PCBs, Dioxin and Endometriosis
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. |
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
- endometriotic lesion diameter was increased
- endometriotic lesion weight increased
- ovarian weight increased with certain PCBs
- ovarian weight decreased with other PCBs
- Corpora lutea were absent or regressive in the ovaries
- 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
- 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
- highly dosed females developed endometriosis, as did controls
- 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
- no correlation found between PCBs and endometriosis
- 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
- no compelling evidence for an organochlorine dependent, estrogen mediated effect on endometriosis
- no evidence excluding the possibility either
- (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
- Eleven (13%) of 80 female monkeys were removed from study because they developed endometriosis, cervical cancer and PCB toxicity
- 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
- certain non-coplanar PCBs are estrogenic
- certain coplanar PCBs (dioxin-like) disrupt estrogen function in a manner that is dose, species and tissue specific
- 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
- 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
- multifocal endometrial epithelial hyperplasia
- increased duration of gestation
- decreased number of pregnancies
- defects in inguinal zone
- reduced in weight of several reproductive organs
- reduced number of corpora lutea
- 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
- multifocal endometrial epithelial hyperplasia
- increased duration of gestation
- decreased precoital time
- decreased number of pregnancies
- defects in inguinal zone
- reduced in weight of several reproductive organs
- reduced number of corpora lutea
- changes in the liver, uterus and ovaria
- enlarged clitoris
- reduction in testis, epididymis and seminal vesicle weight and in number of epididymal spermatocytes
- effects primarily due to PCB exposure in the womb, rather than through breastfeeding
- 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
- inhibited progesterone cytosolic receptor binding (changed the hormone balance)
- 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) |
