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PCBs, Dioxin and
Endometriosis
| Introduction
Endometriosis is a serious disorder involving chronic
abdominal pain and infertility, which may be present in 6 million women
in the U.S. alone. It involves the unnatural growth
outside of the
uterus of the endometrial tissue which normally lines only the inside
of the uterus.
Endometriosis forms adhesions and tissue growths
between organs in the abdominal cavity, which interfere with reproduction,
become painful during a woman’s monthly cycle, and cause pain during bowel
movements and during intercourse. Severe cases require multiple surgeries,
strong medication, and sometimes hysterectomies to remove the uterus and/or
ovaries.
The incidence of endometriosis has risen dramatically
in the last few decades, but scientists aren’t sure of the cause. |
Adhesions on Uterus, Ovaries and Fallopian Tubes
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A normal woman’s endometrium undergoes a predictable monthly
menstrual cycle based on well organized cell-cell interactions regulated
locally by cytokines and growth factors under the direction of steroid
sex hormones. Scientists believe that the onset and progression of endometriosis
may result from disruptions of this well balanced cellular equilibrium,
and may involve a faulty immune system. Endometriosis is probably caused
by an interaction between multiple inherited genetic traits (vulnerabilities)
and environmental influences. Endometrial tissue growth is promoted by
estrogen; therefore, traditional medical therapy uses hormones to limit
the action of estrogen in patients’ bodies.
Certain kinds of PCBs and dioxin act like or interfere
with estrogen hormones and can disrupt steroid action. In addition, they
suppress the immune system. The studies below indicate that because PCBs
and dioxins have these traits they are suspected promoters or causes of
endometriosis. Several studies show links between the chemicals and the
disease in humans and animals More study results should be released soon.
Only a few endometriosis studies have been conducted involving
PCBs, with mixed results. Results may vary depending on the types of PCBs
used or sampled for. The many Dioxin studies listed below show that dioxin
is strongly linked to endometriosis. Certain types of PCBs are "dioxin-like"
in behavior, while other PCBs operate in completely different ways; therefore,
a PCB endometriosis study must research the right types of PCBs in order
to be helpful in proving or disproving an endometriosis link.
Both PCBs and dioxins are present in fish from the Fox
River and Green Bay. The potential for increased rates of endometriosis
should be a local concern and deserves further study.
The PCB Studies
Study #1
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endometriotic lesion diameter was increased
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endometriotic lesion weight increased
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ovarian weight increased with certain PCBs
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ovarian weight decreased with other PCBs
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Corpora lutea were absent or regressive in the ovaries
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different PCBs produce different effects
The effects of polychlorinated-dibenzo-p-dioxins, polychlorinated-dibenzofurans,
and polychlorinated biphenyls on endometriosis were examined. Female
B6C3F1-mice were exposed by oral gavage to 0 to 10 micrograms per kilogram
(microg/kg) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), 0 to
30mg/kg of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153), 100 to 1000microg/kg
of 3,3',4,4',5-pentachlorobiphenyl (PCB126), 10 to 100microg/kg of 2,3,4,7,8-pentachlorodibenzofuran
(4-PeDCF), or 0 to 20mg/kg of 1,3,6,8-tetrachlorodibenzo-p-dioxin (1,3,6,8-TCDD).
The mice were treated five times at 3 week intervals. During the week of
the second exposure, endometriosis was surgically induced. Animals
were sacrificed 3 weeks after the final dose. The endometriotic
lesions and various organs were weighed and examined microscopically for
histopathological changes. The activity of ethoxyresorufin-O-deethylase
(EROD) in liver microsomes was determined. Mice treated with 2,3,7,8-TCDD,
PCB126, or 4-PeCDF exhibited significant, dose dependent increases in EROD
activity, compared to controls. The EROD activity in mice exposed to either
1,3,6,8-TCDD or PCB153 did not differ from that of the controls. Endometriotic
lesion diameter was increased in mice treated with 2,3,7,8-TCDD, 4-PeCDF,
or PCB126. Lesions were not enhanced by treatment with either 1,3,6,8-TCDD
or PCB153. Endometriotic lesion weights were significantly higher
in mice exposed to 2,3,7,8-TCDD than in controls. Nonsignificant elevations
in endometriotic lesion weight were also noted in mice treated with 4-PeCDF
or PCB126. While ovarian weight was increased in mice treated with
PCB153, decreased ovarian weight was observed in mice treated with PCB126
or 4-PeCDF. Corpora lutea were absent or regressive in the ovaries
of mice treated with 2,3,7,8-TCDD or PCB126. The uterine weights of exposed
animals did not differ significantly from those of the controls. Thymus
weight decreased dose dependently in mice exposed to 4-PeCDF or PCB126.
Liver
weight increased dose dependently in mice treated with 2,3,7,8-TCDD,
PCB126, or 4-PeCDF. The authors conclude that the enhancement of endometriosis
by halogenated aromatic hydrocarbons may involve the Ah receptor. (Johnson
et al, 1997)
Study #2
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PCBs may be a factor in endometriosis
Considering the worldwide threat to health and reproduction
related to endocrine disruptors (by-products of the chemical industry);
considering the untrammelled development of the industrialization and engineering
of the living, ethics and gynaecology/obstetrics itself is at a crossroads.
Endocrine disruptors (derived from organochlorines and persistent organic
pollutants such as PCBs, dioxins and furans, and pesticides such
as aldrin, chlordane and DDT), are prime suspects in the deterioration
of fertility and intellectual faculties and possibly a key factor in
endometriosis, breast cancer and prostate cancer. The long-term and
pernicious impacts of endocrine disruptors show our poor understanding
of the complexities of life's mechanisms. Paradoxically, with our short-term
perspectives and predilection for a technological fix, the problem posed
by endocrine disruptors may accelerate the use of reproductive technologies
such as ICSI and even cloning, as well as the dissemination of genetically
modified organisms. The cure could be worse than the disease. Given the
gravity of the challenge to humanity related to the chemical erosion of
human health, the mutation of human conception introduced by reproductive
technologies and by the drive to genetically modify nature and even human
nature, we must urgently re-evaluate the direction in which our societies
are headed and the reliance on profit-oriented technology to save us from
ourselves. In these circumstances, the collective exercise of wisdom, prudence
and responsibility towards the essence and integrity of humanity has become,
more than ever, an ethical, and perhaps even a survival, imperative. (Vandalac
et al, 1999)
Study #3
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highly dosed females developed endometriosis, as did controls
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authors conclude daily doses of PCBs at background levels
do not induce endometriosis
Endometriosis induction and associated immunological
effects associated with the polychlorinated biphenyl Aroclor-1254 (PCB)
were investigated in Rhesus-monkeys. A group of 80 menstruating monkeys
were administered daily oral doses of 0, 5, 20, 40, or 80 micrograms/kilogram
(microg/kg) PCB over a 6 year study. During the 37 month prebreeding phase,
antibodies to sheep red blood cells (SRBC) and natural killer cell activity
were assessed. Laparoscopic examinations were conducted during the 25 month
breeding phase. PCB congener analysis was performed during a 43 month depletion
study in which PCB dosing of 12 monkeys was discontinued. No dose related
induction of endometriosis was observed; the highest incidence occurred
in the control and high PCB dose groups. No evidence of endometriosis
was detected in monkeys born in captivity but did occur in 22 of 71 feral
monkeys. During the first 3 years of the study, 4 of the treated monkeys
became moribund and were euthanized; 3 had endometriosis. This finding
suggested a possible link between the PCB treatment and the occurrence
of endometriosis. However, neither a laparoscopic examination of
the control and high-dose monkeys nor the necropsy data provided evidence
for a possible link between the PCB treatment and the observed incidence
(37% (6/16) of controls; 25% (16/64) of treated monkeys and/or the severity
of the endometrial lesions. Statistically significantly PCB dose
related decreases in anti-SRBC titers and increases in natural killer cell
activity were observed. Significant differences in anti-SRBC titers between
monkeys with or without endometriosis were seen only in the high
dose PCB group. No significant differences in killer cell activity, levels
of tumor necrosis factor, interleukin-1, or thymosin alpha1 and beta2 were
found between monkeys with or without endometriosis. The authors
conclude that daily doses of PCBs comparable to human exposures do not
induce endometriosis in Rhesus-monkeys. (Arnold et al, 1996) [Only
9 of the 80 monkeys was captive-reared with a controlled diet. The rest
were wild and could have been exposed to PCBs, dioxins or other chemicals
in their prior lives.]
Study #4
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no correlation found between PCBs and endometriosis
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study used 14 congeners of PCBs [study may have used the
wrong types of PCBs]
Objective: To compare mean concentrations of organochlorine
in women with a new diagnosis of endometriosis and in controls.
Design: Case-control study. Setting: Women attending an institutional clinic
of reproductive endocrinology. Patient(s): Cases and controls were selected
among women who underwent laparoscopy for chronic pelvic pain, infertility,
or tubal fulguration between January 1994 and December 1994. Eighty-six
women with endometriosis and 70 controls, matched for the indication
for laparoscopy, were recruited. Main Outcome Measure(s): Mean organochlorine
plasma concentrations of 14 polychlorinated biphenyl congeners and 11 chlorinated
pesticides were compared between the cases and controls. Analysis of covariance
was used to adjust means for confounding variables, and odds ratios were
estimated by logistic regression. Result(s): Crude geometric mean concentrations
did not differ significantly between cases and controls for any of the
organochlorine compounds. (Lebel et al, 1998)
Study #5
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no compelling evidence for an organochlorine dependent, estrogen
mediated effect on endometriosis
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no evidence excluding the possibility either
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(This was a 1995 paper --- many studies occurred later.)
The chemical and experimental data linking organochlorine
compounds to cancer of the breast, endometriosis, and endometrial
cancer through an estrogenic effect were reviewed. Estrogenicity was defined
as producing biological responses comparable to endogenous estrogen, such
as increased uterine weight. Surveys found that organochlorine compounds
accumulate in adipose tissue. Human exposure resulted from eating contaminated
foods, particularly those high in fat. Body burden increased with increasing
age. Geographical variation in body burden varied with local use and environmental
burden. DDT (50293) mimicked the effects of estrogen in several animal
studies, elevating uterine weights, enzymes, and glycogen content, and
stimulating cell division in the uterus. Polychlorinated biphenyls (PCB)
also showed estrogenic properties in animal studies, including binding
to estrogen receptors leading to increased uterine weights and blocking
ovulation. When hydroxylated, PCB congeners structurally resembled estradiol.
Other organochlorine compounds, such as chlorinated dioxins, showed antiestrogenic
properties in-vivo. Most available data regarding estrogenic effects of
various organochlorinated compounds were based on either in-vitro testing
or short term, single exposure in-vivo tests. Few studies provided information
about long term exposure to low doses of potentially estrogenic compounds
that would parallel exposure in young women. Data concerning endometrial
cancer and endometriosis were especially limited. The authors conclude
that laboratory data do not provide compelling evidence for an organochlorine
dependent, estrogen mediated effect on cancer of the breast, endometrial
cancer, or endometriosis, although they do not exclude the possibility
of such an effect. (Ahlborg et al, 1995)
Study #6
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Eleven (13%) of 80 female monkeys were removed from study
because they developed endometriosis, cervical cancer and PCB toxicity
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immune system damage
The immunomodulatory effects of aroclor-1254 (11097691) were
studied in monkeys. Female rhesus-monkeys were administered 0, 5, 20, 40,
or 80 micrograms per kilogram (microg/kg) aroclor-1254 daily. Peripheral
blood samples were collected after 55 months and assayed for aroclor-1254.
The effects on immune function were assessed at this time by determining
the immunoglobulin-M (IgM) and immunoglobulin-G (IgG) responses to sheep
red blood cells (SRBCs), the antibody response to pneumococcal antigen,
the lymphocyte proliferative response to concanavalin-A (conA), phytohemagglutinin
(PHA), and pokeweed-mitogen, the mixed lymphocyte response, the monocytic
response to zymosan or phorbol-myristate-acetate (PMA), and the production
of interleukin-1. A flow cytometric analysis of peripheral blood leukocyte
subpopulations was performed. Serum hydrocortisone concentrations were
measured. Eleven of 80 monkeys were removed from the study because they
developed endometriosis, cervical cancer, and polychlorinated biphenyl
(PCB) toxicity. Blood aroclor-1254 concentrations ranged from 21.276
parts per million (ppm) in the 5microg/kg group to 285.919ppm in the 80microg/kg
dose group. Aroclor-1254 caused a significant dose related decrease in
the IgM and IgG response to conA and PHA. The monocyte response to zymosan
stimulation was nonsignificantly increased. The monocyte response to PMA
was significantly increased in a dose related manner. The mean proportion
of CD2 cells was significantly decreased by aroclor-1254; however, the
absolute number of CD2 cells was unaffected. None of the other parameters
of immune system function was significantly affected by aroclor-1254. The
authors conclude that low level chronic PCB exposure causes moderate changes
in several parameters of immune system function in rhesus-monkeys. These
changes may reflect alterations in T-cell or macrophage function. (Tryphonas
et al, 1991)
Study #7
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certain non-coplanar PCBs are estrogenic
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certain coplanar PCBs (dioxin-like) disrupt estrogen function
in a manner that is dose, species and tissue specific
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dioxin is correlated with endometriosis
Environmental pollutants are known to exert endocrine-disrupting
effects on several hormonal axes of animals, including reproduction and
development. Many of these xenobiotics modulate the estrogen-receptor signaling
pathway(s) in agonistic or antagonistic ways. Some of the compounds are
themselves estrogenic (so-called xenoestrogens, environmental estrogens,
or ecoestrogens), and are classified as synthetic estrogens, phyto- or
fungal estrogens, alkylphenol ethoxylates; certain non-coplanar polychlorinated
biphenyls (PCBs), etc. Other molecules are antiandrogenic, e.g., p,p'-dichloro-diphenyl-dichloroethylene
(DDE); while still others disrupt estrogen function in a manner that is
dose, species and tissue specific, e.g., certain co-planar PCBs
and dioxin-like molecules (e.g., tetrachlorodibenzo-p-dioxin (TCDD)). Exposure
to some compounds has been correlated with skewing of sex ratios in aquatic
species, and feminization and demasculinization of male animals; declines
in human sperm counts; and overall diminution in fertility of birds, fish,
and mammals. This review will cover these various xenobiotics and evaluate
them for their estrogen-modulating effects; and then further concentrate
on TCDD specifically. Dioxins are produced as by-products of herbicide
overuse, from paper bleaching, plastics manufacture, and waste incineration.
TCDD has been correlated with altered fecundity and endometriosis
in monkeys, and with certain cancers in experimental animals and humans.
TCDD is also correlated with reproductive deficits in many laboratory species.
In summary, we believe that some of the reproductive deficits from endocrine-disrupting
xenobiotics may be attributable to the modulation of the estrogen-signaling
pathway, in positive and negative manners, depending on dose, species,
and tissue specificity. (Hutz, 1999)
Study #8
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cytokine expression in endometrial cells is altered by PCBs
Cytokine expression in human uterine endometrial rl95-2 cells
is altered by polychlorinated biphenyls, 2,3,7,8-tetrachlorodibenzo-p-dioxin
and benzo(a)pyrene. Meeting Abstract. Meeting Poster: rl95-2 cell line
carcinogen-induced cytokine expression alteration human endometrial
adenocarcinoma cell line tumor biology polychlorinated biphenyls carcinogen
2,3,7,8-tetrachlorodibenzo-p-dioxin benzo-&(a&)-pyrene (Shiverick
et al, 1999) (citation incomplete)
Study #9
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multifocal endometrial epithelial hyperplasia
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increased duration of gestation
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decreased number of pregnancies
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defects in inguinal zone
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reduced in weight of several reproductive organs
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reduced number of corpora lutea
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study used PCB 169 (co-planar and dioxin-like) or PCB 153
(non-planar)
The polyhalogenated biphenyls were all administered by gavage
to sperm-positive female albino Wistar rats on day 1 of gestation, as a
single dose. The effects on the next generation of rats (F1), which was
exposed in utero and during lactation, were studied. This offspring was
constantly monitored for general health. Several developmental landmarks
were recorded and once the rats were sexually mature, they were tested
for their reproduction capacity. Finally the rats were necropsied. Maternal
administration of PCB#169 (3,4,5,3',4',5'-hexachlorobiphenyl), a planar
and therefore dioxin-like PCB, increased the duration of gestation and
decreased the number of pregnancies. Upon necropsy, morphological defects
in the inguinal zone and a reduction in the weight of several reproductive
organs were recorded. Furthermore, in the females a reduced number of corpora
lutea and multifocal endometrial epithelial hyperplasia was observed.
Administration of PCB#153 (2,4,5,2',4',5'-hexachlorobiphenyl), a non-planar
PCB, increased the duration of gestation exceptionally, finally resulting
in the death of the dam which was unable to deliver the fully grown pups.
Currently the effects of gestational administration on the next generation
of the planar PCB#126 (3,4,5,3',4'-pentachlorobiphenyl), the non-planar
PCB#118 (2,3',4,4',5-pentachlorobiphenyl), and 2,3,4,7,8-pentachlorodibenzofuran
are investigated in similar 2-generation reproduction studies. (Waalkens-Berendsen
et al, 1995)
Study #10
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multifocal endometrial epithelial hyperplasia
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increased duration of gestation
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decreased precoital time
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decreased number of pregnancies
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defects in inguinal zone
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reduced in weight of several reproductive organs
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reduced number of corpora lutea
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changes in the liver, uterus and ovaria
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enlarged clitoris
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reduction in testis, epididymis and seminal vesicle weight
and in number of epididymal spermatocytes
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effects primarily due to PCB exposure in the womb, rather
than through breastfeeding
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study used PCB 169 (co-planar and dioxin-like)
In the Netherlands, the potential long-term effects of foetal
and/or neonatal exposure to PCBs in rats and humans were studied in a collaboration
between five institutes. The animal research included studies into the
effects of PCBs on metabolism and kinetics, neurology, behaviour and fertility
of rats exposed to single isomers or commercial mixtures. The present paper
describes effects of 2,2',3,3',4,4'-hexachlorobiphenyl (PCB 169) on the
fertility, reproduction and early postnatal development of albino Wistar
rats. At the start of a 2-generation reproduction study, sperm-positive
females were exposed on day 1 of gestation by gavage to a single dose of
0.2, 0.6 or 1.8 mg PCB 169/kg bw dissolved in corn oil, or to corn oil
(2 mL/kg bw) only. The offspring (F1-generation) was studied for changes
in body weight, general health, development of physical landmarks and several
aspects of behaviour. Few of these parameters were affected, but only to
a slight extent. The reproduction capacity of the F1-generation animals
was also studied, by mating the rats with partners from the same dose group.
Only 33% of the mating pairs in the 1.8 mg/kg PCB 169 group produced a
viable litter, following an increased duration of gestation. Treatment-related
histopathological changes were observed in the liver, epididymides, uterus
and ovaria. The same procedures were largely followed in a subsequent cross-fostering
study in which initially only two dose groups were formed, vehicle control
and 1.8 mg PCB 169/kg bw, respectively. Upon birth all litters were mutually
exchanged, thus creating 4 differently exposed groups of offspring: A)
exposed neither in utero, nor during lactation; B) exposed in utero but
not during lactation; C) exposed both in utero and during lactation; D)
exposed during lactation, and not in utero. The F1-generation rats were
mated with untreated partners of the same strain and age. Reproduction
data of the treated males showed a reduced number of pregnancies in all
treatment groups. Reproduction data of the treated females showed a decreased
precoital time and number of pregnancies and an increased duration of gestation
in the females of groups B and C. During the study morphological defects
in the inguinal zone were detected both in treated males and females. Histological
examination revealed a reduction in testis, epididymis and seminal vesicle
weight and in number of epididymal spermatocytes in the males of group
B, and an enlarged clitoris, reduced number of corpora lutea and multifocal
endometrial epithelial hyperplasia in the females of groups B and C.
Other parameters like vaginal opening, testes descent, anogenital distance,
sperm physiology and morphology were not affected or showed minor differences
between the groups. The results of the cross-fostering study show that
the results found in the first study are caused by defects in the reproduction
capacity of both in males and females. These reproduction defects are induced,
particularly upon intrauterine exposure to PCB 169, while lactational exposure
appeared less critical. (Waalkens-Berendsen et al, 1995)
Study #11
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inhibited progesterone cytosolic receptor binding (changed
the hormone balance)
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study used PCB commercial mixture Aroclor 1242
The effects of DDE isomers, aroclor-1242, and chlordane
(57749) on progesterone/cytoplasmic binding in the eggshell and mucosa
of birds and the uterine mucosa of rabbits were studied in-vitro.
Eggshell gland mucosa cytosol obtained from Indian-Runner-ducks, Swedish-Rouen-ducks,
and White-Leghorn-hens and the uterine mucosa of rabbits were incubated
with 0 to 110x10(-6) molar (M) p,p'-DDE (72559), o,p'-DDE (3424826), aroclor-1242,
or chlordane. The effects on binding of tritium labeled progesterone to
the cytoplasmic receptor were assessed. In untreated cytosol the extent
of progesterone receptor binding was significantly higher in hens and rabbits
than in the ducks. The DDE isomers, aroclor-1242, and chlordane
inhibited progesterone cytosolic receptor binding in a dose dependent
manner. The largest inhibitory effects occurred in ducks and rabbits. o,p'-DDE
was more potent than p,p'-DDE in the hens and ducks. In rabbits, the inhibitory
effects of o,p'-DDE and p,p'-DDE were similar except at the 110x10(-6)M
dose, where o,p'-DDE had a greater effect. Aroclor-1242 and chlordane
inhibited progesterone cytosolic receptor binding to a greater extent in
ducks. Shell gland mucosa cytosol from hens was incubated with 1x10(-6)
to 5x10(-5)M p,p'-DDE, o,p'-DDE, and the calmodulin inhibitors calmidazolium
and trifluoperazine. The effects on progesterone cytoplasmic receptor binding
were evaluated. Calmidazolium and trifluoperazine inhibited progesterone
cytosolic receptor binding to about the same extent as p,p'-DDE, but to
a lesser extent than o,p'-DDE. (Lundholm, 1988)
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