DNA Damage from Chemical Carcinogens

Research from the lab of Prof. Ken Roberts

An area of research we are pursuing is the development of chemical biomarkers for early cancer detection and cancer risk-assessment from chemical carcinogens and other forms of oxidative stress. Many environmental genotoxins such as polycyclic aromatic hydrocarbons, heterocyclic and aromatic amines, and mycotoxins are known to cause cancer even though the “mode-of-action” is still highly debated. However, what is well established is that many chemical carcinogens require metabolic activation to reactive intermediates prior to covalently binding (adducting) DNA. Incorrect (or inefficient) enzymatic removal of the carcinogen-DNA adduct may lead to genetic mutation and cancer. From this, there is tremendous interest in developing biomarkers from this mechanistic pathway to monitor the dose-response relationship and polymorphic susceptibility of humans and animals to chemical carcinogens. To measure biomarkers on a real-world level in humans, highly sensitive and selective analytical tools are required. Currently we are developing a biomarker method for probing DNA damage (apurinic sites) as a dosimeter of exposure and susceptibility to chemical carcinogens and oxidative stress. Our current approach aims at detecting apurinic sites by combining the selectivity provided by enzymology, high-performance liquid chromatography, and triple-quadrupole mass spectrometry. This project is currently being pursued in collaboration with the National Center for Toxicological Research. The relative apurinic DNA damage levels should provide evidence on the mode-of-action of a particular carcinogen, and further characterize initial events in chemical carcinogenesis.