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The Environmental Contaminant di-(2-ethylhexyl)phthalate (DEHP) Induces Endometriosis

by

University of Cincinnati College of MedicineUniversity of Cincinnati College of Medicine

Principal Investigator:

Katherine A. Burns, PhD University of Cincinnati College of Medicine

Key Personnel

Stephanie Lang is a Research Associate in the Burns Laboratory. Stephanie had 12 years of research experience before joining the Burns Laboratory. Stephanie joined the laboratory with experience in histology, microscopy, immunohistochemistry, Western Blotting, animal surgery, and PCR analysis. Since joining the Burns Laboratory, she has become very proficient in mouse endometriosis surgery, ovariectomy, mouse dosing, and necropsy. Stephanie is well trained to perform the experimental procedures in this application.

Summary

Endometriosis is an inflammatory disease where endometrial tissue is found at sites outside of the uterine cavity, including the peritoneal cavity and ovaries. Although endometriosis is so prevalent, little is known about the mechanisms behind the initiation of endometriosis as a disease. Endometriosis is considered an estrogen-dependent disease (3, 4). Recent research investigated a link between endocrine disrupting chemicals (EDCs) as an environmental participant in reproductive diseases, including endometriosis (5). Xenoestrogens, or synthetic EDCs, include a group of chemicals known as phthalates which weakly mimic estrogen (6, 7). Phthalates are a group of similar phthalic acid esters that are used as plasticizers in polyvinyl chloride plastics. Phthalates are not covalently bound to the plastic matrix; therefore, they easily leach out of the products into the external environment (8). The most commonly used phthalate is di-(2-ethylhexyl)phthalate (DEHP). Humans are exposed to phthalates through multiple routes of exposure including food and drink, inhalation, skin absorption, and even medical procedures (9). Growing literature suggests that phthalates are increased in women with endometriosis (1, 2). Although phthalates are considered xenoestrogens, it is possible that the primary response is not via estrogen-mediated action, but rather through immune-mediated responses, as phthalates affect cytokine secretion from macrophages (10) that are the same cytokines dysregulated in women with endometriosis (11). Preliminary data from the Burns laboratory suggests the initiation of endometriosis is estrogen independent but dependent on the immune system; therefore, we hypothesize phthalates, specifically DEHP, play a role in the early initiation of endometriosis. To determine if this may be a mechanism of action, we will perform multiple experiments examining the effect of phthalates on endometrial cells, the impact of macrophage secretions on endometrial cells after phthalate exposure, and finally the effect of phthalates on the development of endometriosis in a mouse model. Our hypothesis is that DEHP alters the innate immune system to exacerbate the proliferative and invasive properties of endometriosis.

Specific Aims: There are three specific aims delineated in this research:

  1. Determine the impact of DEHP on endometrial cell functions.
  2. Determine the impact of macrophage secretions after DEHP treatments on endometrial cell functions.
  3. Determine the effect of DEHP on the development of endometriosis in a mouse model.

 

  1. Hunt PA, Sathyanarayana S, Fowler PA, Trasande L. Female Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine Disrupting Chemicals in the European Union. J Clin Endocrinol Metab. 2016;101(4):1562-70. doi: 10.1210/jc.2015-2873. PubMed PMID: 27003299.
  2. Buck Louis GM, Peterson CM, Chen Z, Croughan M, Sundaram R, Stanford J, Varner MW, Kennedy A, Giudice L, Fujimoto VY, Sun L, Wang L, Guo Y, Kannan K. Bisphenol A and phthalates, and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study. Fertil Steril. 2013;100(1):162-9 e1-2. doi: 10.1016/j.fertnstert.2013.03.026. PubMed PMID: 23579005; PMCID: PMC3700684.
  3. Fritz MA SL. In: S. S, editor. Clinical Gynecologic Endocrinology and Infertility. Eighth ed. Philadelphia: Lippincott Williams and Wilkins; 2011.
  4. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268-79. doi: 10.1056/NEJMra0804690. PubMed PMID: 19144942.
  5. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, Toppari J, Zoeller RT. EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev. 2015;36(6):E1-E150. doi: 10.1210/er.2015-1010. PubMed PMID: 26544531; PMCID: PMC4702494.
  6. Singh S, Li SS. Bisphenol A and phthalates exhibit similar toxicogenomics and health effects. Gene. 2012;494(1):85-91. doi: 10.1016/j.gene.2011.11.035. PubMed PMID: 22173104.
  7. Singh S, Li SS. Phthalates: toxicogenomics and inferred human diseases. Genomics. 2011;97(3):148-57. doi: 10.1016/j.ygeno.2010.11.008. PubMed PMID: 21156202.
  8. Heudorf U, Mersch-Sundermann V, Angerer J. Phthalates: toxicology and exposure. Int J Hyg Environ Health. 2007;210(5):623-34. doi: 10.1016/j.ijheh.2007.07.011. PubMed PMID: 17889607.
  9. Thompson PA, Khatami M, Baglole CJ, Sun J, Harris SA, Moon EY, Al-Mulla F, Al-Temaimi R, Brown DG, Colacci A, Mondello C, Raju J, Ryan EP, Woodrick J, Scovassi AI, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Amedei A, Hamid RA, Lowe L, Guarnieri T, Bisson WH. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis. 2015;36 Suppl 1:S232-53. doi: 10.1093/carcin/bgv038. PubMed PMID: 26106141; PMCID: PMC4492068.
  10. Nishioka J, Iwahara C, Kawasaki M, Yoshizaki F, Nakayama H, Takamori K, Ogawa H, Iwabuchi K. Di-(2-ethylhexyl) phthalate induces production of inflammatory molecules in human macrophages. Inflamm Res. 2012;61(1):69-78. doi: 10.1007/s00011-011-0390-x. PubMed PMID: 22005928.
  11. Greene AD, Lang SA, Kendziorski JA, Sroga-Rios JM, Herzog TJ, Burns K. Endometriosis: Where are We and Where are We Going? Reproduction. 2016. doi: 10.1530/REP-16-0052. PubMed PMID: 27165051.

Bio

Dr. Katherine (Katie) Burns is an Assistant Professor at the University of Cincinnati College of MedicineDr. Katherine (Katie) Burns is an Assistant Professor at the University of Cincinnati College of Medicine in the Department of Environmental Health. She earned her PhD from the Pennsylvania State University in Pathobiology with a concentration in Toxicology. Dr. Burns did her postdoctoral research at the National Institute for Environmental Health Sciences where she used a mouse model of endometriosis that recapitulates retrograde menstruation to study the roles of estrogen receptors in endometriosis. The Burns Laboratory studies how the immune system and interaction with endocrine disrupting chemicals contribute to or exacerbate endometriosis. Dr. Burns is also an endometriosis patient. During her 5th surgery, she was a subject in a clinical trial. At that point, as a PhD student, she saw the clinical and translational aspect of endometriosis and knew her future career direction. Her goal is to contribute to endometriosis research with the hope that girls become healthy reproductively competent women.

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