Pilot Project: 3 "Dietary Fat Potentiation of B(a)P Induced Colon Cancer"

苯并(a)芘（BaP）是一种广泛分布的多环类环境毒物

Benzo(a)pyrene (BaP) is a lipophilic, widely distributed environmental toxicant that belongs to the polycyclic aromatic hydrocarbon (PAH) family of compounds. This chemical is known to cause toxicity and cancer in various organ systems. Our preliminary studies have shown that exposure of rats to BaP and other PAHs cause induction of cytochrome P450 (CYP) family of enzymes resulting in the formation and distribution of reactive metabolites in plasma and target tissues. Our studies have also shown that dietary exposure of rats to PAHs via saturated fat results in increased concentration of reactive metabolites, which stayed in target tissues for a longer time causing DNA damage compared to those that received these chemicals through unsaturated fat. Our hypothesis is that dietary fat contributes to BaP-induced colon carcinogenesis through CYP mediated epoxide and quinone pathways. The rationale behind this study is that every year 56,000 deaths are attributed to colorectal cancer in United States of America and in a great majority of the cases surveyed, consumption of well-done red meat and other saturated fats, rich in PAHs were implicated as a possible causative factor. This implies that formation and progression of colon tumors depends on altered BaP biotransformation by the type of dietary lipids ingested. We intend to test our hypothesis by studying the effects of oral exposure of adult Apc Min mice to BaP in saturated fat, using the following specific aims: 1. Investigate the potentiating effect of dietary fat on BaP-induced adenomas in small intestine and colon of adult Apc Min mice; 2. Determine the dietary fat induced alteration of BaP biotransformation enzyme activities and pharmacokinetics in Ape Min mice; 3. Assess the contribution of dietary fat to BaP-DNA adduct formation and persistence in Ape Min mice; 4. Evaluate the role of dietary fat in BaP-induced oxidative damage and isoprostane production in Apc Min mice. This pilot project is expected to provide new . information to conduct mechanism-based chemoprevention studies for colorectal carcinogenesis. In other words, information gained from these studies will help to understand the contribution of consumption of fatty foods contaminated with toxic chemicals towards the development of colorectal cancers in humans. Furthermore, the knowledge gained from these studies will help to synthesize drugs that could be used to prevent the development of tumors in colon.