Effect of heavy metals on aryl hydrocarbon receptor-regulated genes

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Co-contamination with complex mixtures of heavy metals and aryl hydrocarbon receptor (AhR)-ligands is a common environmental problem with multiple biological consequences, including birth defects, immune suppression, endocrine disruption and cancer. Both AhR ligands and heavy metals are ranked highly on the list of the most hazardous xenobiotics in the environment, prepared by the Canadian Environmental Protection Act (CEPA). The AhR plays a central role in the toxicity of numerous aromatic compounds by controlling the expression of a battery of enzymes responsible for their metabolism. The toxicity of AhR ligands is based on their bioactivation by the cytochrome P450 1A1 (CYP1A1) to yield mutagenic and carcinogenic intermediates. Many sources of environmental exposure to AhR ligands involve metal co-exposure. For example, heavy metals and AhR ligands are common contaminants of hazardous waste sites and are co-released from sources such as fossil fuel combustion and municipal waste incineration and as components of tobacco. Although environmental exposures involve co-exposure to complex mixtures, methods for assessing the potential risk to mixtures often assume additivity of responses, even though antagonism or synergy might exist. The novel aspect of this work is to understand the potential interaction between heavy metals and AhR ligands, which are common in the environment, on the expression of AhR-regulated genes to broaden our understanding of the important consequences for the toxicity of these environmental pollutants.