Dioxin and Endometrial Progesterone Resistance

Development of endometriosis likely requires multiple, interactive mechanisms involving both the endocrine and immune systems. Environmental toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are of particular interest as potential contributory agents in the development of this disease because they can disrupt both systems. Nevertheless, defining the potential role that environmental exposure to TCDD plays in the development of endometriosis requires a better understanding of how this toxicant affects the biological processes that promote the disease. Although the disease mechanism(s) responsible for progesterone resistance in the endometrium of endometriosis patients remains speculative, our studies indicate that developmental exposure of mice to TCDD leads to a progesterone-resistant phenotype in adult animals that can persist for several generations. These studies and others underscore the importance of developing a greater understanding of the mechanisms of TCDD action that relate to reproductive disorders such as endometriosis.

Endometriosis - TCDD - developmental exposure

- 1 Sampson J A. Peritoneal endometriosis due to menstrual dissemination of endometrial tissues into the peritoneal cavity. Am J Obstet Gynecol. 1927; 14 422-469 - 2 Giudice L C, Kao L C. Endometriosis. Lancet. 2004; 364(9447) 1789-1799 - 3 Bulun S E. Endometriosis. N Engl J Med. 2009; 360(3) 268-279 - 4 Bruner-Tran K L, Yeaman G R, Crispens M A, Igarashi T M, Osteen K G. Dioxin may promote inflammation-related development of endometriosis. Fertil Steril. 2008; 89(5, Suppl) 1287-1298 - 5 Foster W G. Environmental estrogens and endocrine disruption: importance of comparative endocrinology. Endocrinology. 2008; 149(9) 4267-4268 - 6 Crain D A, Janssen S J, Edwards T M et al.. Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril. 2008; 90(4) 911-940 - 7 Okino S T, Whitlock Jr J P. The aromatic hydrocarbon receptor, transcription, and endocrine aspects of dioxin action. Vitam Horm. 2000; 59 241-264 - 8 Kerkvliet N I. AHR-mediated immunomodulation: the role of altered gene transcription. Biochem Pharmacol. 2009; 77(4) 746-760 - 9 Heindel J J. Role of exposure to environmental chemicals in the developmental basis of reproductive disease and dysfunction. Semin Reprod Med. 2006; 24(3) 168-177 - 10 National Toxicology Program .Current directions and emerging strategies, 2001. Available at: http://ntp.niehs.nih.gov/ntp/Main_Pages/PUBS/NTP2001CurrDir.pdf Accessed April 2009 - 11 Birnbaum L S. Endocrine effects of prenatal exposure to PCBs, dioxins, and other xenobiotics: implications for policy and future research. Environ Health Perspect. 1994; 102(8) 676-679 - 12 Harrad S, Wang Y, Sandaradura S, Leeds A. Human dietary intake and excretion of dioxin-like compounds. J Environ Monit. 2003; 5(2) 224-228 - 13 Pompa G, Caloni F, Fracchiolla M L. Dioxin and PCB contamination of fish and shellfish: assessment of human exposure. Review of the international situation. Vet Res Commun. 2003; 27(Suppl 1) 159-167 - 14 Schecter A, Wallace D, Pavuk M, Piskac A, Päpke O. Dioxins in commercial United States baby food. J Toxicol Environ Health A. 2002; 65(23) 1937-1943 - 15 Domingo J L, Bocio A. Levels of PCDD/PCDFs and PCBs in edible marine species and human intake: a literature review. Environ Int. 2007; 33(3) 397-405 - 16 Dewailly E, Ryan J J, Laliberté C et al.. Exposure of remote maritime populations to coplanar PCBs. Environ Health Perspect. 1994; 102(Suppl 1) 205-209 - 17 Focant J F, Pirard C, Thielen C, De Pauw E. Levels and profiles of PCDDs, PCDFs and cPCBs in Belgian breast milk. Estimation of infant intake. Chemosphere. 2002; 48(8) 763-770 - 18 Koninckx P R, Braet P, Kennedy S H, Barlow D H. Dioxin pollution and endometriosis in Belgium. Hum Reprod. 1994; 9(6) 1001-1002 - 19 De Felip E, Porpora M G, di Domenico A et al.. Dioxin-like compounds and endometriosis: a study on Italian and Belgian women of reproductive age. Toxicol Lett. 2004; 150(2) 203-209 - 20 Bruner-Tran K L, Eisenberg E, Yeaman G R, Anderson T A, McBean J, Osteen K G. Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. J Clin Endocrinol Metab. 2002; 87(10) 4782-4791 - 21 Kao L C, Germeyer A, Tulac S et al.. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003; 144(7) 2870-2881 - 22 Bruner-Tran K L, Rier S E, Eisenberg E, Osteen K G. The potential role of environmental toxins in the pathophysiology of endometriosis. Gynecol Obstet Invest. 1999; 48(Suppl 1) 45-56 - 23 Psychoyos A. Uterine receptivity for nidation. Ann N Y Acad Sci. 1986; 476 36-42 - 24 Bergh P A, Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation. Fertil Steril. 1992; 58(3) 537-542 - 25 Edwards R G. Physiological and molecular aspects of human implantation. Hum Reprod. 1995; 10(Suppl 2) 1-13 - 26 Tabibzadeh S. Human endometrium: an active site of cytokine production and action. Endocr Rev. 1991; 12(3) 272-290 - 27 Giudice L C. Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine. Fertil Steril. 1994; 61(1) 1-17 - 28 Simón C, Frances A, Piquette G, Hendrickson M, Milki A, Polan M L. Interleukin-1 system in the materno-trophoblast unit in human implantation: immunohistochemical evidence for autocrine/paracrine function. J Clin Endocrinol Metab. 1994; 78(4) 847-854 - 29 Tazuke S I, Giudice L C. Growth factors and cytokines in endometrium, embryonic development, and maternal: embryonic interactions. Semin Reprod Endocrinol. 1996; 14(3) 231-245 - 30 Critchley H O, Kelly R W, Brenner R M, Baird D T. The endocrinology of menstruation—a role for the immune system. Clin Endocrinol (Oxf). 2001; 55(6) 701-710 - 31 Lessey B A, Killam A P, Metzger D A, Haney A F, Greene G L, McCarty K D. Immunohistochemical analysis of human uterine estrogen and progesterone receptors in the normal human uterus throughout the menstrual cycle. J Clin Endocrinol Metab. 1988; 67 334-340 - 32 Ravn V, Rasmussen B B, Højholt L et al.. Estrogen- and progesterone receptors in normal cycling endometrium as studied by end-point titration. Cell Tissue Res. 1994; 276(3) 419-428 - 33 Cunha G R, Cooke P S, Kurita T. Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol. 2004; 67(5) 417-434 - 34 Lessey B A. Two pathways of progesterone action in the human endometrium: implications for implantation and contraception. Steroids. 2003; 68(10-13) 809-815 - 35 Anderson T L, Gorstein F, Osteen K G. Stromal-epithelial cell communication, growth factors, and tissue regulation. Lab Invest. 1990; 62(5) 519-521 - 36 Cunha G R, Young P. Role of stroma in oestrogen-induced epithelial proliferation. Epithelial Cell Biol. 1992; 1 18-31 - 37 Osteen K G, Rodgers W H, Gaire M et al.. Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci U S A. 1994; 91(21) 10129-10133 - 38 Giudice L C. Multifaceted roles for IGFBP-1 in human endometrium during implantation and pregnancy. Ann N Y Acad Sci. 1997; 828 146-156 - 39 Osteen K G, Sierra-Rivera E, Keller N R, Fox D B. Interleukin-1 alpha opposes progesterone-mediated suppression of MMP-7. A possible role of this cytokine during human implantation. Ann N Y Acad Sci. 1997; 828 137-145 - 40 Sanguansermsri D, Pongcharoen S. Pregnancy immunology: decidual immune cells. Asian Pac J Allergy Immunol. 2008; 26(2-3) 171-181 - 41 Igarashi T M, Bruner-Tran K L, Yeaman G R et al.. Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fertil Steril. 2005; 84(1) 67-74 - 42 Le T N, Johansson A. Impact of chemical warfare with agent orange on women's reproductive lives in Vietnam: a pilot study. Reprod Health Matters. 2001; 9(18) 156-164 - 43 Heimler I, Rawlins R G, Owen H, Hutz R J. Dioxin perturbs, in a dose- and time-dependent fashion, steroid secretion, and induces apoptosis of human luteinized granulosa cells. Endocrinology. 1998; 139(10) 4373-4379 - 44 Morán F M, VandeVoort C A, Overstreet J W, Lasley B L, Conley A J. Molecular target of endocrine disruption in human luteinizing granulosa cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin: inhibition of estradiol secretion due to decreased 17α-hydroxylase/17,20-lyase cytochrome P450 expression. Endocrinology. 2003; 144(2) 467-473 - 45 Pocar P, Fischer B, Klonisch T, Hombach-Klonisch S. Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction. Reproduction. 2005; 129(4) 379-389 - 46 Whitlock Jr J P. Induction of cytochrome P4501A1. Annu Rev Pharmacol Toxicol. 1999; 39 103-125 - 47 Whitlock Jr J P, Chichester C H, Bedgood R M et al.. Induction of drug-metabolizing enzymes by dioxin. Drug Metab Rev. 1997; 29(4) 1107-1127 - 48 Schrenk D. Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochem Pharmacol. 1998; 55(8) 1155-1162 - 49 Eskenazi B, Kimmel G. Workshop on perinatal exposure to dioxin-like compounds. II. Reproductive effects. Environ Health Perspect. 1995; 103(Suppl 2) 143-145 - 50 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(4) 433-441 - 51 Rier S E, Turner W E, Martin D C, Morris R, Lucier G W, Clark G C. Serum levels of TCDD and dioxin-like chemicals in rhesus monkeys chronically exposed to dioxin: correlation of increased serum PCB levels with endometriosis. Toxicol Sci. 2001; 59(1) 147-159 - 52 Yang J Z, Foster W G. Continuous exposure to 2,3,7,8-tetracholordibenzo-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 - 53 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(2) 374-381 - 54 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(1) 131-139 - 55 Cummings A M, Hedge J M, Birnbaum L S. Effect of prenatal exposure to TCDD on the promotion of endometriotic lesion growth by TCDD in adult female rats and mice. Toxicol Sci. 1999; 52(1) 45-49 - 56 Mann P C. Selected lesions of dioxin in laboratory rodents. Toxicol Pathol. 1997; 25(1) 72-79 - 57 Safe S, Wang F, Porter W, Duan R, McDougal A. Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms. Toxicol Lett. 1998; 102–103 343-347 - 58 Bofinger D P, Feng L, Chi L H et al.. Effect of TCDD exposure on CYP1A1 and CYP1B1 expression in explant cultures of human endometrium. Toxicol Sci. 2001; 62(2) 299-314 - 59 Hayes C L, Spink D C, Spink B C, Cao J Q, Walker N J, Sutter T R. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci U S A. 1996; 93(18) 9776-9781 - 60 Liehr J G, Ricci M J. 4-Hydroxylation of estrogens as marker of human mammary tumors. Proc Natl Acad Sci U S A. 1996; 93(8) 3294-3296 - 61 Bruner K L, Eisenberg E, Gorstein F, Osteen K G. Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis. Steroids. 1999; 64(9) 648-653 - 62 Rodgers W H, Osteen K G, Matrisian L M, Navre M, Giudice L C, Gorstein F. Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am J Obstet Gynecol. 1993; 168(1 Pt 1) 253-260 - 63 Rodgers W H, Matrisian L M, Giudice L C et al.. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest. 1994; 94(3) 946-953 - 64 Curry Jr T E, Osteen K G. The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev. 2003; 24(4) 428-465 - 65 Bruner K L, Matrisian L M, Rodgers W H, Gorstein F, Osteen K G. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997; 99(12) 2851-2857 - 66 Bruner K L, Rodgers W H, Gold L I et al.. Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci U S A. 1995; 92(16) 7362-7366 - 67 Sever L E, Arbuckle T E, Sweeney A. Reproductive and developmental effects of occupational pesticide exposure: the epidemiologic evidence. Occup Med. 1997; 12(2) 305-325 - 68 Gregoraszczuk E L, Zabielny E, Ochwat D. Aryl hydrocarbon receptor (AhR)-linked inhibition of luteal cell progesterone secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin treated cells. J Physiol Pharmacol. 2001; 52(2) 303-311 - 69 Miller K P, Borgeest C, Greenfeld C, Tomic D, Flaws J A. In utero effects of chemicals on reproductive tissues in females. Toxicol Appl Pharmacol. 2004; 198(2) 111-131 - 70 Birnbaum L S, Cummings A M. Dioxins and endometriosis: a plausible hypothesis. Environ Health Perspect. 2002; 110(1) 15-21 - 71 Anger D L, Foster W G. The link between environmental toxicant exposure and endometriosis. Front Biosci. 2008; 13 1578-1593 - 72 Dolinoy D C, Weidman J R, Jirtle R L. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol. 2007; 23(3) 297-307 - 73 Tang W Y, Ho S M. Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord. 2007; 8(2) 173-182 - 74 Nayyar T, Bruner-Tran K L, Piestrzeniewicz-Ulanska D, Osteen K G. Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis. Reprod Toxicol. 2007; 23(3) 326-336 Kaylon Bruner-TranPh.D. Women's Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine B-1100, Medical Center North, Nashville, TN 37232-2519 Email: [email protected]