Polycyclic Aromatic Hydrocarbons (PAHs) are a re-emerging class of environmental pollutants formed from incomplete combustion of fossil fuels (diesel or gasoline exhaust, burning of coal, petroleum or tobacco) and found at Superfund sites. Increasing energy needs world-wide, especially in countries such as China, are the reason why PAHs, unlike other Superfund contaminants of concern in the past (e.g., PCBs, TCDD, etc.), will be increasing over the next quarter century. PAHs produce cancers at multiple sites in animal models and, in fact, were the first class of chemicals identified as environmental carcinogens. Even so, we know relatively little about critical aspects of PAH-dependent carcinogenesis. Much of the work to date has, for simplicity, employed a single PAH, such as benzo[a]pyrene (BaP) or dibenzo[a,l]pyrene (DBP) rather than actual environmental mixtures. In this proposal we compare the carcinogenicity of PAH mixtures, from locations where high human exposures are known or suspected, to BaP and DBP in two cancer models. The first, skin cancer, is rapidly increasing in incidence world-wide. The second model is novel and innovative and examines transplacental lymphorna (significant cancer in children), lung (highest mortality in U.S.) and liver (highest mortality in parts of the world and increasing in the U.S.) In studying these environmentally relevant PAH mixtures, we address critical questions of mechanism and the potential for intervention by chemoprevention. The common mechanistic goals in both cancer models provide a high degree of integration. The human relevance has been markedly enhanced with the use of the """"""""Humanized"""""""" CYP1B1 mouse studies and the connection to project 2 strengthened by our use of accelerator mass spectrometry to examine DBP pharmacokinetics in human volunteers, an unprecendented approach. Preliminary studies have already demonstrated the success of this approach with aflatoxin B1 in humans and the effect of coadministration with the chemopreventive agent, chlorophyllin. Thus, this project, focusing on PAH-dependent carcinogenesis, is highly relevant to human health concerns associated with Superfund sites. In addition, it complements very well the endpoints pursued by the other biomedical research projects and makes excellent use of the resources and materials provided by the Cores. Finally, our creative use of new technologies has markedly increased the translational nature of the research.
Showing the most recent 10 out of 174 publications
