Project 1: PCBs:Metabolism, Genotoxicity and Gene Expression in vivo

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Airborne PCBs are those that have higher vapor pressures, lower chlorination, and are substrates for metabolic activation. We hypothesize that lower chlorinated airborne PCBs and their natural electrophilic metabolites interact with DNA and DNA-associated proteins and/or initiate oxidative events that alter the intracellular redox environment, thereby compromising cellular structures and functions. Our data show that PCBs are initiators in rat liver and that PCB3 (4-chlorobiphenyl) induces mutations in the liver and possibly lung of transgenic BigBlue rats after ip injection. Also, PCB3 metabolites cause various, compound-specific types of genotoxic damage in cells in culture. We have shown that prostaglandin synthase and myeloperoxidase bioactivate dihydroxy-PCBs and that the PCB-quinones can react with nucleophiles like GSH by Michael addition or a substitution reaction with dechlorination. We have also observed, for the first time, a PCB semiquinone radical in cells. We therefore propose to extend our studies to: 1) Examine the mechanisms of PCB genotoxicity by comparing nuclear vs. mitochondrial effects and elucidating PCB interactions with DNA-associated protein; 2) Investigate interactions of airborne PCBs and their metabolites with telomeres and telomerase; 3) Determine the reactions of PCB-semiquinone radicals and how factors, such as conjugation with thiols, affect this reactivity; 4) Analyze the genotoxicity of airborne PCBs after inhalation exposure and explore mechanisms to ameliorate/mediate against those effects. Jointly these studies may explain which and how PCBs are genotoxic, which organs, subcellular structures, and macromolecules are the targets, the mechanisms of these reactions, and whether these upset the delicate redox balance of the natural environment of the cell. Emphasis is placed on the kinetics and consequences of inhalation exposure to airborne PCBs. These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations.