Environmental Immunotoxicants in the Development of Endometriosis

Endometriosis, the presence of proliferating endometrial tissue outside the uterine cavity, affects ~10 million American women. This disease causes immense suffering and costs the U.S. a staggering $100 billion annually. The prevalence is increasing, diagnosis is made only through invasive surgery, no cure exists, and clinical management remains focused on treatment of symptoms. The cause of endometriosis is poorly understood. Studies by us and others indicate that hormonal and immune factors are important, and these factors are influenced by environmental chemicals. Of particular interest are phthalates—high and low molecular weight environmental toxicants (HMW, LMW) that are classified as both endocrine disrupting chemicals and immunotoxicants. These chemicals are often found as mixtures in consumer items ranging from personal care products to flooring. Phthalates are increased in women with endometriosis. To address the possible link(s), bis(2-ethylhexyl) phthalate (DEHP, HMW) and dibutyl phthalate (DBP, LMW) will be used as tools to dissect mechanisms underpinning endometriosis development. We will use a mouse model of endometriosis that mimics human disease in mice “at-risk” and “not-at-risk” for endometriosis. In our model, during the first 72 h of disease initiation, endometriosis is immune-dependent with dis¬ease progres¬sion reliant on cytokine signaling and infiltration of innate immune cells—primarily neutrophils (PMN) and macro¬phages (MΦ). Interleukin 6 (IL6) signaling is dramatically increased during the initiation of endometriosis. Our preliminary data suggest DEHP further enhances this increased signaling and that long term DEHP treatment leads to increased endometriosis lesion number and severity of disease. Our findings regarding immune response, together with the effect of DEHP on disease development, lead to our central hypothesis that long-term phthalate exposure creates a pro-inflammatory environment via IL6 trans-signaling to induce and exacerbate EMS lesion formation, cell survival, cell adhesion, and angiogenesis. The hypothesis will be tested with the following specific aims: 1: Elucidate the mechanism by which long-term phthalate exposure alters PMN secretions to promote uterine cell adhesion and initiation of EMS lesions; 2: Determine the process by which long-term phthalate exposure via IL6 trans-signaling stimulates MΦ polarization and angiogenesis to promote EMS lesion growth; and 3: Determine the mechanisms by which phthalate-mediated IL6 trans-signaling modulates the functions of key EMS-associated cell types during the processes of EMS cell adhesion, lesion growth, and angiogenesis. At the successful completion of the proposed research, it is our expectation to have identified factors relevant to uterine cell survival, adhesion, vascularization, endometriosis lesion growth, and identify how these environmental immunotoxicants impact disease.