Endometriosis, a disease of unknown etiology, is characterized y infertility, chronic pain and adhesion formation, and may affect up to 6 million women of reproductive-age in the USA. Inspite of clinical reliance on endocrine based therapies, the role of sex steroid hormones in the growth of endometriotic tissue remains unclear. Normal uterine endometrium undergoes predictable histologic and biochemical changes in response to sex hormones throughout the menstrual cycle, but it is unknown whether this results from direct action on target cells or is exerted indirectly by soluble factors or cytokines produced within the endometrium. The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) alters the action of estrogen within reproductive organs and adversely affects immunocompetence. We have shown that TCDD exposure in the rhesus is associated with a dose-dependent increase in the incidence and severity of endometriosis. Additional studies demonstrated that the phenotype of peripheral blood leukocytes and in vitro secretion of cytokines by leukocytes from TCDD-exposed monkeys differed from unexposed animals more than 13 years after TCDD exposure was terminated. Immune cells are present within uterus and play a critical role in reproductive physiology and pathology. Furthermore, cytokines produced by activated leukocytes may participate in TCDD- mediated toxicity and in the pathogenesis f endometriosis. Using the unique resources of the NIH-funded Human Female Reproductive Tract Immunology Program Project (PP), the proposed studies will extend these findings from peripheral blood and animal models to the human uterine mucosal immune system. Using powerful new techniques developed for the PP, we will: determine the in vitro effects of TCDD exposure on sex hormone regulation of cytokine production and myeloid cell activation by cultured human endometrial tissue. These studies will give valuable insights into the role of a ubiquitous environmental toxin in the pathogenesis of endometriosis, and may ultimately lead to the development of biomarkers of immunotoxicity and novel therapeutic and diagnostic approaches to endometriosis. Furthermore, the techniques used in these studies will enable the future investigation of many potential environmental endocrine disruptors with respect to human reproductive disease pathogenesis at the interface between the immune and endocrine systems.
| Abrahams, Vikki M; Collins, Jane E; Wira, Charles R et al. (2003) Inhibition of human polymorphonuclear cell oxidative burst by 17-beta-estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Am J Reprod Immunol 50:463-72 |
| Yeaman, G R; Collins, J E; Currie, J K et al. (1998) IFN-gamma is produced by polymorphonuclear neutrophils in human uterine endometrium and by cultured peripheral blood polymorphonuclear neutrophils. J Immunol 160:5145-53 |
