Environmental Dioxins and Endometriosis

ABSTRACT

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 support 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;ndinduced toxicity in endometriosis, important knowledge needs, potential animal models for endometriosis studies, and considerations integral to future human case-control studies are discussed.

KEYWORDS

endometriosis - environmental dioxins - TCDD - dioxin-like polychlorinated biphenyls

REFERENCES

• 1 Wheeler J M. Epidemiology and prevalence of endometriosis.  Infertil Reprod Med Clin North Am . 1992;  3 545-549
• 2 Carlson K, Miller B, Fowler F J. The Maine women's health study: I. Outcomes of hysterectomy.  Obstet Gynecol . 1994;  83 556-565
• 3 Halme J, Stovall D. Endometriosis and its medical management. In: Wallach EE, Zacur HA, eds. Reproductive Medicine and Surgery St. Louis: Mosby 1995: 695-710
• 4 Eskenazi B, Warres M. Epidemiology of endometriosis.  Obstet Gynecol Clin North Am . 1997;  24 235-258
• 5 Sampson J A. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity.  Am J Obstet Gynecol . 1927;  14 422-469
• 6 Suginami H. A reappraisal of the coelomic metaplasia theory by reviewing endometriosis occurring in unusual sites and instances.  Am J Obstet Gynecol . 1991;  165 214-218
• 7 Fujii S. Secondary mullerian system and endometriosis.  Am J Obstet Gynecol . 1991;  165 219-225
• 8 Olive D L, Henderson D Y. Endometriosis and mullerian anomalies.  Obstet Gynecol . 1987;  69 412-415
• 9 D'Hooghe T M, Bambra C S, Suleman M A. et al . Development of a model of retrograde menstruation in baboons (Papio anubis).  Fertil Steril . 1994;  62 635-638
• 10 Halme J, Hammond M G, Hulka J F, Raj S G, Talbert L M. Retrograde menstruation in healthy women and in patients with endometriosis.  Obstet Gynecol . 1984;  64 151-154
• 11 Zamah N M, Dodson M G, Stephens L C. et al . Transplantation of normal and ectopic human endometrial tissue into athymic nude mice.  Am J Obstet Gynecol . 1984;  149 591-597
• 12 Noble L S, Simpson E R, Johns A, Bulun S E. Aromatase expression in endometriosis.  J Clin Endocrinol Metab . 1996;  81 174-179
• 13 Zarmakoupis P N, Rier S E, Maroulis G B, Becker J L. Inhibition of human endometrial stromal cell proliferation by interleukin 6.  Hum Reprod . 1995;  10 2395-2399
• 14 Rier S E, Zarmakoupis P N, Hu X, Becker J L. Dysregulation of interleukin-6 responses in ectopic endometrial stromal cells: correlation with decreased soluble receptor levels in peritoneal fluid of women with endometriosis.  J Clin Endocrinol Metab . 1995;  80 1431-1437
• 15 Whitlock J P. Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action.  Annu Rev Pharmacol . 1990;  30 251-277
• 16 Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs).  Crit Rev Toxicol . 1990;  21 51-88
• 17 Safe S H. Polychlorinated biphenyls (PCBs): environmental impact, biochemical and toxic responses, and implications for risk assessment.  Crit Rev Toxicol . 1994;  24 87-149
• 18 Hankinson O. The aryl hydrocarbon receptor complex.  Annu Rev Pharmacol . 1995;  35 307-340
• 19 Van den Berg M, Birnbaum L, Bosveld A TC. et al . Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife.  Environ Health Perspect . 1998;  106 775-792
• 20 Schecter A, Stanley J, Boggess K. et al . Polychlorinated biphenyl levels in the tissues of exposed and nonexposed humans.  Environ Health Perspect . 1994;  102 149-158
• 21 Schecter A, Furst P, Furst C. et al . Chlorinated dioxins and bibenzofurans in human tissue from general populations: a selective review.  Environ Health Perspect . 1994;  102 159-171
• 22 DeVito M J, Birnbaum L S, Farland W H, Gasiewicz T A. Comparisons of estimated human body burdens of dioxinlike chemicals and TCDD body burdens in experimentally exposed animals.  Environ Health Perspect . 1995;  103 820-831
• 23 Farland W, Schaum J, Winters D. et al . USEPAs risk characterization of dioxin and related compounds.  Organohalogen Compd . 2000;  48 248-251
• 24 Rier S E, Martin D C, Bowman R E, Dmowski W P, Becker J L. Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.  Fundam Appl Toxicol . 1993;  21 433-441
• 25 Yang J Z, Agarwal S K, Foster W G. Subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates the pathophysiology of endometriosis in the cynomolgus monkey.  Toxicol Sci . 2000;  56 374-381
• 26 Rier S E, Turner W E, Martin D C. et al . Serum levels of TCDD and dioxinlike chemicals in rhesus monkeys chronically exposed to dioxin: correlation of increased serum PCB levels with endometriosis.  Toxicol Sci . 2001;  59 147-159
• 27 Vanden Heuvel P J, Clark G C, Tritscher A M, Lucier G W. Accumulation of polychlorinated dibenzo-p-dioxins and dibenzofurans in liver of control laboratory rats.  Fundam Appl Toxicol . 1994;  23 465-469
• 28 Yoshida K, Ikeda S, Nakanishi J. Assessment of human health risk of dioxins in Japan.  Chemosphere . 2000;  40 177-185
• 29 Cummings A M, Metcalf J L, Birnbaum L. Promotion of endometriosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats and mice: time-dose dependence and species comparison.  Toxicol Appl Pharmacol . 1996;  138 131-139
• 30 Johnson K L, Cummings A M, Birnbaum L S. Promotion of endometriosis in mice by polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls.  Environ Health Perspect . 1997;  105 750-755
• 31 Yang J Z, Foster W G. Continuous exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits the growth of surgically induced endometriosis in the ovariectomized mouse treated with high dose estradiol.  Toxicol Ind Health . 1997;  13 15-25
• 32 Matsui K A, Okamura S, Yamashita K, Fujii-Kuriyama Y, Yasuda M. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on surgically induced endometriosis in mice and the role of Ah receptor.  Organohalogen Compd . 2000;  49 345-348
• 33 Koninckx P R, Braet P, Kennedy S H, Barlow D H. Dioxin pollution and endometriosis in Belgium.  Hum Reprod . 1994;  9 1001-1002
• 34 WHO Report. Levels of PCBs, PCDDs and PCDFs in Breast Milk: Result of WHO Coordinated Inter-Laboratory Quality Control Studies and Analytical Field Studies. WHO Environmental Series, 1989
• 35 Mayani A, Barel S, Soback S, Almagor M. Dioxin concentrations in women with endometriosis.  Hum Reprod . 1997;  12 373-375
• 36 Boyd J A, Clark G C, Walmer D K, Needham L L, Lucier G W. Endometriosis and the environment: biomarkers of toxin exposure. Presented at the Endometriosis Workshop; May 15-17, 1995; National Institutes of Health, Bethesda, MD
• 37 Eskenazi B, Mocarelli P, Warner M. et al . Seveso Women's Health Study: a study of the effects of 2,3,7,8,-tetrachlorodibenzo-p-dioxin on reproductive health.  Chemosphere . 2000;  40 1247-1253
• 38 Pauwels A, Brouwer A, Weyler J, Schepens P JC. The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case-control study of infertile women.  Hum Reprod . 2001;  16 2050-2055
• 39 Van Larebeke N, Hens L, Schepens P. et al . The Belgian PCB and dioxin incident of January-June 1999; exposure data and potential impact on health.  Environ Health Perspect . 2001;  109 265-273
• 40 Brown D J, Chu M, Overmeire I V, Chu A, Clark G C. Determination of rep values for the CALUX bioassay and comparison to the WHO TEF values.  Organohalogen Compd . 2000;  48 211-214
• 41 Fernandez-Salguero P, Pineau T, Hilbert D M. et al . Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor.  Science . 1995;  268 722-726
• 42 Abbott B D, Schmid J E, Pitt J A. et al . Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse.  Toxicol Appl Pharmacol . 1999;  155 62-70
• 43 Hasan A, Fischer B. Hormonal control of arylhydrocarbon (AhR) expression in the rabbit uterus.  Anat Embryol . 2001;  204 189-196
• 44 Yeaman G R, Collins J E. Arylhydrocarbon receptor expression in human female reproductive tract tissues and peritoneal fluid. Abstract presented at Endometriosis 2000 7th Annual World Congress; May 15, 2000; London
• 45 Igarashi T, Osuga U, Tsutsumi O. et al . Expression of Ah receptor and dioxin-related genes in human uterine endometrium in women with or without endometriosis.  Endocr J . 1999;  46 765-772
• 46 Bofinger D P, Feng L, Chi L. et al . Effect of TCDD exposure on CYP1A1 and CYP1B1 expression in explant cultures of human endometrium.  Toxicol Sci . 2001;  62 299-314
• 47 Pitt J A, Feng L, Abbott B D. et al . Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD.  Toxicol Sci . 2001;  62 289-298
• 48 Khorram O, Garthwaite M, Golos T. Uterine and ovarian aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions.  Mol Hum Reprod . 2002;  8 75-80
• 49 Bulun S E, Zeitoun K M, Kilic G. Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues.  Am J Obstet Gynecol . 2000;  182 767-775
• 50 Takayama K, Zeitoun K, Gunby R T. et al . Treatment of severe postmenopausal endometriosis with an aromatase inhibitor.  Fertil Steril . 1998;  69 709-713
• 51 Rier S E, Yeaman G R. Immune aspects of endometriosis: relevance of the uterine mucosal immune system.  Semin Reprod Endocrinol . 1997;  15 209-220
• 52 Osteen K G, Bruner K L, Sharpe-Timms K L. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis.  Semin Reprod Endocrinol . 1996;  14 247-255
• 53 Watson A J. Chemopreventive effects of NSAIDs against colorectal cancer: regulation of apoptosis and mitosis by COX-1 and COX-2.  Histol Histopathol . 1998;  13 591-597
• 54 Yeh W C, Hakem R, Woo M, Mak T W. Gene targeting in the analysis of mammalian apoptosis and TNF receptor superfamily signaling.  Immunol Rev . 1999;  169 283-302
• 55 Weitzmann S A, Gordon L I. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis.  Blood . 1990;  655-663
• 56 Kerkvliet N I, Oughton J A. Acute inflammatory response to sheep red blood cell challenge in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): phenotypic and functional analysis of peritoneal exudate cells.  Toxicol Appl Pharmacol . 1993;  119 248-257
• 57 Clark G C, Taylor M J, Tritscher A M, Lucier G W. Tumor necrosis factor involvement in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated endotoxin hypersensitivity in C57BL/6J mice congenic at the Ah locus.  Toxicol Appl Pharmacol . 1991;  111 422-431
• 58 Moos A B, Oughton J A, Kerkvliet N I. The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on tumor necrosis factor production by peritoneal cells.  Toxicol Lett . 1997;  90 145-153
• 59 Moos A B, Baecher-Steppan L, Kerkvliet N I. Acute inflammatory response to sheep red blood cells in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin: the role of proinflammatory cytokines, IL-1 and TNF.  Toxicol Appl Pharmacol . 1994;  127 331-335
• 60 Taylor M J, Lucier G W, Mahler J F. et al . Inhibition of acute TCDD toxicity by treatment with anti-tumor necrosis factor antibody or dexamethasone.  Toxicol Appl Pharmacol . 1992;  117 126-132
• 61 Halme J. Release of tumor necrosis factor-alpha by human peritoneal macrophages in vivo and in vitro.  Am J Obstet Gynecol . 1989;  161 1718-1725
• 62 Rier S E, Parsons A K, Becker J L. Altered interleukin-6 production by peritoneal leukocytes from patients with endometriosis.  Fertil Steril . 1994;  61 294-299
• 63 Rana N, Braun D P, House R. et al . Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis.  Fertil Steril . 1996;  65 925-930
• 64 Klein N A, Pergola G M, Rao-Tekmal R, Dey T D, Schenken R S. Enhanced expression of resident leukocyte interferon gamma mRNA in endometriosis.  Am J Reprod Immunol . 1993;  30 74-81
• 65 Tseng J F, Ryan I P, Milam T D. et al . Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis.  J Clin Endocrinol Metab . 1996;  81 1118-1122
• 66 Gottschalk C, Malberg K, Arndt M. et al . Matrix metalloproteinases and TACE play a role in the pathogenesis of endometriosis.  Adv Exp Med Biol . 2000;  477 483-486
• 67 D'Antonio M, Martelli F, Peano S, Papoian R, Borrelli F. Ability of recombinant human TNF binding protein-1 (r-hTBP-1) to inhibit the development of experimentally-induced endometriosis in rats.  J Reprod Immunol . 2000;  48 81-98
• 68 Zhang R J, Wild R A, Ojago J M. Effect of tumor necrosis factor-alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: an in vitro system.  Fertil Steril. 1993;  59 1196-1201
• 69 Leibovich S J, Polverini P J, Shepard H M. et al . Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha.  Nature . 1987;  329 630-632
• 70 Lai Z W, Pineau T, Esser C. Identification of dioxin-responsive elements (DREs) in the 5′ regions of putative dioxin-inducible genes.  Chem Biol Interact . 1996;  100 97-112
• 71 Lai Z W, Hundeiker C, Gleichmann E, Esser C. Cytokine gene expression during ontogeny in murine thymus on activation of aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin.  Mol Pharmacol . 1997;  52 30-37
• 72 Rier S E, Coe C L, Lemieux A M. et al . Increased tumor necrosis factor alpha by peripheral blood leukocytes from TCDD-exposed rhesus monkeys.  Toxicol Sci . 2001;  60 327-337
• 73 Bruner K L, Rodgers W H, Korc M. et al . Transforming growth factor-β mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma.  Proc Natl Acad Sci U S A . 1995;  92 7362-7366
• 74 Bruner K L, Rodgers W H, Gorstein F, Osteen K G. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human tissue in nude mice.  J Clin Invest . 1997;  99 2851-2857
• 75 Osteen K G, Keller N R, Feltus F A, Melner M H. Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium.  Gynecol Obstet Invest . 1999;  48 (suppl 1) 2-13
• 76 Bruner-Tran K, Rier S E, Eisenberg E, Osteen K G. The potential role of environmental toxins in the pathophysiology of endometriosis.  Gynecol Obstet Invest . 1999;  48 45-56
• 77 Vernon M W. Animal models in endometriosis research.  Infertil Reprod Med Clin North Am . 1992;  3 565-581
• 78 Fanton J W, Golden J G. Radiation-induced endometriosis in Macaca mulatta Radiat Res .  1991;  126 141-146
• 79 D'Hooghe T M, Bambra C S, Raeymaekers B M. et al . Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus and Papio anubis).  Am J Obstet Gynecol . 1995;  173 125-134
• 80 Povlsen C O, Fialkow P J, Klein E. et al . Growth and antigenic properties of a biopsy-derived Burkitt's lymphoma in thymus-less (nude) mice.  J Cancer . 1973;  11 30-39
• 81 Merenda C, Sordat B, Mach J P, Carrel S. Human endometrial carcinomas serially transplanted in nude mice and established in continuous cell lines.  Int J Cancer . 1975;  16 559-570
• 82 Bergqvist A, Jeppsson S, Kullander S, Ljungberg O. Human uterine endometrium and endometriotic tissue transplanted into nude mice. Morphologic effects of various steroid hormones.  Am J Pathol . 1985;  121 337-341
• 83 Aoki D, Katsuki Y, Shimizu A, Kakinuma C, Nozawa S. Successful heterotransplantation of human endometrium in SCID mice.  Obstet Gynecol . 1994;  83 220-228
• 84 Awwad J T, Sayegh R A, Tao X J. et al . The SCID mouse: an experimental model for endometriosis.  Hum Reprod . 1999;  14 3107-3111
• 85 D'Hooghe T M, Bambra C S, Isahakia M, Koninckx P R. Evolution of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus) over a 12-month period.  Fertil Steril . 1992;  58 409-412
• 86 Redwine D B. Age-related evolution in color appearance of endometriosis.  Fertil Steril . 1987;  48 1062-1063