The biological effects of dioxins are mediated by the Aryl hydrocarbon receptor (AhR) and its dimerisation partner, the AhR nuclear translocator (ARNT), and include interference with hormonal signalling pathways like the response to estrogens. The effects of estrogens are mediated by two estrogen receptor (ER) isoforms, ER and ER, which belong to the family of nuclear receptors. We have previously shown that ARNT can act as co-activator of the ERs,. In this study, we show that recruitment of ARNT to AhR- or HIF-1-signalling pathways, as well as siRNA-mediated down-regulation of ARNT levels, leads to a reduction in ER transcriptional activity. Using ChIP assays, we demonstrate that this decrease coincides with reduced recruitment of ARNT to estradiol-regulated promoters. We show further that co-activation by ARNT as well as inhibition by dioxin acts stronger on ER than on ER activity. Additionally, we demonstrate that the effects of ARNT are dependent on the A/B domain of the estrogen receptors with A/B domain of ER being considerable stronger in mediating the coactivating effects of ARNT.

Taken together, our studies show that recruitment of ARNT to the AhR following dioxin treatment can account for the anti-estrogenic effect of dioxins. Moreover, we show for the first time that the inhibitory effects of dioxin are more pronounced on ER than on ER.