Received for publication February 8, 2005.
Revised April 28, 2005.
Accepted for publication May 12, 2005.

Arsenite-induced aryl hydrocarbon receptor nuclear translocation results in additive induction of phase I and synergistic induction of phase II genes

Abstract

Complex mixtures of carcinogenic metalloids, such as arsenic, and PAHs or HAHs are common environmental contaminants. The biological consequences of exposure to these mixtures are unpredictable and, although the health effects of individual chemicals may be known, the toxicity of environmental mixtures is largely unexplored. Arsenic, not a potent mutagen by itself, is comutagenic with many DNA-damaging agents. Mixtures of arsenite plus B[a]P augment B[a]P mutagenicity, suggesting that arsenite might uncouple expression of phase I and phase II genes responsible for detoxification. We have studied the effects of arsenite exposure on the activation of the AHR and its subsequent role in gene transactivation. Treatment of mouse Hepa-1 cells with arsenite induces AHR nuclear translocation and binding to the Cyp1a1 gene promoter with the same efficiency as TCDD, the AHR most potent ligand; however, TCDD and B[a]P are one order of magnitude more potent than arsenite in up-regulating Cyp1a1 transcription. Global profiling analyses of cells treated with arsenite plus B[a]P indicate that several phase I and phase II detoxification genes are in some cases additively and in others synergistically deregulated by the mixtures. Real- time RT-PCR analyses of MEFs showed that the mixtures had an additive effect on the mRNA levels of Cyp1b1, a prototypical phase I detoxification gene, and an AHR- dependent synergistic effect on the corresponding levels of Nqo1, a prototypical phase II gene. We conclude that exposure to arsenite/B[a]P mixtures causes regulatory changes in the expression of detoxification genes that ultimately affect the metabolic activation and disposition of toxicants.

Key words: Regulation of gene expression, Quinone oxidoreductase, Regulation - transcriptional, Regulation - xenobiotic, Ah receptor, Metals and chelators, Toxicant-induced gene express

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