Dioxin and Steroid Regulation in an Endometriosis ModelEPA Grant Number: R826300
Title: Dioxin and Steroid Regulation in an Endometriosis Model
Investigators: Osteen, Kevin G.
Institution: Vanderbilt University School of Medicine
EPA Project Officer: Deener, Kacee
Project Period: December 15, 1997 through December 14, 2000
Project Amount: $381,404
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Endocrine Disruptors , Health , Safer Chemicals
Endometriosis is a complex and persistent endocrine disease which typically develops from the ectopic implantation of endometrial fragments as a consequence of retrograde menstruation. Compounds such as 2,3,7,8-tetrachlorobenzo-p-dioxin (dioxin), can disrupt steroid action and may influence the development of endometriosis. Dioxin is a by-product of manufacture and combustion of chlorinated phenols and is considered by some to be one of the most toxic substances ever released into the environment. A woman's exposure to ovarian steroids impacts her chance of developing this disease through poorly understood mechanisms. Using a nude mouse model to examine ectopic growth of human endometrium, matrix metalloproteinases (MMPs), enzymes which regulate extracellular matrix turnover, have been shown to mediate establishment of human endometrial lesions in mice. Specifically, estrogen-associated MMP expression supports development of experimental endometriosis while progesterone-mediated suppression of these enzymes inhibits the development of ectopic lesions.
Dioxin has been linked to the development of endometriosis in primates and has been demonstrated by this laboratory to promote the establishment of experimental endometriosis by human endometrium injected into the peritoneal space of nude mice. It is hypothesized that the mechanism by which dioxin promotes experimental endometriosis is by the disruption of steroid-mediated MMP expression. By disrupting normal progesterone regulation of MMPs in human endometrial tissue, dioxin blocks the ability of this steroid to prevent the invasive process by which ectopic lesions are established.
Approach:The ability of dioxin to disrupt progesterone action and block normal MMP regulation during the development of experimental endometriosis will be assessed in nude mice. Additionally, the cellular and molecular mechanisms of progesterone action on endometrial cells, including the ability of dioxin to disrupt progesterone action in each cell type, will be explored using appropriate tissue culture models and molecular techniques.
Expected Results:Since progesterone has been demonstrated clinically to offer some protection against the development or recurrence of endometriosis, the ability of dioxin to interefere with progesterone action is expected to play a key role in the disease process. As the cellular and molecular mechanisms of progesterone action on MMP regulation become better understood, the specific role(s) dioxin plays in interfering with these mechanisms will be revealed.
Publications and Presentations:Publications have been submitted on this project: View all 15 publications for this project
Journal Articles:Journal Articles have been submitted on this project: View all 7 journal articles for this project
Supplemental Keywords:TCDD, progesterone action, animal model, RFA, Health, Scientific Discipline, Toxics, Environmental Chemistry, Health Risk Assessment, Endocrine Disruptors - Environmental Exposure & Risk, pesticides, endocrine disruptors, Risk Assessments, Children's Health, Biology, Endocrine Disruptors - Human Health, adverse outcomes, TCDD, enzymes, dose response, steroid, 2, 3, 7, 8-Tetrachloro-dibenzo-p-dioxin (TCDD), animal models, toxicity, human exposure, biochemistry, biological effects, dioxins, endometriosis, chlorinated phenols, ectopic growth, ovary
Progress and Final Reports:1999 Progress Report