Superfund Research Program

Epigenetic Effects on Individual Susceptibility to Heavy Metal and Polycyclic Aromatic Hydrocarbon- Induced DNA Damage

Project Leader: Moon-shong Tang
Grant Number: P42ES010344
Funding Period: 2000 - 2006

Project-Specific Links

Final Progress Reports

Year:   2005 

The objectives of this Superfund basic research project are: 1) to determine the underlying mechanisms for synergism in both tumorigenic and mutagenic effects of exposure to heavy metals and polycyclic aromatic hydrocarbons (PAHs) contaminants in Superfund sites, and 2) the epigenetic effects on metal and PAH-induced DNA damage and its repair.   Since Dr. Moon-Shong Tang’s research team and others have found that transition metals such as chromium and nickel are poor mutagens by itself but can greatly enhance mutagenicity of PAH and ultraviolet light irradiation they hypothesize that this synergistic effect is due to two effects of metal exposure: one, enhancing DNA susceptibility to PAH-DNA adduction, and two, reducing the DNA repair efficiency.   The researchers also hypothesize those epigenetic factors such as DNA methylation and chromatin structure greatly affecting DNA susceptibility to PAH-induced damage.  They have developed host cell reactivation on a reporter gene, and in vitro DNA repair synthesis assays to determine the effect metal exposure on DNA repair capacity.  They have found that both chromium and nickel exposures can greatly inhibit cellular nucleotide excision repair capacity.  However, they have also found that chromium can bind to DNA with sequence selectivity; many mutational hotspots in the p53 and ras genes are the preferential sites of chromium-DNA binding.  Project researchers conclude that the two detrimental effects of metal exposure, damaging DNA and reducing DNA repair capacity, contribute to metal mutagenesis and carcinogenesis.   To address the epigenetic effect on metal and PAH mutagenesis and carcinogenesis, they have developed a method using the DNA repair enzyme complex in combination with ligation-mediated polymerase chain reaction to map DNA damage at the nucleotide resolution level in the tumor suppressor gene p53 and the oncogenes K-ras, N-ras and H-ras in primary cultured human epithelial cells.  The researchers have found that 1) mutational hotspots in these cancer-related genes are preferential damage sites for PAH, 2) damage formed in these hotspots is poorly repaired, and 3) metals such as chromium enhance DNA susceptibility to PAH damage and reduce the repair capacity. They have also found that not only DNA methylation but also unknown factors in these genes determine their sensitivity toward PAH; they are in the process of determining these unknown factors.  The researchers have found that chromium preferentially binds to the p53 mutational hotpsot (codon 249) of nonsmoker lung cancer.  It is known that exposed to fine and ultrafine particular matter (PM2.5) enhances lung cancer incidence.  Based on these findings they propose that chromium in PM play an important role in lung carcinogenesis in nonsmokers.  To test this hypothesis they will determine DNA damage induced by PM and chromium binding in the p53 gene in cultured human lung epithelial cell.  These results enhance their understanding of metal, PM and PAH mutagenesis at molecular level and enable them to better design animal experiments to understand metal, PM and PAH carcinogenesis in the coming funding period.