Ph.D. 1971, University of Wisconsin
Polycyclic aromatic hydrocarbons are widespread environmental contaminants formed during incomplete combustion; some are potent carcinogens in experimental animals. Our laboratory is examining the relationship of various hydrocarbon metabolism pathways to the induction of biological effects. We are examining the role of induction of specific cytochrome P450 isozymes in the activation of different polycyclic aromatic hydrocarbons by Northen and Western blotting, the use of specific inhibitory antibodies and antisense oligonucleotides.
After metabolic activation, hydrocarbons bind covalently to DNA, and these DNA interactions are involved in the induction of mutation. The role of specific metabolites of polycyclic aromatic hydrocarbons in the induction of biological effects is being investigated through analysis of the hydrocarbon-DNA adducts by high-performance liquid chromatography. In addition to activation and detoxification, the amount of hydrocarbon bound to specific genes in DNA can be affected by the sequence of the DNA, the structure of chromatin, and repair of the DNA adducts. The role of chromatin structure is being determined by the use of polyclonal antibodies to hydrocarbon-modified DNA. The repair of hydrocarbon-DNA adducts is being investigated in total genomic DNA and in specific genes through laser-induced cleavage and Southern blotting analysis and by LM-PCR techniques. We are also examining how hydrocarbon-DNA interactions affect the tumor suppressor gene P53, its signal transduction through P21 and how the cell cycle is arrested. These studies will help to determine how hydrocarbons are activated to carcinogenic forms and how they induce biological events.