Estrogens have been shown to regulate the immune system and modulate multiple autoimmune diseases. 17α-ethinyl estradiol (EE), a synthetic analog of 17β-estradiol, is prescribed commonly and found in oral contraceptives and hormone replacement therapies. Surprisingly, few studies have investigated the immunoregulatory effects of exposure to EE, especially in autoimmunity. In this study, we exposed autoimmune-prone female MRL/lpr mice to a human-relevant dose of EE through the oral route of exposure. Since lupus patients are prone to infections, groups of mice were injected with viral (Imiquimod, a TLR7 agonist) or bacterial (ODN 2395, a TLR9 agonist) surrogates. We then evaluated autoimmune disease parameters, kidney disease, and response to in vivo TLR7/9 pathogenic signals. EE-exposed mice had increased proteinuria as early as 7 weeks of age. Proteinuria, blood urea nitrogen, and glomerular immune complex deposition were also exacerbated when compared to controls. Production of cytokines by splenic leukocytes were altered in EE-exposed mice. Our study shows that oral exposure to EE, even at a very low dose, can exacerbate azotemia, increase clinical markers of renal disease, enhance glomerular immune complex deposition, and modulate TLR7/9 cytokine production in female MRL/lpr mice. This study may have implications for EE-exposure risk for genetically lupus-prone individuals.Environmental exposure of animals and people to low doses of estrogenic endocrine disrupting chemicals (EEDCs) occurs through a variety of sources, including ingestion of food and water, pharmaceuticals, outdoor activities, pesticides and fertilizers in agricultural applications, industrial chemicals, plastics, sewage, detergents, and cosmetics 1 . One such EEDC, 17α-ethinyl estradiol (EE), a synthetic analog of endogenously produced 17β-estradiol (E2), is a primary component in oral contraceptive pills (OCP) and has been widely used in hormone replacement therapy (HRT). EE is also used as a treatment for breast cancer, vasomotor symptoms in menopause, female hypogonadism, hirsutism, acne vulgaris, and dysmenorrhea 2 .EE has been found in aquatic environments and water sources even after water treatment has been performed 3 . The high likelihood of chronic or repeated human exposure to multiple EEDCs throughout one's lifetime is a significant health concern. Although EE is commonly prescribed, the immunomodulatory effects are not yet well understood. It is likely that there may be subsets of populations, such as autoimmune-prone individuals, who may be particularly vulnerable to the effects of EE exposure.Estrogens have been shown to alter various functions of the immune system and regulate the responses to stimuli in both normal and autoimmune individuals through estrogen receptor-dependent or -independent mechanisms 4-12 . Another such EEDC, bisphenol A (BPA) has been shown to dysregulate the immune system and may promote autoimmunity 13,14 . We recently compared the immunoregulatory effects of pharmaceutical administration of EE and E2 a...