It is generally recognized that a substantial fraction of cancer incidence is of environmental origin, initiated (at least in part) by the covalent binding of chemicals with DNA to form addition products, commonly referred to as DNA adducts. The widely held hypothesis is that, if the system's repair mechanism fails, this damage may have serious biological implications including the accumulation of genetic mutations and the onset of cancer. However, the complete relationship between DNA adducts formation and cancer development in humans is not fully understood. This is, in part, because of the low levels at which adducts are found in affected tissues, the difficulties associated with their analysis and lack of knowledge about the role of genetic predisposition on the repair or other physiological responses subsequent to adduct formation. In recent years, toxicogenomics has developed into a sophisticated area of research focused on understanding how toxicant-induced effects on cells, including DNA and protein adduct formation and interaction with receptor molecules and cell membranes, are translated into cellular responses such as toxicity, abnormal growth and differentiation, mutation, apoptosis and carcinogenesis. The characterization of the human genome and recent advances in microarray technologies now offer unique opportunities for research to understand the link between exposure to environmental carcinogens and global genome functions in cells from living organisms. In this program, we propose to capitalize on the unique strengths of two collaborating laboratories in the areas of trace level analysis of DNA adducts by capillary HPLC-electrospray ionization mass spectrometry (PV) and microarray technology, cellular biology and toxicogenomics (HZ) to generate comprehensive hypotheses that relate tumor growth with mutations initiated by exposure to smoking or other toxic environmental agents. It is hoped that, ultimately, the type of data generated in this study may be used for exposure monitoring and risk assessment that will help transform toxicology into a predictive science.
