Superfund site chemicals such as polycyclic aromatic hydrocarbons (PAHs), halogenated aromatic hydrocarbons (HAHs) and polychlorinated biphenyls (PCBs) are known human health toxicants. Their toxicity is associated with altered gene expression. The molecular mechanisms that underlie gene activation by these agents are linked to activation of the dioxin or aryl hydrocarbon (Ah) receptor (AhR). Our laboratory and others have demonstrated that AhR ligands signal gene activation by modifying other signal transduction pathways such as those under the regulation of protein kinase C. Evidence is presented that oxidative-stress induced pathways such as those under the protein kinase C. Evidence is presented that oxidative-stress induced pathways, such as JNK and NF- kappaB may also participate in AhR ligand mediated gene expression. In line with the theme of the SBRP, we will be examining the actions of AhR ligands on gene expression. We are developing a sensitive AhR ligand reporter gene system that takes advantage of the beta-lactamase gene as the reporter system. This AhR-reporter gene system will be useful as a model for monitoring the presence of AhR ligands in mixtures. To further understand the underlying mechanisms associated with AhR ligand toxicity, experiments are outlined to characterize genes that are targeted by AhR dependent mechanisms and those that are coordinately regulated by PKC and AP-1. Other pathways that link AhR Ligand induced gene expression by oxidative-stress mediated mechanisms will also be examined. We will take advantage of the expertise offered in the Microarray Technology Core to screen mouse ESTs spotted on microarray chips to identify those genes modified by these toxicants. As new genes and cDNAs are discovered, they will be characterized following expression in tissue culture cells, and we will utilize the Macromolecular Characterization Core for help with these studies. Finally, to the study and functional role of some of the altered genes, we will knock-out selected genes in mice with help from the Mouse Genetics Core. The broad scope of the SBRP and the centralized goals to study the actions of Superfund toxicants on gene expression will allow us to work closely with Drs. Karin (Project 1), Tsien (Project 3), Kelner (Project 5) and Glass (Project 6) to better understand the signal transduction pathways involved in the toxic actions of these agents.
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