Project Summary (2000-2005)

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). AhR ligands signal gene activation by modifying other signal transduction pathways such as those under the regulation of protein kinase C (PKC). Project investigators are examining the actions of AhR ligands on gene expression and are developing a sensitive AhR ligand reporter gene 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, project experiments will characterize genes that are targeted by AhR dependent mechanisms, and those that are coordinately regulated by PKC and a sequence-specific transcriptional activator (AP-1). The Microarray Technology Core will be utilized to determine which genes have been modified by these toxicants. Finally, to study the functional role of some of the altered genes, researchers will knock-out selected genes in mice. Investigators will collaborate with other projects to develop an understanding of the signal transduction pathways involved in the toxic actions of these agents.