Abstract
Polychlorinated biphenyls (PCBs) contain 209 congeners with various structure–activities. Exposure to PCBs was related to disorders of female reproduction. Endometriosis (EM) is an estrogen- and inflammation-dependent disease with high prevalence and severe health outcomes. Epidemiological studies have shown the effects of PCBs exposure on EM in regard to various structures of PCBs. However, little evidence is available from the toxicology considering the structure of PCBs. In the study, environmentally relevant concentrations of PCBs were used to treat primary cultured endometrial cells and an EM mouse model. Dioxin-like CB126, but not non-dioxin-like CB153, significantly enhanced 17β-estradiol (E2) biosynthesis in a dose-dependent manner. Among the genes related to estrogen metabolism, the level of 17β-hydroxysteroid dehydrogenase 7 (HSD17B7) showed significant increase following CB126 exposure. We further found that CB126 exposure decreased the methylation of the HSD17B7 promoter. Elevated expression of HSD17B7 was observed in the eutopic endometrium of EM patients. CB126 rather than CB153 triggered the inflammatory response by directly stimulating the secretion of inflammatory factors and indirectly reducing the level of lipoxin A4 (LXA4). Furthermore, the inflammation enhanced the expression of HSD17B7. Antagonism of the aryl hydrocarbon receptor (AhR) diminished the effects induced by CB126. In vivo, the PCB-treated EM mouse model confirmed that CB126 rather than CB153 increased the levels of both E2 and inflammatory factors in peritoneal fluid and promoted the development of endometriotic lesions. In all, CB126, but not CB153, triggered EM development by stimulating estrogen biosynthesis, inflammation and their interactions and that these effects were mediated by the AhR receptor.
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References
Ben Hassine S, Hammami B, Ben Ameur W, El Megdiche Y, Barhoumi B, El Abidi R et al (2014) Concentrations of organochlorine pesticides and polychlorinated biphenyls in human serum and their relation with age, gender, and BMI for the general population of Bizerte, Tunisia. Environ Sci Pollut Res Int 21(10):6303–6313. doi:10.1007/s11356-013-1480-9
Berkley KJ, Rapkin AJ, Papka RE (2005) The pains of endometriosis. Science 308(5728):1587–1589. doi:10.1126/science.1111445
Bruner-Tran KL, Osteen KG (2010) Dioxin-like PCBs and endometriosis. Syst Biol Reprod Med 56(2):132–146. doi:10.3109/19396360903381023
Bulun SE (2009) Endometriosis. New Engl J Med 360(3):268–279. doi:10.1056/NEJMra0804690
Canny GO, Lessey BA (2013) The role of lipoxin A4 in endometrial biology and endometriosis. Mucosal Immunol 6(3):439–450. doi:10.1038/mi.2013.9
CDC (Centers for Disease Control and Prevention) (2009) 4th National report on human exposure to environmental chemicals. http://www.cdcgov/exposurereport/
Chen Q, Zhou W, Pu D, Li Z, Huang Q (2009) The inhibitory effect of 15-R-LXA4 on experimental endometriosis. Eur J Obstet Gynecol Reprod Biol 145(2):200–204. doi:10.1016/j.ejogrb.2009.05.015
Chen S, Wu RF, Su L, Zhou WD, Zhu MB, Chen QH (2014) Lipoxin A regulates expression of the estrogen receptor and inhibits 17beta-estradiol induced p38 mitogen-activated protein kinase phosphorylation in human endometriotic stromal cells. Fertil Steril 1:264–271. doi:10.1016/j.fertnstert.2014.03.029
Colette S, Donnez J (2009) Endometriosis. N Engl J Med 360(18):1911–1912. doi:10.1056/NEJMc090328
Dirtu AC, Cernat R, Dragan D, Mocanu R, Van Grieken R, Neels H et al (2006) Organohalogenated pollutants in human serum from Iassy, Romania and their relation with age and gender. Environ Int 32(6):797–803. doi:10.1016/j.envint.2006.04.002
Gibbons A (1993) Dioxin tied to endometriosis. Science 262(5138):1373
Giudice LC (2010) Clinical practice. Endometriosis. New Engl J Med 362(25):2389–2398. doi:10.1056/NEJMcp1000274
Guo SW, Simsa P, Kyama CM, Mihalyi A, Fulop V, Othman EER et al (2009) Reassessing the evidence for the link between dioxin and endometriosis: from molecular biology to clinical epidemiology. Mol Hum Reprod 15(10):609–624. doi:10.1093/molehr/gap075
Han SJ, Jung SY, Wu SP, Hawkins SM, Park MJ, Kyo S et al (2015) Estrogen receptor beta modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163(4):960–974. doi:10.1016/j.cell.2015.10.034
Haynes BP, Straume AH, Geisler J, A’Hern R, Helle H, Smith IE et al (2010) Intratumoral estrogen disposition in breast cancer. Clin Cancer Res 16(6):1790–1801. doi:10.1158/1078-0432.CCR-09-2481
Heilier J-F, Donnez J, Lison D (2008) Organochlorines and endometriosis: a mini-review. Chemosphere 71(2):203–210. doi:10.1016/j.chemosphere.2007.09.044
Huhtinen K, Desai R, Stahle M, Salminen A, Handelsman DJ, Perheentupa A et al (2012) Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J Clin Endocrinol Metab 97(11):4228–4235. doi:10.1210/jc.2012-1154
Johnson KL, Cummings AM, Birnbaum LS (1997) Promotion of endometriosis in mice by polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls. Environ Health Perspect 105(7):750–755. doi:10.1289/Ehp.97105750
Kayisli UA, Guzeloglu-Kayisli O, Arici A (2004) Endocrine-immune interactions in human endometrium. Ann NY Acad Sci 1034:50–63. doi:10.1196/annals.1335.005
Khan KN, Kitajima M, Inoue T, Fujishita A, Nakashima M, Masuzaki H (2015) 17 beta-estradiol and lipopolysaccharide additively promote pelvic inflammation and growth of endometriosis. Reprod Sci 22(5):585–594. doi:10.1177/1933719114556487
Kim MJ, Pelloux V, Guyot E, Tordjman J, Bui LC, Chevallier A et al (2012) Inflammatory pathway genes belong to major targets of persistent organic pollutants in adipose cells. Environ Health Perspect 120(4):508–514. doi:10.1289/ehp.1104282
Liu D, Perkins JT, Petriello MC, Hennig B (2015) Exposure to coplanar PCBs induces endothelial cell inflammation through epigenetic regulation of NF-kappaB subunit p65. Toxicol Appl Pharmacol 289(3):457–465. doi:10.1016/j.taap.2015.10.015
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta][Delta]CT method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262
Louis GMB, Chen Z, Peterson CM, Hediger ML, Croughan MS, Sundaram R et al (2012) Persistent lipophilic environmental chemicals and endometriosis: the ENDO study. Environ Health Perspect 120(6):811–816. doi:10.1289/ehp.1104432
Martinez-Zamora MA, Mattioli L, Parera J, Abad E, Coloma JL, van Babel B et al (2015) Increased levels of dioxin-like substances in adipose tissue in patients with deep infiltrating endometriosis. Hum Reprod 30(5):1059–1068. doi:10.1093/humrep/dev026
May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM (2010) Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update 16(6):651–674. doi:10.1093/humupd/dmq009
Meeker JD, Maity A, Missmer SA, Williams PL, Mahalingaiah S, Ehrlich S et al (2011) Serum concentrations of polychlorinated biphenyls in relation to in vitro fertilization outcomes. Environ Health Perspect 119(7):1010–1016. doi:10.1289/ehp.1002922
Meeker JD, Missmer SA, Altshul L, Vitonis AF, Ryan L, Cramer DW et al (2009) Serum and follicular fluid organochlorine concentrations among women undergoing assisted reproduction technologies. Environ Health 8:32. doi:10.1186/1476-069X-8-32
Mes J, Marchand L, Davies DJ (1990) Organochlorine residues in adipose tissue of Canadians. Bull Environ Contam Toxicol 45(5):681–688
Nokelainen P, Peltoketo H, Vihko R, Vihko P (1998) Expression cloning of a novel estrogenic mouse 17 beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase (m17HSD7), previously described as a prolactin receptor-associated protein (PRAP) in rat. Mol Endocrinol 12(7):1048–1059. doi:10.1210/mend.12.7.0134
Polishuk ZW, Wassermann D, Wassermann M, Cucos S, Ron M (1977) Organochlorine compounds in mother and fetus during labor. Environ Res 13(2):278–284. doi:10.1016/0013-9351(77)90104-9
Porta M, Lopez T, Gasull M, Rodriguez-Sanz M, Gari M, Pumarega J et al (2012) Distribution of blood concentrations of persistent organic pollutants in a representative sample of the population of Barcelona in 2006, and comparison with levels in 2002. Sci Total Environ 423:151–161. doi:10.1016/j.scitotenv.2012.02.001
Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL (1993) Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol 21(4):433–441. doi:10.1093/toxsci/21.4.433
Rizner TL (2009) Estrogen metabolism and action in endometriosis. Mol Cell Endocrinol 307(1–2):8–18. doi:10.1016/j.mce.2009.03.022
Russell R, Gori I, Pellegrini C, Kumar R, Achtari C, Canny GO (2011) Lipoxin A4 is a novel estrogen receptor modulator. FASEB J 25(12):4326–4337. doi:10.1096/fj.11-187658
Salama SA, Kamel MW, Diaz-Arrastia CR, Xu X, Veenstra TD, Salih S et al (2009) Effect of tumor necrosis factor-alpha on estrogen metabolism and endometrial cells: potential physiological and pathological relevance. J Clin Endocr Metab 94(1):285–293. doi:10.1210/Jc.2008-1389
Shehu A, Albarracin C, Devi YS, Luther K, Halperin J, Le J et al (2011) The stimulation of HSD17B7 expression by estradiol provides a powerful feed-forward mechanism for estradiol biosynthesis in breast cancer cells. Mol Endocrinol 25(5):754–766. doi:10.1210/me.2010-0261
Simoens S, Hummelshoj L, D’Hooghe T (2007) Endometriosis: cost estimates and methodological perspective. Hum Reprod Update 13(4):395–404. doi:10.1093/humupd/dmm010
Trabert B, De Roos AJ, Schwartz SM, Peters U, Scholes D, Barr DB et al (2010) Non-dioxin-like polychlorinated biphenyls and risk of endometriosis. Environ Health Perspect 118(9):1280–1285. doi:10.1289/ehp.0901444
Upson K, De Roos AJ, Thompson ML, Sathyanarayana S, Scholes D, Barr DB et al (2013) Organochlorine pesticides and risk of endometriosis: findings from a population-based case-control study. Environ Health Perspect 121(11–12):1319–1324. doi:10.1289/ehp.1306648
Wang SB, Hu KM, Seamon KJ, Mani V, Chen Y, Gronert K (2012) Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea. FASEB J 26(4):1506–1516. doi:10.1096/fj.11-198036
Weuve J, Hauser R, Calafat AM, Missmer SA, Wise LA (2010) Association of exposure to phthalates with endometriosis and uterine leiomyomata: findings from NHANES, 1999–2004. Environ Health Perspect 118(6):825–832. doi:10.1289/ehp.0901543
Wittsiepe J, Fobil JN, Till H, Burchard GD, Wilhelm M, Feldt T (2015) Levels of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and biphenyls (PCBs) in blood of informal e-waste recycling workers from Agbogbloshie, Ghana, and controls. Environ Int 79:65–73. doi:10.1016/j.envint.2015.03.008
Wojtowicz AK, Goch M, Gregoraszczuk EL (2005) Polychlorinated biphenyls (PCB 153 and PCB 126) action on conversion of 20-hydroxylated cholesterol to progesterone, androstenedione to testosterone, and testosterone to estradiol 17 beta. Exp Clin Endocr Diab 113(8):464–470. doi:10.1055/s-2005-865776
Wu R, Zhou W, Chen S, Shi Y, Su L, Zhu M et al (2014) Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol 171(21):4927–4940. doi:10.1111/bph.12816
Zhang Z, Liu L, Li YF, Wang D, Jia H, Harner T et al (2008) Analysis of polychlorinated biphenyls in concurrently sampled Chinese air and surface soil. Environ Sci Technol 42(17):6514–6518. doi:10.1021/es8004078
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We gratefully acknowledged the supports by National Natural Science Foundation of China (41390240, 21477123, 21107107) and Institute of Urban Environment, Chinese Academy of Sciences (IUEMS201405).
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Qiansheng Huang and Yajie Chen have contributed equally to the paper.
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Huang, Q., Chen, Y., Chen, Q. et al. Dioxin-like rather than non-dioxin-like PCBs promote the development of endometriosis through stimulation of endocrine–inflammation interactions. Arch Toxicol 91, 1915–1924 (2017). https://doi.org/10.1007/s00204-016-1854-0
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DOI: https://doi.org/10.1007/s00204-016-1854-0