EFFECT OF ENVIRONMENTAL ESTROGENS ON IL-1-BETA PROMOTER ACTIVITY IN AMACROPHAGE CELL-LINE

Environmental estrogens or estrogen disrupters have recently received a great deal of attention because of their potential health impact on reproductive tissues. Few, if ally, studies have been made on the impa ct of these compounds on the immune system. We sought to determine the activities of various environmental estrogens on the modulation of th e interleukin-1 beta (IL-1 beta) gene in a model monocytic cell line, hER + IL-1 beta-CAT+. This cell ine stably transfected with the human estrogen receptor, and an IL-1 beta promoter construct fused to the CA T reporter gene allows us to monitor the effect of estrogenic compound s on IL-1 beta promoter activity. 17 beta-Estradiol (E-2) markedly enh anced lipopolysaccharide- (LPS) induced IL-1 beta promoter-driven CAT activity in a dose-dependent manner. The mycotoxins c-zearalenol and z earalenone both exhibited full agonist activity, but at lower potencie s, with EC50 values of 1.8 and 54 nM, respectively, compared with E-2 at 0.5 nM. In addition, genistein was a very low-potency agonist, havi ng an EC50 of 1.5 mu M. Similar to the E-2 response, the slope factors for alpha-zearalenol, zearalenone, and genistein were close to 3.0, s uggesting posit ve cooperativity in the estrogenic response. The activ ity of the mycotoxins appeared to be mediated through the estrogen rec eptor, since both the antiestrogens H1285 and ICI 182,780 effectively inhibited their agonist activity in a dose-dependent manner. Represent ative environmental estrogenic compounds both from plant and industria l sources were ale, tested. Unlike the mycoestrogens, none of the comp ounds, with the exception of genistein, synergized with LPS to enhance IL-1 beta promoter activity. When tested for antiestrogenic activity, the industrial con pound 4-octylphenol was able to antagonize the res ponse to E-2; however, the response was three orders of magnitude less potent than H1285. Naringenin, a plant flavonoid, showed little or no ability to antagonize the response to E-2. Overall, the results show that some environmental estrogens that display agonist activity in rep roductive tissue also have an effect on IL-1 gene expression in hemopo ietic-derived tissue.