Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic.
Recent work suggesting that cellular oxidative stress exerts an inhibitory effect on aromatic hydrocarbon receptor (AHR)-dependent gene expression led us to test the hypothesis that pro-oxidant environmental pollutants might alter the induction of detoxification genes by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AHR ligand. We found that, in mouse hepatoma Hepa-1 cells, TCDD-inducible cytochrome P450, Cyp1a1, and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase (Nqo1) mRNA accumulation were differentially affected by cadmium (Cd(2+)), chromium (Cr(6+)), and arsenic (As(3+)). Cadmium or arsenic did not change Cyp1a1 mRNA levels but did enhance TCDD-inducible levels of Nqo1 mRNA, an effect that paralleled the ability of these metals to activate a beta-galactosidase gene reporter system regulated by an electrophile response promoter element. Chromium inhibited mRNA accumulation for both Cyp1a1 and Nqo1. Manipulation of cellular thiol status did not modify the response to combined chromium-TCDD exposure, suggesting that the response was not caused by oxidative stress. Chromium did not block DNA-binding competence of the AHR and did not have an effect on mRNA stability, but it inhibited Cyp1a1 gene transcription and the expression of an AHR-dependent luciferase reporter. These data indicate that coexposure to pro-oxidant metals and AHR ligands, which is common in the environment, can disrupt the regulation of phase I and phase II detoxification genes, leading to imbalances in gene expression that may have important consequences for the toxicity of complex mixtures.
Maier
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Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
Dalton
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Puga
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D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D002104:Cadmium / Q000494:pharmacology*; D002857:Chromium / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D008114:Liver Neoplasms, Experimental; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics
D000072317:Polychlorinated Dibenzodioxins; D011994:Recombinant Proteins; D002104:Cadmium; D002857:Chromium; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1; D013482:Superoxide Dismutase; D016660:NAD(P)H Dehydrogenase (Quinone); D001616:beta-Galactosidase; D001151:Arsenic