Cigarette Smoking Affects Uterine Receptivity Markers

Objective Smoking negatively affects fertility and the rate of other endometrial diseases. To determine the effect of smoking on endometrial physiology, we evaluated 2 endometrial regulatory cytokines and receptivity markers, C-X-C motif chemokine ligand 12 (CXCL12) and fibroblast growth factor 2 (FGF2), both in vitro and in vivo. Study Design The human endometrial stromal cell line (HESC) and primary human endometrial stromal cells were treated with cigarette smoking extract (CSE) or with vehicle control. Twenty female mice were randomly assigned to either cigarette smoke (CS) exposure for 8 weeks or to a nonsmoke (NS) group that received room air. Immunohistochemical analysis of CXCL12 and FGF2 expression was performed in mouse uterine tissue. Human endometrial samples were obtained from both nonsmokers and smokers. Real-time reverse transcription-polymerase chain reaction was performed for all cell cultures and human samples.

Compared to controls, CXCL12 and FGF2 mRNA expression were significantly decreased in CSE-exposed HESC and primary cells. In mice, immunohistochemical analysis showed that both CXCL12 and FGF2 protein expression was lower in the CS group compared to controls. Similarly, both CXCL12 and FGF2 expression were decreased in women who smoke compared to nonsmokers.

Decreased endometrial CXCL12 and FGF2 expression contribute to the impaired endometrial receptivity in women who smoke. Smoking is also associated with decreased rates of endometrial cancer and endometriosis; increased CXCL12 and FGF2 are implicated in both conditions. The changes in the expression of cytokines described here may explain the impact of smoking on all of these diseases. Tobacco has direct effects on normal endometrium that impacts endometrial health and disease. Similar content being viewed by others

Waylen AL, Metwally M, Jones GL, Wilkinson AJ, Ledger WL. Effects of cigarette smoking upon clinical outcomes of assisted reproduction: a meta-analysis. Hum Reprod Update. 2009;15(1):31–44. Soares SR, Simon C, Remohi J, Pellicer A. Cigarette smoking affects uterine receptiveness. Hum Reprod. 2007;22(2):543–547. Psychoyos A. Hormonal control of ovoimplantation. VitamHorm. 1973;31:201–256. Salamonsen LA, Nie G, Hannan NJ, Dimitriadis E. Society for Reproductive Biology Founders’ Lecture 2009. Preparing fertile soil: the importance of endometrial receptivity. Reprod Fertil Dev. 2009;21(7):923–934. Kumar A, Kumar S, Dinda AK, Luthra K. Differential expression of CXCR4 receptor in early and term human placenta. Placenta. 2004;25(4):347–351. Wu X, Jin LP, Yuan MM, Zhu Y, Wang MY, Li DJ. Human first-trimester trophoblast cells recruit CD56brightCD16-NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1. J Immunol. 2005;175(1):61–68. Ren L, Liu YQ, Zhou WH, Zhang YZ. Trophoblast-derived chemokine CXCL12 promotes CXCR4 expression and invasion of human first-trimester decidual stromal cells. Hum Reprod. 2011;27(2):366–374. Quinn KE, Ashley AK, Reynolds LP, Grazul-Bilska AT, Ashley RL. Activation of the CXCL12/CXCR4 signaling axis may drive vascularization of the ovine placenta. Dornest Anim Endocrinol. 2014;47:11–21. Paiva P, Hannan NJ, Hincks C, et al. Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum Reprod. 2011;26(5):1153–1162. Zhou Y, Jorgensen EM, Gan Y, Taylor HS. Cigarette smoke increases progesterone receptor and homeobox A10 expression in human endometrium and endometrial cells: a potential role in the decreased prevalence of endometrial pathology in smokers. Biol Reprod. 2011;84(6):1242–1247. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997;277(5334):2002–2004. Sharpe-Timms KL, Ricke EA, Piva M, Horowitz GM. Differen-tial expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions. Hum Reprod. 2000;15(10):2180–2185. Lessey BA, Castelbaum AJ, Sawin SW, et al. Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab. 1994;79(2):643–649. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(Delta Delta C(T)) Method. Methods. 2001;25(4):402–408. Jick H, Porter J. Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveil-lance Program, Boston University Medical Center. Lancet. 1977;1(8026):1354–1355. Augood C, Duckitt K, Templeton AA. Smoking and female infer-tility: a systematic review and meta-analysis. Hum Reprod. 1998;13(6):1532–1539. de Mouzon J, Belaisch-Allart J. Consequences on women’s fecundity and on assisted reproductive technology [in French]. J Gynecol Obstet Biol Reprod. 2005;34(spec no 1):112–118. Baird DD, Wilcox AJ. Cigarette smoking associated with delayed conception. JAMA. 1985;253(20):2979–2983. Tzonou A, Hsieh CC, Trichopoulos D, et al. Induced abortions, miscarriages and tobacco smoking as risk factors for secondary infertility. J Epidemiol Community Health. 1993;47(1):36–39. Bolumar F, Olsen J, Boldsen J. Smoking reduces fecundity: a European multicenter study on infertility and subfecundity. The European Study Group on Infertility and Subfecundity. Am J Epidemiol. 1996;143(6):578–587. Hull MG, North K, Taylor H, Farrow A, Ford WC. Delayed con-ception and active and passive smoking. The Avon Longitudinal Study of Pregnancy and Childhood Study Team. Fertil Steril. 2000;74(4):725–733. Hughes EG, Brennan BG. Does cigarette smoking impair natural or assisted fecundity? Fertil Steril. 1996;66(5):679–689. Feichtinger W, Papalambrou K, Poehl M, Krischker U, Neumann K. Smoking and in vitro fertilization: a meta-analysis. J Assist Reprod Genet. 1997;14(10):596–599. Klonoff-Cohen H, Natarajan L, Marrs R, Yee B. Effects of female and male smoking on success rates of IVF and gamete intra-Fallopian transfer. Hum Reprod. 2001;16(7):1382–1390. Neal MS, Hughes EG, Holloway AC, Foster WG. Sidestream smoking is equally as damaging as mainstream smoking on IVF outcomes. Hum Reprod. 2005;20(9):2531–2535. Wright KP, Trimarchi JR, Allsworth J, Keefe D. The effect of female tobacco smoking on IVF outcomes. Hum Reprod. 2006;21(11):2930–2934. Cha J, Vilella F, Dey SK, Simon C. Molecular Interplay in Successful Implantation. In: Sanders S, ed. Ten Critical Topics in Reproductive Medicine. Washington, DC: Science/AAA; 2013:44–48. Wang L, Li X, Zhao Y, et al. Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placen-tal angiogenesis. Acta Biochim Biophys Sin (Shanghai). 2015;47(9):663–672. Zhou WH, Du MR, Dong L, Yu J, Li DJ. Chemokine CXCL12 promotes the cross-talk between trophoblasts and decidual stro-mal cells in human first-trimester pregnancy. Hum Reprod. 2008;23(12):2669–2679. Li MQ, Tang CL, Du MR, et al. CXCL12 controls over-invasion of trophoblasts via upregulating CD82 expression in DSCs at maternal-fetal interface of human early pregnancy in a paracrine manner. Int J Clin Exp Pathol. 2011;4(3):276–286. Taniguchi F, Harada T, Yoshida S, et al. Paracrine effects of bFGF and KGF on the process of mouse blastocyst implantation. Mol Reprod Dev. 1998;50(1):54–62. Gupta A, Bazer FW, Jaeger LA. Immunolocalization of acidic and basic fibroblast growth factors in porcine uterine and conceptus tissues. Biol Reprod. 1997;56(6):1527–1536. Hrabé de Angelis M, Gründker C, Herrmann BG, Kispert A, Kirchner C. Promotion of gastrulation by maternal growth factor in cultured rabbit blastocysts. Cell Tissue Res. 1995;282(1):147–154. Thorsteinsdottir S. Basement membrane and fibronectin matrix are distinct entities in the developing mouse blastocyst. Anat Rec. 1992;232(1):141–149. Shimomura Y, Ando H, Furugori K, et al. Possible involvement of crosstalk cell-adhesion mechanism by endometrial CD26/ dipeptidyl peptidase IV and embryonal fibronectin in human blas-tocyst implantation. Mol Hum Reprod. 2006;12(8):491–495. Winter E, Wang J, Davies MJ, Norman R. Early pregnancy loss following assisted reproductive technology treatment. Hum Reprod. 2002;17(12):3220–3223. Freour T, Masson D, Mirallie S, Jean M, Bach K, Dejoie T, Bar-riere P. Active smoking compromises IVF outcome and affects ovarian reserve. Reprod Biomed Online. 2008;16(1):96–102. Genbacev OD, Prakobphol A, Foulk RA, et al. Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface. Science. 2003;299(5605):405–408. Prakobphol A, Genbacev O, Gormley M, Kapidzic M, Fisher SJ. A role for the L-selectin adhesion system in mediating cytotropho-blast emigration from the placenta. Dev Biol. 2006;298(1):107–117. Zdravkovic T, Genbacev O, Prakobphol A, et al. Nicotine down-regulates the L-selectin system that mediates cytotrophoblast emigration from cell columns and attachment to the uterine wall. Reprod Toxicol. 2006;22(1):69–76. Zhou B, Yang L, Sun Q, et al. Cigarette smoking and the risk of endometrial cancer: a meta-analysis. Am J Med. 2008;121(6):501–508. Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann N Y Acad Sci. 2002;955:11–22; discussion 34–36, 396–406. Cramer DW, Wilson E, Stillman RJ, et al. The relation of endo-metriosis to menstrual characteristics, smoking, and exercise. JAMA. 1986;255(14):1904–1908. Van Voorhis BJ, Dawson JD, Stovall DW, Sparks AE, Syrop CH. The effects of smoking on ovarian function and fertility during assisted reproduction cycles. Obstet Gynecol. 1996;88(5):785–791. Pickar JH, Yeh IT, Wheeler JE, Cunnane MF, Speroff L. Endo-metrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril. 2003;80(5):1234–1240. Yoshida H, Broaddus R, Cheng W, Xie S, Naora H. Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial- mesenchymal transition. Cancer Res. 2006;66(2):889–897. Yoshida S, Harada T, Iwabe T, et al. Induction of hepatocyte growth factor in stromal cells by tumour-derived basic fibroblast growth factor enhances growth and invasion of endometrial cancer. J Clin Endocrinol Metab. 2002;87(5):2376–2383. Billottet C, Elkhatib N, Thiery JP, Jouanneau J. Targets of fibro-blast growth factor 1 (FGF-1) and FGF2 signaling involved in the invasive and tumourigenic behavior of carcinoma cells. Mol Biol Cell. 2004;15(10):4725–4734. Moridi I, Mamillapalli R, Cosar E, Sahin Ersoy G, Taylor HS. Bone marrow stem cell chemotactic activity is induced by elevated CXC112 in endometriosis [Published online October 11, 2016]. Reprod Sci. 2016. doi:10.1177/1933719116672587. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8):2082–2086. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–85. Sakr S, Naqvi H, Komm B, Taylor HS. Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology. 2014;155(4):1489–97. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Ersoy, G.S., Zhou, Y., Inan, H. et al. Cigarette Smoking Affects Uterine Receptivity Markers. Reprod. Sci. 24, 989–995 (2017). https://doi.org/10.1177/1933719117697129 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719117697129