Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signalingpathways

Most if not all of the toxic responses of 2,3,7,8-tetrachlorodibenzo-p-diox in (TCDD) are mediated through the AhR, which requires ARNT to regulate gen e expression. ARNT is also required by HIF-1 alpha to enhance the expressio n of various genes in response to hypoxia. Since both the AhR and hypoxia t ranscriptional pathways require ARNT, some of the effects of TCDD and simil ar types of ligands could be explained by interaction between the AhR and h ypoxia pathways involving ARNT. The studies on which we report here were co nducted to lest the hypothesis that there is cross talk between AhR- and HI F-1-mediated transcription pathways. TCDD significantly reduced the hypoxia -mediated reporter gene activity in B-1 cells. Reciprocally, the hypoxia re sponse inducers desferrioxamine or CoCl2 inhibited AhR-mediated CYP1A1 enzy me activity in B-1 and Hepa 1 cells, and the AhR-mediated luciferase report er gene activity in H1L1.1c2 cells. The inhibition of AhR-mediated transcri ption by hypoxia inducers, however, was not observed in H4IIE-luc cells. Th e interaction between the AhR- and HIF-1-mediated transcription can be attr ibuted to changes in DNA binding activities. TCDD-induced protein binding t o dioxin responsive element (DRE) was diminished by desferrioxamine, and TC DD reduced the binding activity to HIF-1 binding site in desferrioxamine-tr eated Hepa 1 cells. This mutual repression may provide an underlying mechan ism for many TCDD-induced toxic responses. The results reported here indica te that there is cross talk between ARNT-requiring pathways. Since ARNT is possibly required by a number of pathways, this type of interaction may exp lain some of the pleiotropic effects caused by TCDD. (C) 2001 Elsevier Scie nce B.V. All rights reserved.