Endometriosis, described as the ectopic growth of endometrial tissue, is a debilitating disease of reproductive age women. In North America, at least 5.5 million women are affected by endometriosis at any one time and estimates of the economic cost of treating this disease range from $1-20 billion annually in the United States alone. An emerging view is that a reduced endometrial responsiveness to progesterone (P4), a defect referred to as the """"""""endometriosis phenotype,"""""""" may play a significant role in development and/or progression of endometriosis. Relative to this question, we have explored whether exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin or dioxin) promotes development of the P4- resistant, endometrial phenotype. During our past funding period, we utilized adult human endometrial cell and tissue culture models, a chimeric model of experimental endometriosis in immunocompromised mice and a murine model of early life TCDD exposure to examine the impact of this toxicant. Using human cells, TCDD exposure was found to disrupt the anti-inflammatory action of P4, leading to cellular changes that potentiated the invasive behavior of endometrial tissues in our experimental endometriosis model. Our murine model of early life toxicant exposure revealed that TCDD-mediated defects in uterine P4 sensitivity can indeed arise from a developmental exposure. Perhaps more significant, our murine model also revealed that early life toxicant exposure leads to a heightened sensitivity to inflammation for multiple generations in the absence of additional toxicant exposure. Taken together our studies strongly suggest that disrupting the anti-inflammatory action(s) of P4 during endometrial maturation is the key mechanism by which TCDD-like toxicants alter reproductive function and impact a woman's risk of developing endometriosis. Thus, therapeutic interventions which target inflammatory signaling may have significant efficacy in blocking TCDD-mediated development of the P4 resistant endometrial phenotype associated with endometriosis. To validate this appoach we will utilize in vitro and in vivo studies designed to prevent the development and progression of the endometriosis phenotype as well as prevent the transmission of this phenotype to future generations. We propose three Specific Aims: 1): To evaluate the therapeutic potential(s) of resveratrol (RES) and PGE2 signaling inhibitors to reduce TCDD mediated loss of P4 responsiveness in human endometrial cells.. 2): To evaluate whether the anti- inflammatory effect(s) of RES and PGE2 signaling inhibitors alone or in combination will limit TCDD- mediated growth of experimental endometriosis in our humanized Rag2?(c) mouse model. 3): To evaluate the ability of RES and PGE2 signaling inhibitors to restore uterine progesterone sensitivity and reproductive function in a novel murine model of early life TCDD exposure that exhibits an adult endometriosis-like uterine phenotype.

Public Health Relevance

In this application, will we examine the influence of dioxin (TCDD) on biological processes within the eutopic endometrium that promote the development of endometriosis using human cells and animal models. Utilizing pharmacologic and nutritional therapy, we will inhibit TCDD-mediated inflammatory processes in our model systems in an attempt to inhibit the development of experimental endometriosis and prevent the transmission of the endometriosis phenotype to future generations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014942-07
Application #
8538382
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Heindel, Jerrold
Project Start
2006-09-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
7
Fiscal Year
2013
Total Cost
$341,637
Indirect Cost
$109,667
Name
Vanderbilt University Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bruner-Tran, Kaylon L; Gnecco, Juan; Ding, Tianbing et al. (2016) Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models. Reprod Toxicol :
Arosh, Joe A; Lee, JeHoon; Balasubbramanian, Dakshnapriya et al. (2015) Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis. Proc Natl Acad Sci U S A 112:9716-21
Rahmioglu, Nilufer; Fassbender, Amelie; Vitonis, Allison F et al. (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: III. Fluid biospecimen collection, processing, and storage in endometriosis research. Fertil Steril 102:1233-43
Fassbender, Amelie; Rahmioglu, Nilufer; Vitonis, Allison F et al. (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research. Fertil Steril 102:1244-53
Becker, Christian M; Laufer, Marc R; Stratton, Pamela et al. (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. Fertil Steril 102:1213-22
Bruner-Tran, Kaylon L; Ding, Tianbing; Yeoman, Kallie B et al. (2014) Developmental exposure of mice to dioxin promotes transgenerational testicular inflammation and an increased risk of preterm birth in unexposed mating partners. PLoS One 9:e105084
Vitonis, Allison F; Vincent, Katy; Rahmioglu, Nilufer et al. (2014) World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril 102:1223-32
Bruner-Tran, K L; Herington, J L; Duleba, A J et al. (2013) Medical management of endometriosis: emerging evidence linking inflammation to disease pathophysiology. Minerva Ginecol 65:199-213
Herington, Jennifer L; Glore, Dana R; Lucas, John A et al. (2013) Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model. Fertil Steril 99:543-50
Resuehr, David; Glore, Dana R; Taylor, Hugh S et al. (2012) Progesterone-dependent regulation of endometrial cannabinoid receptor type 1 (CB1-R) expression is disrupted in women with endometriosis and in isolated stromal cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Fertil Steril 98:948-56.e1

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