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Analysis of Pro-Oxidant Metal-Induced Changes in Toxic Responses to Ligands of the AH ReceptorEPA Grant Number: U915214
Title: Analysis of Pro-Oxidant Metal-Induced Changes in Toxic Responses to Ligands of the AH Receptor
Investigators: Maier, Michael A.
Institution: University of Cincinnati
EPA Project Officer: Boddie, Georgette
Project Period: January 1, 1997 through January 1, 1998
Project Amount: $102,000
RFA: STAR Graduate Fellowships (1997) RFA Text | Recipients Lists
Research Category: Fellowship - Toxicology , Academic Fellowships , Health Effects
The objective of this research project is to characterize the biological consequences of exposure to mixtures of the pro-oxidant metals, cadmium, chromium, arsenic, or nickel, and ligands for the aromatic hydrocarbon receptor (AHR), such as benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).Approach:
To test the hypothesis that pro-oxidant metals could alter AHR-dependent responses, I we have pursued three specific aims: (1) the evaluation of a yeast model for assessing the effects of pro-oxidants on AHR activation; (2) the characterization of the effect of pro-oxidant metals on AHR-dependent gene expression in mammalian cells; and (3) the evaluation of the biological consequences of gene expression changes by analyzing BaP-DNA adduct patterns. Using a yeast two-hybrid system, we show that AHR activity in yeast accurately reflects ligand affinities reported for whole-animal studies, but cadmium or chromium do not eaffect AHR-activation. We found that pro-oxidant metals differentially affect TCDD-inducible cytochrome P450 CYP1A1, and NADPH-quinone oxidoreducatase mRNA accumulation, and enzyme activities in mouse hepatoma cells. Cadmium and arsenic effects paralleled the ability of these metals to activate an b-galactosidase reporter regulated by oxidative stress, while the effects of chromium were not oxidative stress- dependent. Chromium did not block AHR activation, but it inhibited gene transcription. These data indicate that co-exposure to pro-oxidant metals and aromatic hydrocarbon receptor ligands disrupt the coordinate regulation of detoxification genes, leading to enzymatic imbalances that may have important consequences for the toxicity of complex mixtures. To test the biological significance of altered detoxification gene expression, we will correlate changes in enzyme activity with BaP-DNA adduct formation in human lung cell lines.Supplemental Keywords:
fellowship, toxic responses, aromatic hydrocarbon receptor, AHR, pro-oxidant metals, cadmium, chromium, TCDD.