Interactions in the toxicity of polycyclic hydrocarbon and metal mixtures

The aromatic hydrocarbon receptor (AHR) plays a pivotal role in molecular toxicology, serving as the initiating step in a pathway that unleashes the diverse effects elicited by many polycyclic aromatic hydrocarbons (PAHs). The mechanisms of toxicity of PAHs have been extensively studied, but little work has been done to characterize potential toxicological interactions between PAHs and metals. The published literature suggesting that cellular oxidative stress exerts an inhibitory effect on AHR-dependent responses led us to test the hypothesis that pro-oxidant metals might alter cellular responses to AHR ligands. We report that in mouse hepatoma cells, TCM-inducible cytochrome P450 Cyp1a1 and NADPH-quinone oxidoreductase mRNA accumulation were differentially affected by metal co-treatments. Arsenic or cadmium did not change Cyp1a1 mRNA levels but enhanced TCDD-inducible levels of Nqo1 mRNA, an effect that paralleled the ability of these metals to activate a reporter gene regulated by electrophile responses. Chromium, on the other hand, inhibited mRNA accumulation for both Cyp1a1 and Nqo1 possibly via a direct transcriptional inhibition due to chromium-DNA interactions or interference with assembly of transcriptional complexes.; To determine if these changes in inducible gene expression would be reflected by changes in the biological activation of AHR ligands, we studied BaP-DNA adduct formation with metal co-exposures. We found that arsenic increases total adduct yields when co-administered with BaP, while chromium had no effect. In a series of experiments to identify the mechanisms involved, we found that the rate of adduct removal is decreased by arsenic, suggesting that DNA repair inhibition could be at least partially responsible for the increased adduct yields.; As a whole, the data show that metal co-exposures can have dramatic effects on biological responses to AHR ligands. The degree and direction of effects, however, vary from one metal to another reflecting the differences in molecular mechanisms involved. The ability of metals to abrogate cellular responses to PAH exposure, suggests that quantitative risk assessment models that ignore these interactions, may not accurately account for health risks from exposures to mixtures that are likely to occur in the environment.