Superfund Research Program
Mutagenic and Carcinogenic Mechanisms of Environmental Chromium (ARRA Funded)
Project Leader: Moon-shong Tang
Grant Number: P42ES010344
Funding Period: 2009-2011
Project Summary (2009-2011)
Hexavalent chromium [Cr (VI)], a ubiquitous environmental contaminant, is a human carcinogen. Occupational exposure to Cr (VI) is strongly associated with a high incidence of lung cancer. Intriguingly, Cr(VI) by itself is a weak mutagen and carcinogen. The mechanisms of how Cr induces mutagenesis and carcinogenesis have yet to be discovered. It has been reported that cigarette smokers exposed to Cr have a high incidence of lung cancer and that these lung cancers are rich in G to T transversion mutations in the p53 gene. More than 85% of lung cancers are associated with cigarette smoke (CS); CS-related lung cancers have a high frequency of G to T mutations and distinct mutational pattern in the p53 gene. Although CS contains more than 40 carcinogens, Dr. Tang’s group has found that the distributions of DNA adducts induced by diolepoxides of polycyclic aromatic hydrocarbons (PAHs) and acrolein (Acr) in the p53 gene are similar to the lung cancer p53 mutational pattern. These findings raise the possibility that Cr(VI) exposure may exacerbate the PAH- and Acr-induced mutagenicity and cytotoxicity and consequently contributes to the high incidence of lung cancer. Since humans are frequently exposed to Cr (VI), PAHs and Acr, understanding the effects of Cr(VI) on the PAH and Acr induced biological effects is imperative not only for understanding lung carcinogenesis but also for risk assessment, and cancer prevention. Dr. Tang recently found that not only is Cr able to bind DNA to form binary and ternary Cr-DNA and Cr-amino acid-DNA adducts with the same sequence specificity in the p53 gene, but also that Cr is able to reduce nucleotide excision repair, thereby significantly enhancing PAH- induced mutations. These findings lead the researchers to hypothesize that the mutagenicity and carcinogenicity of Cr are derived from its two detrimental effects: formation of DNA adducts and inhibition of DNA repair. This research aims to further understand the molecular mechanism of these two effects and to test the hypothesis in mouse models. The goals of this research are to determine the molecular mechanisms of Cr(VI)-induced mutagenesis and carcinogenesis. Dr. Tang is determining the sequence specificity of Cr-DNA adducts in the p53 and K-ras genes, two frequently mutated genes in lung cancer, and how the adducts in these two genes are processed in human cells, the effect of Cr exposure on the repair of benzo(a)pyrene diol epoxide- and Acr- DNA adducts in these two genes in human cells, the effect of Cr on excision repair, and finally the effect of Cr on PAH-induced lung carcinogenesis in mouse models.