Altered regulation of immune genes by chemicals or disease states can seriously compromise immune function. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is a persistent environmental contaminant that produces a variety of toxic effects. Among these effects, alterations in immune function are some of the earliest detected at the lowest exposure levels. There have been more papers written about TCDD's effects on the immune system than about any other environmental hazard, but, despite almost 30 years of research, there is still no clear understanding of TCDD's mechanism of action on any aspect of the immune system. Additionally, TCDD is only one representative of a large class of chemicals that likely constitute a significant hazard to human health. Many of the toxic effects of TCDD and related chemicals have been attributed to activation of the aryl hydrocarbon receptor (AhR) and transcriptional modulation through binding of the AhR to DNA at dioxin responsive elements (DRE). Although there are likely several immune genes modulated by TCDD through an AhR/DRE mechanism, our previous studies have specifically demonstrated TCDD- mediated inhibition of Ig heavy chain gene expression in activated B cells, coupled with TCDD-induced binding of AhR to DRE sites located within the immunoglobulin heavy chain 3' regulatory region (3' IgH RR). With the stated specific aims (SA), we will test the HYPOTHESIS that TCDD inhibits Ig heavy chain gene transcription and class switch recombination through an AhR-dependent modulation of 3'IgH RR activity which involves protein binding to DRE and KB motifs within this regulatory region. SA1: Determine the enhancer regions responsible for LPS-induced activation and TCDD-induced inhibition of 3'IgH RR activity in the context of chromatin. SA2: Determine if AhR and/or NF-icB/Rel proteins are essential to the effects of TCDD on Ig expression and 3'IgH enhancer modulation. SA 3: Determine the effect of TCDD on Ig heavy chain class switch recombination. These studies will contribute to our long-term goal of elucidating the physiological role of the AhR in regulating Ig gene expression. The proposed work is significant in that it will contribute new insights into the molecular basis for the effects of TCDD on B-cell biology. These insights will be important not only to improving our understanding of the human exposure risks to a group of persistent environmental contaminants but they will also likely provide new perspectives on approaches to modulating B-cell function. ? ? ? ?
