Project 1: PCBs: Metabolism, Genotoxicity and Gene Expression In Vivo

University Of Iowa, Iowa City IA

Investigators

Linked publications & trials

Abstract

Airborne PCBs are those that have higher vapor pressures, lower chlorination, and should be substrates for[unreadable] metabolic activation. We hypothesize that the lower halogenated biphenyls are activated by hepatic[unreadable] enzymes to oxygenated species that are electrophilic and bind to proteins and DNA. Our preliminary data[unreadable] indeed show that PCBs are metabolized to electrophiles and free radicals that bind to cellular targets and[unreadable] that the metabolism of PCBs produces reactive oxygen species, resulting in DNA strand breaks and 8-[unreadable] oxodeoxyguanosine formation in DNA and that a quinone/semiquinone may be a/the major metabolite[unreadable] involved in these effects. Employing the Solt-Farber initiation-selection protocol, we also identified several[unreadable] lower chlorinated biphenyls as initiators of hepatocarcinogenesis in the rat. We therefore propose to extend[unreadable] our studies to: 1) determine the initiating potential of airborne, semi-volatile PCBs and to analyze the[unreadable] structural and metabolic requirements needed for carcinogenic potency, 2) analyze for oncogene[unreadable] mutations and karyoptypic changes during PCB carcinogenesis in the Solt-Farber experiments, 3)[unreadable] investigate the types of genotypic damage induced by PCBs and their metabolites in vitro, in cells in[unreadable] culture, and in vivo, 4) examine the ease of formation and the reactivity of PCB-derived semiquinone[unreadable] radicals, and 5) determine the biologic effects and the influence of Route of Exposure (IP vs. inhalation)[unreadable] of airborne PCBs (a typical "air mixture" of PCBs, or single PCB congeners, or hydroxy-PCBs) on specific[unreadable] changes in expression of xenobiotic-metabolizing enzymes, antioxidant enzymes or redox indicators in[unreadable] the rat. Jointly these studies may explain why some PCBs are activated to genotoxins, while others are[unreadable] not, which target genes are involved, the nature of the DNA lesions, and the mutations that ensue. These[unreadable] data may also provide clues about whether nutritional or other interventions are warranted to protect highlyexposed[unreadable] humans. These mechanistic and susceptibility issues will form a basis for the quantitative human[unreadable] health risk assessment for these important Superfund Chemicals, arising from multiple sources.