Effect of heavy metals on aryl hydrocarbon 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 foreign compounds. These programs entail upregulation of discrete batteries of genes for foreign compounds metabolizing enzymes, foreign compounds transporters, and various protective proteins that allow an increased rate of foreign compounds elimination from the body, restoration of normal homeostasis, and removal of damaged macromolecules. Rarely is the response regulated by one transcription factor; rather, it is generally a coordinated effort between two or more transcription factors. Among the 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 cell protection. Understanding the cross-talk between these two transcription factors can be exploited to therapeutic advantage or to improve chemopreventive strategies. My long-term objectives is to understand the potential outcome upon exposure to heavy metals and environmental pollutants, which commonly co-exist in the environment, on the expression of genes that is involved in the cellular response to toxicants and oxidative stress. This research uses a collaborative and multidisciplinary approach to elucidate the cellular and molecular mechanisms responsible for the modulation of genes that is involved in the cellular response to toxicants. This research may reveal novel points of intervention to be exploited in the development of new therapies for the treatment and prevention of heavy metals toxicity.