
could effectively inhibit the invasiveness of ESC and the expression
of MMP-2 and MMP-9. CONCLUSIONS: The combination of 17beta-estradiol
with TCDD may facilitate the onset of endometriosis and contribute to
its development by increasing the invasion of ESC mediated by CC-motif
chemokines. PMID: 18456672
Combination of 17beta-estradiol with the environmental pollutant TCDD
is involved in pathogenesis of endometriosis via up-regulating the
chemokine I-309-CCR8.
OBJECTIVE: To explore the effects of the combined E(2) with the
environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on
CCR8-I-309 expression by the endometriotic lesion-associated cells in
the pathogenesis of endometriosis. DESIGN: Prospective laboratory
study. SETTING: University hospital. PATIENT(S): Chinese women with
endometriosis. INTERVENTION(S): The endometriotic tissue and matched
eutopic endometrium were collected. Endometrial stromal cells (ESCs),
HPMC, and U937 cells were treated with 17beta-E(2) or TCDD. The ESCs
were stimulated with I-309. MAIN OUTCOME MEASURE(S): The expression of
CCR8 in tissues was analyzed by reverse transcription-polymerase chain
reaction and immunohistochemistry. The effect of I-309 on integrin
beta1 and alphavbeta3 expression intensity was analyzed by flow
cytometry, and the chemotactic activity of I-309 on the ESC was
explored by chemotactic assay. Concentration of I-309 in the culture
supernatant was quantified by enzyme-linked immunosorbent assay.
RESULT(S): CCR8 was overexpressed in the endometriotic tissue. I-309
promoted the expression of integrin beta1. Estradiol and TCDD up-
regulated CCR8 expression by ESCs. Estradiol magnified the stimulatory
effect of TCDD on I-309 secretion by U937. The interaction of HPMC and
U937 cells promoted I-309 secretion. CONCLUSION(S): These findings
imply that the combination of 17beta-E(2) with the environmental
pollutant TCDD is involved in the pathogenesis of endometriosis via up-
regulating the chemokine CCR8-I-309. PMID: 17693327
Effects of some endocrine disruptors on the proliferation and
viability of human endometrial endothelial cells in vitro.
Endocrine disrupting chemicals (EDCs) pose a potential threat to human
reproductive health. We studied the proliferation and viability of
human endometrial endothelial cells (HEECs) in vitro after exposure to
2,2-bis(o,p-chlorophenyl)-1,1,1-trichloroethane (o,p'-DDT), 3,3',4,4'-
tetrachlorobiphenyl (CB 77), 3,3',4,4',5-pentachlorobiphenyl (CB 126),
di-n-butyl phthalate (DBP), bisphenol A (BPA), 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD), and 17beta-oestradiol,
progesterone, 17alpha-ethynyl oestradiol and levonorgestrel. Cell
proliferation was studied using immunocytochemistry for PCNA
expression and a 5-bromo-2'-deoxyuridine assay. Cell viability was
studied by vital staining with propidium iodide and Hoechst 33258.
HEECs in primary culture responded with increased proliferation to
oestradiol and with decreased proliferation to levonorgestrel and the
EDCs. Some EDCs also affected cell viability and increased the
pro****tion of necrotic cells. However, the decrease in proliferation
in response to DBP and TCDD cannot be explained by cell death. In
light of these results, it is possible that the EDCs could have
effects in vivo as well as in vitro, and influence processes involving
for example endometrial angiogenesis. PMID: 17493787
Developmental exposure of mice to TCDD elicits a similar uterine
phenotype in adult animals as observed in women with endometriosis.
Whether environmental toxicants impact an individual woman's risk for
developing endometriosis remains uncertain. Although the growth of
endometrial glands and stroma at extra-uterine sites is associated
with retrograde menstruation, our studies suggest that reduced
responsiveness to progesterone may increase the invasive capacity of
endometrial tissue in women with endometriosis. Interestingly, our
recent studies using isolated human endometrial cells in short-term
culture suggest that experimental exposure to the environmental
contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the
expression of progesterone receptor isotypes. Compared to adult
exposure, toxicant exposure during development can exert a
significantly greater biological impact, potentially affecting the
incidence of endometriosis in adults. To address this possibility, we
exposed mice to TCDD at critical developmental time points and
subsequently examined uterine progesterone receptor expression and
steroid responsive transforming growth factor-beta2 expression in
adult animals. We find that the uterine phenotype of toxicant-exposed
mice is markedly similarly to the endometrial phenotype of women with
endometriosis. PMID: 17056225
Environmental and host-associated risk factors in endometriosis and
deep endometriotic nodules: a matched case-control study.
Peritoneal endometriosis (PE) and deep endometriotic nodules (DEN) are
gynecological diseases recently shown to be associated with elevated
serum concentrations of organochlorines. The objective of the present
study was to compare risk factors associated with both forms of the
disease, with a particular attention to potential sources of
organochlorine exposure. This matched case-control study with
prospective recruitment included 88 triads (PE-DEN-control). All women
were face-to-face interviewed with a standardized questionnaire, and
serum dioxin and polychlorinated biphenyl measurements were available
for 58 of them. Alcohol consumption (odds ratio (OR): 5.82 [confidence
interval at 95% (95%CI) 1.20-28.3]) in DEN and low physical activity
at work for DEN (OR: 4.58 [95%CI 1.80-11.62]) and PE (OR: 5.61 [95%CI
1.90-16.60]) were traced as significant risk factors. Organochlorine-
related factors (use of tampons, occupational or environmental
exposure) were not related to the disease. The current consumption of
foodstuffs that were more likely to contribute to organochlorine body
burden did not differ among the groups. Only some of these fatty
foodstuffs (marine fish, pig meat) were traced by multiple regression
analysis as significant determinants of organochlorine body burden,
explaining only a small fraction (20%) of the interindividual
variation of organochlorine body burden. We conclude that PE and DEN
share similar patterns of risk or protective factors. PMID: 16781705
2,3,7,8-Tetrachlorodibenzo-p-dioxin increases glycodelin gene and
protein expression in human endometrium.
CONTEXT: Glycodelin (GdA) is an immunosuppressive endometrial
glycoprotein critical for embryonic implantation and pregnancy
establishment. OBJECTIVE: The aim of the present study was to examine
the effect of dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] on
GdA production in human endometrial cells. DESIGN: Controlled
endometrial explant (EE) and cell cultures were used in this study.
SETTING: Work was conducted at university hospital research
laboratories in Bern, Switzerland, and in San Francisco, California.
PATIENTS: Ovulatory women provided endometrial biopsies in the
proliferative or secretory phase. INTERVENTION(S): EEs and cells were
cultured without and with TCDD. MAIN OUTCOME MEASURE(S): GdA protein
and gene expression were quantified. RESULTS: A 2.5-fold increase in
GdA production was demonstrated in EEs treated with 10 nm TCDD for 9
d. Fluorography revealed a 3- to 4-fold increase in new GdA
biosynthesis and secretion in TCDD-treated endometrial epithelial
cells. Because the action of dioxin is mediated by the aryl
hydrocarbon receptor (AhR), we ascertained that primary epithelial and
I****kawa cells express AhR. Dose responses to TCDD and expressed AhR
were established in transiently transfected I****kawa cells using
luciferase fusion vectors containing 1.0 kb of 5' flanking DNA
relative to the GdA transcriptional start site but not when shorter
promoter constructs were used. A dioxin response element was mapped to
nucleotides -539 to -533 of the gene promoter and verified by site-
directed mutagenesis. CONCLUSIONS: We demonstrated a direct AhR-
mediated effect of dioxin on GdA gene transcription and protein
secretion that might influence human female fertility. PMID: 15886252
Background exposure to PCDDs/PCDFs/PCBs and its potential health
effects: a review of epidemiologic studies.
Here we review epidemiologic studies dealing with the dietary intake
and the body burden of polychlorinated dibenzo-p-dioxins (PCDDs)/
polychlorinated dibenzo-furans (PCDFs)/ polychlorinated biphenyls
(PCBs) in the general population, and potential adverse health effects
of these substances, especially on the risk of diabetes mellitus and
endometriosis, and on thyroid function and the neurodevelopment of
infants. The mean or median intake of dioxin-related compounds among
the general populations of various countries is lower than the maximum
tolerable daily intake (TDI) set by the WHO in 1998 (4pg TEQ/kg/day).
However, there have been few re****ts on the distribution of intake and
the pro****tion of subjects whose exposure levels exceed the maximum
TDL. At present, it remains unclear whether background exposure to
dioxin-related compounds is associated with increased risk of diabetes
(because of lack of longitudinal studies), endometriosis (because of
lack of studies with sufficient statistical power), or altered thyroid
function (because of inconsistent results on humans). Consistent
results have been re****ted for the association between exposure to
background levels of PCBs/dioxins, especially trans-placental PCBs,
and defective neurodevelopment of infants in the U.S. and Europe.
Thus, efforts should be made to further decrease the body burden among
women of reproductive age by reducing the release of PCDDs/PCDFs/PCBs
into the environment. PMID: 15751269
Environmental dioxins and endometriosis.
Endometriosis is a common gynecologic problem of unknown etiology.
Estrogen dependence and immune modulation are established features of
this disease, and environmental contaminants have been suggested to
play a role in the pathobiology of this disease as well. Previous work
in nonhuman primates has shown that exposure to the dioxin 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) is associated with an increased
prevalence and severity of endometriosis. Further animal experiments
have implicated dioxin and dioxin-like compounds in this disease.
Rodent studies sup****t the plausibility of a role of environmental
contaminants in the pathophysiology of endometriosis, although a
convincing mechanistic hypothesis has yet to be advanced. Small
hospital-based case-control studies have failed to provide compelling
evidence for or against an association of environmental contaminants
and endometriosis. Herein we review evidence that dioxin and dioxin-
like compounds are potent modulators of immune and endocrine function
critical to the pathobiology of endometriosis. Furthermore,
perspectives on the potential mechanism(s) of dioxin and dioxin-like
compound-induced toxicity in endometriosis, im****tant knowledge needs,
potential animal models for endometriosis studies, and considerations
integral to future human case-control studies are discussed. PMID:
12917784
Environmental dioxins and endometriosis.
Endometriosis is a common gynecologic problem of unknown etiology.
Estrogen dependence and immune modulation are established features of
this disease and recently environmental contaminants have been
suggested to play a role in the pathobiology of endometriosis as well.
Previous work in nonhuman primates has shown that exposure to the
dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with
an increased prevalence and severity of endometriosis. Further animal
experiments have implicated dioxin and dioxin-like compounds in this
disease. Rodent studies sup****t the plausibility for a role of
environmental contaminants in the pathophysiology of endometriosis
although a convincing mechanistic hypothesis has yet to be advanced.
Small hospital-based case-control studies have failed to provide
compelling evidence for or against an association of environmental
contaminants and endometriosis. Herein we review the available
literature that provides evidence that dioxin and dioxin-like
compounds are potent modulators of immune and endocrine function
critical to the pathobiology of endometriosis. Furthermore,
perspectives on the potential mechanism(s) of dioxin and dioxin-like
compound-induced toxicity in endometriosis, im****tant knowledge needs,
potential animal models for endometriosis studies, and considerations
integral to future human case-control studies are discussed. PMID:
12441361
The potential role of exposure to environmental toxicants in the
pathophysiology of endometriosis.
Humans and animals are exposed daily to a complex mixture of
polyhalogenated aromatic hydrocarbons (PHAHs). Previous work has shown
that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is
associated with a dose-dependent increase in the incidence and
severity of endometriosis in the rhesus monkey. Dioxin-like chemicals
can also exert effects in combination with TCDD via the aryl
hydrocarbon receptor. Using a rhesus model of chronic TCDD exposure
and endometriosis, serum concentrations of TCDD and 19 dioxin-like
PHAHs were quantified 13 years after termination of exposure to TCDD.
In additional studies, the immune status of TCDD-exposed monkeys was
evaluated. For TCDD-exposed and unexposed animals, TCDD exposure
correlated with an increased serum TCDD concentration. Furthermore,
TCDD exposure and an elevated serum TCDD concentration were associated
with increased serum levels of triglycerides, 1,2,3,6,7,8-
hexachlorodibenzofuran (HxCDF), PCB77, and PCB126. Im****tantly, the
animals with elevated serum levels of PCB77 and PCB126 and increased
total serum TCDD equivalents (TEQs) had a high prevalence of
endometriosis, and the severity of disease correlated with the serum
concentration of PCB77. In immune studies, TCDD exposure correlated
with increased tumor necrosis factor alpha (TNFalpha) production by
peripheral blood mononuclear cells (PBMC) in response to stimulation
by T cell mitogen and decreased NK cytolytic activity. Elevated serum
concentrations of TCDD, 1,2,3,6,7,8-HxCDF, and PCB126 correlated with
increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced
secretion of TNFalpha by mitogen-stimulated PBMC. This evidence
suggests that TCDD exposure and endometriosis in the rhesus monkey may
be associated with increased serum concentrations of specific coplanar
PCB compounds and long-term alterations in systemic immunity.
Furthermore, the data suggest a potential involvement of an increased
body burden of PCB compounds in the etiology of endometriosis in the
rhesus. Recent advances in the detection and assay of individual PHAH
congeners in biological samples have made it possible to *****s total
PHAH body burden in humans and animals. Future studies are expected to
exploit this advance to *****s the health impact of PHAH body burdens
in both exposed individuals and the general population. Serum PHAH
concentrations and TEQs in TCDD-exposed monkeys with endometriosis are
similar to or lower than blood levels in the general human population;
thus, it is im****tant to consider the implications of these findings
for human health and the prevalence of endometriosis in humans.
Additional studies are warranted, particularly in human subjects, to
explore the potential implications of these data. PMID: 11949948
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