Association of Phthalate Exposure with Endometriosis and Idiopathic Infertility in Egyptian Women

Nevein A. EL-Desouky; Mona Elyamany; Amany Fahmy Hanon; Adel Atef; Marwa Issak; Sarah Hamed N. Taha; Riham F. Hussein

doi:10.3889/oamjms.2022.9722

Authors

Nevein A. EL-Desouky Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-5792-9596
Mona Elyamany Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-2039-4380
Amany Fahmy Hanon Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt
Adel Atef Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Cairo, Egypt
Marwa Issak Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-8026-6858
Sarah Hamed N. Taha Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-0777-7678
Riham F. Hussein Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Cairo University, Cairo, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.9722

Keywords:

Endometriosis, Idiopathic infertility, HPLC, Phthalates

Abstract

BACKGROUND: Phthalates are compounds found in medical supplies, cellophane wraps, beverage containers, metal can linings, and other products. They have the potential to be significant endocrine disruptors. In experimental animals, thereby affecting their reproductive capacity. Endometriosis is a gynecological condition defined by ectopic endometrial glands and stromal development. Exposure to phthalates has been linked to the development of endometriosis in numerous studies. The dangers of phthalates to women’s reproductive health and fertility have been widely reported.

AIM: So far, the relationship between phthalates and infertility is not proven so we decided to see if there was a link between the urine phthalate metabolite levels and endometriosis or idiopathic infertility in Egyptian women.

METHODS: Our research was carried out at the infertility outpatient clinic of the Faculty of Medicine of Cairo University. It included 100 female subjects aged 18−40-years-old. Group A (idiopathic infertility; n = 40), Group B (endometriosis; n = 40), and Group C (control; n = 20) were the three age-matched groups that were studied. Using high-performance liquid chromatography (HPLC), the urine levels of mono-2-ethylhexyl phthalate (MEHP) were quantified.

RESULTS: The comparison between the study groups has revealed statistically significant differences regarding the urine MEHP levels between Groups A and B. An analysis of the urine MEHP levels in the study Groups A and B has also revealed that the significantly higher urinary MEHP levels are correlated with the use of dietary plastic containers, the use of cosmetics, and the patients’ estrogen levels. Moreover, the urinary MEHP levels of Group A were associated with a history of abortions.

CONCLUSIONS: Higher levels of urinary MEHP are positively associated with female reproductive disorders, specifically endometriosis, idiopathic infertility, and abortion.

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References

Craig ZR, Singh J, Gupta RK, Flaws JA. Co-treatment of mouse antral follicles with 17β-estradiol interferes with mono-2-ethylhexyl phthalate (MEHP)-induced atresia and altered apoptosis gene expression. Reprod Toxicol. 2014;45:45-1. https://doi.org/10.1016/j.reprotox.2014.01.002 PMid:24412242 DOI: https://doi.org/10.1016/j.reprotox.2014.01.002

Hannon PR, Peretz J, Flaws JA. Daily exposure to Di (2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. Biol Reprod. 2014;90(6):136. https://doi.org/10.1095/biolreprod.114.119032 PMid:24804967 DOI: https://doi.org/10.1095/biolreprod.114.119032

Gupta RK, Singh JM, Leslie TC, Meachum S, Flaws JA, Yao HH. Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro. Toxicol Appl Pharmacol. 2010;242(2):224-30. https://doi.org/10.1016/j.taap.2009.10.011 PMid:19874833 DOI: https://doi.org/10.1016/j.taap.2009.10.011

Toft G, Jönsson BA, Lindh CH, Jensen TK, Hjollund NH, Vested A, et al. Association between pregnancy loss and urinary phthalate levels around the time of conception. Environ Health Perspect. 2012;120(3):458-63. https://doi.org/10.1289/ehp.1103552 PMid:22113848 DOI: https://doi.org/10.1289/ehp.1103552

Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019;15(11):666-82. https://doi.org/10.1038/s41574-019-0245-z PMid:31488888 DOI: https://doi.org/10.1038/s41574-019-0245-z

Giudiee LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789-99. PMid:15541453 DOI: https://doi.org/10.1016/S0140-6736(04)17403-5

Eisenberg VH, Weil C, Chodick G, Shalev V. Epidemiology of endometriosis: A large population-based database study from a healthcare provider with 2 million members. BJOG. 2018;125(1):55-62. https://doi.org/10.1111/1471-0528.14711 PMid:28444957 DOI: https://doi.org/10.1111/1471-0528.14711

Louis GM, Peterson CM, Chen Z, Croughan M, Sundaram R, Stanford J, et al. Bisphenol A and phthalates and endometriosis: The endometriosis: Natural history, diagnosis and outcomes study. Fertil Steril. 2013;100(1):162-9. https://doi.org/10.1016/j.fertnstert.2013.03.026 PMid:23579005 DOI: https://doi.org/10.1016/j.fertnstert.2013.03.026

Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: An update andreview of practice. Reprod Biomed Online. 2012;24(6):591-602. https://doi.org/10.1016/j.rbmo.2012.02.021 PMid:22503948 DOI: https://doi.org/10.1016/j.rbmo.2012.02.021

Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA. 2003;290(13):1767-70. https://doi.org/10.1001/jama.290.13.1767 PMid:14519712 DOI: https://doi.org/10.1001/jama.290.13.1767

Sifakis S, Androutsopoulos VP, Tsatsakis AM, Spandidos DA. Human exposure to endocrine disrupting chemicals: Effects on the male and female reproductive systems. Environ Toxicol Pharmacol. 2017;51:56-70. https://doi.org/10.1016/j.etap.2017.02.024 PMid:28292651 DOI: https://doi.org/10.1016/j.etap.2017.02.024

Chan YH. Biostatistics 102: Quantitative data-parametric and non-parametric tests. Blood Press. 2003;140(8):79.

Chan YH. Biostatistics 103: Qualitative data-tests of independence. Singapore Med J. 2003;44(10):498-503. PMid:15024452

Chan YH. Biostatistics 104: Correlational analysis. Singapore Med J. 2003;44(12):614-9. PMid:14770254

Doherty BT, Engel SM, Buckley JP, Silva MJ, Calafat AM, Wolff MS. Prenatal phthalate biomarker concentrations and performance on the Bayley Scales of Infant Development-II in a population of young urban children. Environ Res. 2017;152:51-8. https://doi.org/10.1016/j.envres.2016.09.021 PMid:27741448 DOI: https://doi.org/10.1016/j.envres.2016.09.021

Kay VR, Chambers C, Foster WG. Reproductive and developmental effects of phthalate diesters in females. Crit Rev Toxicol. 2013;43(3):200-19. https://doi.org/10.3109/10408444.2013.766149 PMid:23405971 DOI: https://doi.org/10.3109/10408444.2013.766149

Kim MG, Kim TH, Shin BS, Lee YB, Lee JB, Choi HG, et al. Sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous determination of benzyl butyl phthalate and its metabolites, monobenzyl phthalate and monobutyl phthalate, in rat plasma, urine, and various tissues collected from a toxicokinetic study. Anal Bioanal Chem. 2015;407(24):7391-400. https://doi.org/10.1007/s00216-015-8901-1 PMid:26168976 DOI: https://doi.org/10.1007/s00216-015-8901-1

Cho YJ, Park SB, Han M. Di-(2-ethylhexyl)-phthalate induces oxidative stress in human endometrial stromal cells in vitro. Mol Cell Endocrinol. 2015;407:9-17. https://doi.org/10.1016/j.mce.2015.03.003 PMid:25766500 DOI: https://doi.org/10.1016/j.mce.2015.03.003

Ahern TP, Broe A, Lash TL, Cronin-Fenton DP, Ulrichsen SP, Christiansen PM, et al. Phthalate exposure and breast cancer incidence: A Danish nationwide cohort study. J Clin Oncol. 2019;37(21):1800-9. https://doi.org/10.1200/JCO.18.02202 PMid:30995175 DOI: https://doi.org/10.1200/JCO.18.02202

Kim YH, Kim SH, Lee HW, Chae HD, Kim CH, Kang BM. Increased viability of endometrial cells by in vitro treatment with di-(2-ethylhexyl) phthalate. Fertil Steril. 2010;94(6):2413-6. https://doi.org/10.1016/j.fertnster.2010.04.027 PMid:20493477 DOI: https://doi.org/10.1016/j.fertnstert.2010.04.027

Wen X, Xiong Y, Qu X, Jin L, Zhou C, Zhang M, et al. The risk of endometriosis after exposure to endocrine-disrupting chemicals: A meta-analysis of 30 epidemiology studies. Gynecol Endocrinol. 2019;35(8):645-50. https://doi.org/10.1080/09513590.2019.1590546 PMid:30907174 DOI: https://doi.org/10.1080/09513590.2019.1590546

Conforti A, Carbone L, Simeon V, Chiodini P, Marrone V, Bagnulo F, et al. Unravelling the link between phthalate exposure and endometriosis in humans: A systematic review and meta-analysis of the literature. J Assist Reprod Genet. 2021;38(10):2543-57. https://doi.org 10.1007/s10815-021-02265-3 PMid:34227050 DOI: https://doi.org/10.1007/s10815-021-02265-3

Kim SH, Chun S, Jang JY, Chae HD, Kim CH, Kang BM. Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: A prospective case-control study. Fertil Steril. 2011;95(1):357-9. https://doi.org/10.1016/j.fertnstert.2010.07.1059 PMid:20797718 DOI: https://doi.org/10.1016/j.fertnstert.2010.07.1059

Huang PC, Tsai EM, Li WF, Liao PC, Chung MC, Wang YH, et al. Association between phthalate exposure and glutathione S-transferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis. Hum Reprod. 2010;25(4):986-94. https://doi.org/10.1093/humrep/deq015 PMid:20147336 DOI: https://doi.org/10.1093/humrep/deq015

Cai W, Yang J, Liu Y, Bi Y, Wang H. Association between phthalate metabolites and risk of endometriosis: A metaanalysis. Int J Environ Res Public Health. 2019;16(19):3678. https://doi.org/10.3390/ijerph16193678 PMid:31574938 DOI: https://doi.org/10.3390/ijerph16193678

Kalo D, Roth Z. Low level of mono (2-ethylhexyl) phthalate reduces oocyte developmental competence in association with impaired gene expression. Toxicology. 2017;377:38-48. https://doi.org/10.1016/j.tox.2016.12.005 PMid:27989758 DOI: https://doi.org/10.1016/j.tox.2016.12.005

Grande SW, Andrade AJ, Talsness CE, Grote K, Golombiewski A, Sterner-Kock A, et al. A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): Reproductive effects on adult female offspring rats. Toxicology. 2007;229(1-2):114-22. https://doi.org/10.1016/j.tox.2006.10.005 PMid:17098345 DOI: https://doi.org/10.1016/j.tox.2006.10.005

Grande SW, Andrade AJ, Talsness CE, Grote K, Chahoud I. A dose-response study following in utero and lactational exposure to di (2-ethylhexyl) phthalate: Effects on female rat reproductive development. Toxicol Sci. 2006;91(1):247-54. https://doi.org/10.1093/toxsci/kfj128 PMid:16476687 DOI: https://doi.org/10.1093/toxsci/kfj128

Begum TF, Fujimoto VY, McGough A, Lenhart N, Wong R, Mok-Lin E, et al. Associations between Preconception Phthalate Exposure and Infertility Treatment Outcomes among Couples Undergoing In Vitro Fertilization. In: ISEE Conference Abstracts; 2020. DOI: https://doi.org/10.1289/isee.2020.virtual.P-1083

Zhang T, Shen W, De Felici M, Zhang XF. Di (2-ethylhexyl) phthalate: Adverse effects on folliculogenesis that cannot be neglected. Environ Mol Mutagen. 2016;57(8):579-88. https://doi.org/10.1002/em.22037 PMid:27530864 DOI: https://doi.org/10.1002/em.22037

Deng T, Du Y, Wang Y, Teng X, Hua X, Yuan X, et al. The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: A prospective single-center study. Ecotoxicol Environ Saf. 2020;188:109884. https://doi.org/10.1016/j.ecoenv.2019.109884 PMid:31706241 DOI: https://doi.org/10.1016/j.ecoenv.2019.109884

Moreira MA, André LC, Cardeal ZL. Analysis of phthalate migration to food simulants in plastic containers during microwave operations. Int J Environ Res Public Health. 2013;11(1):507-26. https://doi.org/10.3390/ijerph110100507 PMid:24380980 DOI: https://doi.org/10.3390/ijerph110100507

Li C, Xu J, Chen D, Xiao Y. Detection of phthalates migration from disposable tablewares to drinking water using hexafluoroisopropanol-induced catanionic surfactant coacervate extraction. J Pharm Anal. 2016;6(5):292-9. https://doi.org/10.1016/j.jpha.2016.04.002 DOI: https://doi.org/10.1016/j.jpha.2016.04.002

Pacyga DC, Sathyanarayana S, Strakovsky RS. Dietary predictors of phthalate and bisphenol exposures in pregnant women. Adv Nutr. 2019;10(5):803-15. https://doi.org/10.1093/advances/nmz0296 PMid:31144713 DOI: https://doi.org/10.1093/advances/nmz029

Serrano SE, Braun J, Trasande L, Dills R, Sathyanarayana S. Phthalates and diet: A review of the food monitoring and epidemiology data. Environ Health. 2014;13(1):43. https://doi.org/10.1186/1476-069X-13-43 PMid:24894065 DOI: https://doi.org/10.1186/1476-069X-13-43

Pan G, Hanaoka T, Yoshimura M, Zhang S, Wang P, Tsukino H, et al. Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): A cross-sectional study in China. Environ Health Perspect. 2006;114(11):1643-8. https://doi.org/10.1289/ehp.9016 PMid:17107847 DOI: https://doi.org/10.1289/ehp.9016

Philips EM, Jaddoe VW, Trasande L. Effects of early exposure to phthalates and bisphenols on cardiometabolic outcomes in pregnancy and childhood. Reprod Toxicol. 2017;68:105-18. https://doi.org/10.1016/j.reprotox.2016.08.015 PMid:27596818 DOI: https://doi.org/10.1016/j.reprotox.2016.08.015

Aydemir D, Karabulut G, Şimşek G, Gok M, Barlas N, Ulusu NN. Impact of the di (2-ethylhexyl) phthalate administration on trace element and mineral levels in relation of kidney and liver damage in rats. Biol Trace Elem Res. 2018;186(2):474-88. https://doi.org/10.1007/s12011-018-1331-0 PMid:29654488 DOI: https://doi.org/10.1007/s12011-018-1331-0

Darvishmotevalli M, Bina B, Feizi A, Ebrahimpour K, Pourzamani H, Kelishadi R. Monitoring of urinary phthalate metabolites among pregnant women in Isfahan, Iran: The PERSIAN birth cohort. J Environ Health Sci Eng. 2019;17(2):969-78. https://doi.org/10.1007/s40201-019-00412-8 PMid:32030167 DOI: https://doi.org/10.1007/s40201-019-00412-8

Valvi D, Monfort N, Ventura R, Casas M, Casas L, Sunyer J, et al. Variability and predictors of urinary phthalate metabolites in Spanish pregnant women. Int J Hyg Environ Health. 2015;218(2):220-31. https://doi.org/10.1016/j.ijheh.2014.11.003 PMid:25558797 DOI: https://doi.org/10.1016/j.ijheh.2014.11.003

Hlisníková H, Petrovičová I, Kolena B, Šidlovská M, Sirotkin A. Effects and mechanisms of phthalates’ action on reproductive processes and reproductive health: A literature review. Int J Environ Res Public Health. 2020;17(18):6811. https://doi.org/10.3390/ijerph17186811 PMid:32961939 DOI: https://doi.org/10.3390/ijerph17186811

Liu T, Wang Y, Yang M, Shao P, Duan L, Li M, et al. Di-(2-ethylhexyl) phthalate induces precocious puberty in adolescent female rats. Iran J Basic Med Sci. 2018;21(8):848-55. https://doi.org/10.22038%2FIJBMS.2018.28489.6905 PMid:30186573

Gao H, Wu W, Xu Y, Jin Z, Bao H, Zhu P, et al. Effects of prenatal phthalate exposure on thyroid hormone concentrations beginning at the embryonic stage. Sci Rep. 2017;7(1):1-6. https://doi.org/10.1038/s41598-017-13672-x DOI: https://doi.org/10.1038/s41598-017-13672-x

Yao HY, Han Y, Gao H, Huang K, Ge X, Xu YY, et al. Maternal phthalate exposure during the first trimester and serum thyroid hormones in pregnant women and their newborns. Chemosphere. 2016;157:42-8. https://doi.org/10.1016/j.chemosphere.2016.05.023 PMid:27208644 DOI: https://doi.org/10.1016/j.chemosphere.2016.05.023

Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. Erratum: Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect. 2019;124(11):1808-15. https://doi.org/10.1289/EHP170 DOI: https://doi.org/10.1289/EHP170

Al-Saleh I, Coskun S, Al-Doush I, Al-Rajudi T, Abduljabbar M, Al-Rouqi R, et al. The relationships between urinary phthalate metabolites, reproductive hormones and semen parameters in men attending in vitro fertilization clinic. Sci Total Environ. 2019;658:982-95. https://doi.org/10.1016/j.scitotenv.2018.12.261 PMid:30678022 DOI: https://doi.org/10.1016/j.scitotenv.2018.12.261

Suma A, Kumar DS, Kishore P. Endometriosis: An overview of disease and treatment. Pharma Innov J. 2018;7(12):150-154.

Martino-Andrade AJ, Chahoud I. Reproductive toxicity of phthalate esters. Mol Nutr Food Res. 2010;54(1):148-57. https://doi.org/10.1002/mnfr.200800312 PMid:19760678 DOI: https://doi.org/10.1002/mnfr.200800312

Cao M, Pan W, Shen X, Li C, Zhou J, Liu J. Urinary levels of phthalate metabolites in women associated with risk of premature ovarian failure and reproductive hormones. Chemosphere. 2020;242:125206. https://doi.org/10.1016/j.chemosphere.2019.125206 PMid:31678849 DOI: https://doi.org/10.1016/j.chemosphere.2019.125206

Fu X, Han H, Li Y, Xu B, Dai W, Zhang Y, et al. Di-(2-ethylhexyl) phthalate exposure induces female reproductive toxicity and alters the intestinal microbiota community structure and fecal metabolite profile in mice. Environ Toxicol. 2021;36(6):1226-42. https://doi.org/10.1002/tox.23121 PMid:33665894 DOI: https://doi.org/10.1002/tox.23121

Fong JP, Lee FJ, Lu IS, Uang SN, Lee CC. Relationship between urinary concentrations of di (2-ethylhexyl) phthalate (DEHP) metabolites and reproductive hormones in polyvinyl chloride production workers. Occup Environ Med. 2015;72(5):346-53. https://doi.org/10.1136/oemed-2014-102532 PMid:25637220 DOI: https://doi.org/10.1136/oemed-2014-102532

Zong T, Lai L, Hu J, Guo M, Li M, Zhang L, et al. Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice. J Hazard Mater. 2015;297:25-33. https://doi.org/10.1016/j.jhazmat.2015.04.065 PMid:25935407 DOI: https://doi.org/10.1016/j.jhazmat.2015.04.065

Yu Z, Han Y, Shen R, Huang K, Xu YY, Wang QN, et al. Gestational di-(2-ethylhexyl) phthalate exposure causes fetal intrauterine growth restriction through disturbing placental thyroid hormone receptor signaling. Toxicol Lett. 2018;294:1-10. https://doi.org/10.1016/j.toxlet.2018.05.013 PMid:29753845 DOI: https://doi.org/10.1016/j.toxlet.2018.05.013

Yi H, Gu H, Zhou T, Chen Y, Wang G, Jin Y, et al. A pilot study on association between phthalate exposure and missed miscarriage. Eur Rev Med Pharmacol Sci. 2016;20(9):1894-902. PMid:27212185

Shoaito H, Petit J, Chissey A, Auzeil N, Guibourdenche J, Gil S, et al. The role of peroxisome proliferator–activated receptor gamma (PPAR γ) in mono (2-ethylhexyl) phthalate (MEHP)-mediated cytotrophoblast differentiation. Environ Health Perspect. 2019;127(2):27003. https://doi.org/10.1289/EHP3730 PMid:30810372 DOI: https://doi.org/10.1289/EHP3730

Pinkas A, Gonçalves CL, Aschner M. Neurotoxicity of fragrance compounds: A review. Environ Res. 2017;158:342-9. https://doi.org/10.1016/j.envres.2017.06.035 PMid:28683407 DOI: https://doi.org/10.1016/j.envres.2017.06.035