Effect of heavy metals on aryl hyrdocarbon receptor-regulated genes

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Humans are exposed to numerous stressors, including heavy metals, products of combustion, pesticides, herbicides, and other environmental pollutants. To ensure survival in the face of such challenges, mammalian cells have evolved a variety of inducible genetic programs that enable them to adapt to the presence of harmful xenobiotics. These programs entail upregulation of discrete batteries of genes for xenobiotic metabolizing enzymes, xenobiotic transporters, and various cytoprotective proteins that allow an increased rate of xenobiotic elimination from the body, restoration of normal homeostasis, and removal of damaged macromolecules. Among transcription factors that mediate adaptation to foreign compounds, the aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) have been widely studied. Historically, the AhR has been associated with toxicity and carcinogenesis, whereas Nrf2 is associated with cytoprotection. My long-term objectives are to: 1) understand the potential outcome upon exposure to heavy metals and environmental pollutants, which commonly co-exist in the environment, on the expression of AhR-regulated genes, and 2) understand the role of AhR in the regulation of Nrf2 pathway and its downstream genes in response to heavy metals exposure. Our hypothesis is redox-sensitive transcription factors, activated protein 1 (AP-1) and nuclear factor kappaB (NF-kB), and their associated proteins mediate the cross-interactions between AhR and Nrf2 pathways that are involved in the modulation of AhR-regulated genes by heavy metals. This research is expected to have a great impact on the understanding of the cellular and molecular mechanisms responsible for the modulation of AhR-regulated genes by metals. Better recognition of coordinate Phase I and II metabolisms may greatly attenuate health risks posed by CYP1A1 generated toxic intermediates and reactive oxygen species. In addition, it will also reveal novel points of intervention to be exploited in the development of new therapies for the treatment and prevention of metals toxicity.