Endometriosis is a gynecological disease resulting from abnormal growth of endometrial tissue outside the uterine cavity. This disease causes pain and/or infertility in 5.5 million women in the US. The annual cost burden of disease is greater than $22 billion and no cure exists. A common therapy for disease is the suppression of ovarian estrogen production and emphasizes the critical nature of altered estrogen receptor (ER) signaling in endometriosis. Women with endometriosis have aberrant ER expression in the endometrium and in immune cells of the peritoneal fluid. Often, women with endometriosis have higher incidences of autoimmune disorders. However, the pathogenesis of endometriosis remains poorly understood and limited treatment options are available. To investigate mechanisms and toxicants that potentiate disease, a unique endometriosis mouse model was developed to mimic human disease. Minced donor uterine tissue is freely dispersed into the peritoneal cavity of an immunocompetent host for the development of endometriosis-like disease. Initial data demonstrates that ER? in the endometrium is critical for lesion attachment and immune cell infiltration, and ER? in the peritoneal cavity environment is critical for full endometriosis-like lesion responsiveness to hormone. A number of prevalent endocrine disrupting chemicals (EDCs) bind to and activate ER?; in vitro, they exhibit dose-dependent agonist/antagonist effects on estrogen receptor signaling. To determine the mechanism(s) of action of these findings the hypotheses are (1) Endometrial ER? is required for angiogenic signaling, (2) Peritoneal ER? is required for chemotactic and inflammatory signaling in the development of endometriosis-like lesions, and (3) Estrogenic EDCs signal through ER? to potentiate endometriosis- like lesion growth. The following aims are designed to test these hypotheses using this mouse model. Aim 1 will determine the role(s) of ER? in endometrial tissue essential for neo-angiogenesis and endometriosis- like lesion attachment. Aim 2 will determine the role(s) of ER? in the peritoneum critical for full endometriosis- like lesion responsiveness. Aim 3 will investigate the role of ER? in endometriosis-like lesions sensitivity to estrogenic EDC exposure. Understanding the actions of ER? in endometriosis-like disease will identify key targets of angiogenesis and immune modulations involved in disease as well as clarify the effects of EDC exposure on endometriosis. These findings will inform of useful biomarkers for disease detection and preventative measures to limit exposure to environmental toxicants to reduce the risk of endometriosis.