DNA Adducts as Biomarkers of Exposure and Effect - Biomedical

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The research of this project will utilize newly developed biomarkers of oxidative stress to evaluate the mode of action and dose response of hazardous chemicals of importance to Superfund sites. Our studies will primarily address effects of polyhalogenated and polycyclic aromatic hydrocarbons including dibenzo(a,l)pyrene (DBF), RGBs and dioxin. These studies will analyze snap frozen tissues from two of the largest and best characterized carcinogenicity bioassays: the NTP Toxic Equivalency Factor studies on PCBs and dioxin in rats; and the ED(0.1) DBF study in rainbow trout. We hypothesize that oxidative stress is an important mode of action for toxicity and carcinogenesis. These studies will be accomplished by comparing a comprehensive series of biomarkers for oxidative DNA damage that includes lesions removed by long and short patch base excision repair and utilizes different glycosylases, as well as by nucleotide excision repair. The studies will examine dose-response relationships for oxidative DNA damage and compare this with P450 induction, cell proliferation, and in the case of DBF, 32P-postlabeling studies of bulky DNA adducts. In addition, it will conduct similar research on fish from the Hudson River and less polluted waterways that have exposures to different mixtures and amounts of PAHs, PCBs and dioxins. In collaboration with the NYU SBRP, laboratory exposures to similar mixtures of hazardous chemicals will be conducted to investigate the development of resistance to PCBs toxicity and differences in life stage susceptibility to these agents. Finally, we will continue our basic research on oxidative DNA damage and repair to further our understanding of the biology of DNA damage and repair, and its implications for environmental health and individual susceptibility. The long term goals will be to develop an in-depth understanding of how these chemicals cause toxicity and under what conditions they elicit responses. These data will fill critical gaps in knowledge that will impact the basis of low dose extrapolation and improve the scientific basis of risk assessment and the setting of remediation standards. We will interact with each of the other scientific projects of this program by performing biomarker analyses, providing data or determining the ability of various environ-mental chemicals or their metabolites to cause oxidative DNA damage. The research will also make heavy use of both the Chemistry and Analytical Core and the Mathematical and Statistical Analysis and Modeling Core.