Benzo(a)pyrene (BaP), an ubiquitous environmental carcinogen, is a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds. Our preliminary studies have shown that BaP causes colon cancer. Our studies have also shown that administration of resveratrol (RVT) to BaP-treated ApcMn mouse reduces the development of adenomas in colon. Our proposed studies will test the hypothesis that RVT modulates BaP - induced colon carcinogenesis through cytochrome P450 (CYP)-mediated metabolic pathways. These studies, in the context of human exposure, could have a significant effect on the quality of life by reducing the onset of colorectal cancer. Since most colorectal cancers are caused by diet, which is contaminated by toxicants, environmental exposure is a likely factor in initiating or accelerating sporadic colorectal cancer cases. We will test our hypotheses in adult male transgenic mice with the following specific aims: 1. Determine whether RVT exposure simultaneously, or prior-BaP treatment alters its own bioavailability, bioavailability of BaP, the expression and activities of BaP biotransformation enzymes, metabolite profiles of RVT, and BaP in ApcMn mice;and 2. Evaluate whether RVT exposure simultaneously with, or prior- BaP treatment modulates BaP- DNA adduct concentrations and persistence. This project will provide new and interesting information with regard to the contribution of phytochemical such as RVT towards delaying or preventing the development of colorectal carcinogenesis. In addition to dissertation research, the goals of this fellowship application are to provide the intellectual environment and resources necessary for the applicant to enrich herself in various techniques and approaches in her chosen area of research. To meet these objectives, we propose a training plan that incorporates: 1) Completion of didactic course work;2) Mentored research activity;3) Active participation &presentation in meetings, seminars and journal clubs;4) Interaction with visiting scientists;5) Periodic evaluation of applicant's research progress;6) Publishing research findings in peer-reviewed journals;and 7) Participation in career development activities. It is expected that by the end of the training period, the applicant will be creative and successful in her chosen research endeavor and contribute to the diversity of the research workforce, a goal of the Ruth L. Kirschstein predoctoral fellowship. Relevance of this project to human health In U.S alone, every year 56,000 die of colorectal cancer (CRC);consumption of fatty foods rich in BaP was implicated as a possible causative factor. We plan to study the progression of CRC, using a mouse model that mirrors the human CRC scenario. We also propose to use RVT, a component of grapes and berries against CRC. Our findings will be of use to test the efficacy of other plant-based compounds to prevent the development of cancer, and extend the lifespan of people.
This project explores how sporadic colorectal cancer caused by environmental toxicants can be controlled. Specifically, this project focuses on how consumption of resveratrol, a component of grapes, berries and peanuts prevents the development of sporadic colorectal cancer induced by the environmental toxicant, benzo(a)pyrene (BaP).
|Harris, Kelly L; Banks, Leah D; Mantey, Jane A et al. (2013) Bioaccessibility of polycyclic aromatic hydrocarbons: relevance to toxicity and carcinogenesis. Expert Opin Drug Metab Toxicol 9:1465-80|
|Huderson, Ashley C; Myers, Jeremy N; Niaz, Mohammad S et al. (2013) Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol. J Nutr Biochem 24:713-24|
|Diggs, Deacqunita L; Huderson, Ashley C; Harris, Kelly L et al. (2011) Polycyclic aromatic hydrocarbons and digestive tract cancers: a perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 29:324-57|