Accumulating data suggest that endocrine disruptors affect not only the reproductive system, but also the immune system. We demonstrate here that endocrine disruptors including diethylstilbestrol (DES) and bisphenol-A (BPA) enhance autoantibody production by B1 cells both in vitro and in vivo. BWF1 mice, a murine model for systemic lupus erythematosus (SLE), implanted with Silastic tubes containing DES after orchidectomy developed murine lupus characterized by immunoglobulin G (IgG) anti-DNA antibody production and IgG deposition in the glomeruli in the kidney as well as those implanted with 17beta-estradiol (E2). Plaque-forming cells (PFC) producing autoantibodies specific for bromelain-treated red blood cells were significantly increased in mice implanted with DES and BPA. IgM antibody production by B1 cells in vitro was also enhanced in the presence of endocrine disruptors including DES and BPA. Estrogen receptor (ER) expression was upregulated in B1 cells in aged BWF1 mice that developed lupus nephritis. These results suggest that endocrine disruptors are involved in autoantibody production by B1 cells and may be an etiologic factor in the development of autoimmune diseases.