Benzo(a)pyrene (BaP) is an ubiquitous environmental toxicant that belongs to the polycyclic aromatic hydrocarbon (PAH) family of compounds and causes toxicity and cancer to a variety of organs. Our preliminary studies have demonstrated that neonatal administration of rats with resveratrol (RVT) reduces BaP induction of the cytochrome P450 (CYP) family of enzymes in adult rats subsequent to exposure to BaP, with a concomitant reduction in the formation and distribution of reactive metabolites in plasma and target tissues. Our proposed studies will test the hypothesis that RVT modulates BaP-induced colon carcinogenesis through cytochrome P450 (CYP) mediated metabolic pathways. A related hypothesis that will be tested in our studies is that the bioavailable dose of BaP that contributes to toxicity/cancer during a lifespan can be altered by "imprinting" with RVT treatment during the neonatal period, and that such an action, if ultimately translated into human studies, could have a significant effect on the quality and perhaps even the extent of life, in general, and in reducing the onset of colorectal cancer, in particular. More than 90 million Americans - 58 % of whom are men -- have or are at risk of developing cancer of colon and rectum, and the treatment costs are estimated to be $8.4 billion annually in the U.S. Since it is estimated that diet contributes to 80% of the known colorectal cancer cases, and because of PAH's ubiquity in foods and in environment due to industrial emissions, it is not unreasonable to attribute environmental exposure serving as one of the factors in initiating or accelerating colorectal cancer cases. We will test our hypotheses in adult male transgenic mice with the following specific aims: 1. Investigate the chemopreventive effect of neonatal resveratrol on BaP-DNA adduct formation, persistence and BaP-induced adenomas in colon and rectum of adult ApcMin mice; and 2. Determine whether neonatal exposure to resveratrol alters the expression and activities of BaP biotransformation enzymes and metabolite profile in adult ApcMin mice. This pilot project will provide important new information regarding the contribution of phytochemicals such as RVT towards delaying or preventing the development of colorectal carcinogenesis. Also, the data obtained will be useful for assessment and/or synthesis of other naturally occurring plant-based chemicals that could be tested in the early life as a means of preventing the development of cancer in adult life, thus improving the quality of life.

R03CA130112

2007-08-20

2010-07-31