The long range goal of this project is to determine the role of benzo(a)pyrene ingested through dietary fat in the etiology of colon carcinogenesis and to explore appropriate preventive measures. The objective of this investigation is to characterize the mechanistic pathways involved in BaP-induced colon carcinogenesis. The rationale underlying this initiative is that formation and progression of colon tumors depends on altered BaP biotransformation by the type of diet ingested. The central hypothesis is that dietary fat contributes to benzo(a)pyrene induced colon carcinogenesis through cytochrome P450 (CYP) mediated pathways. The applicant intends to test the central hypothesis and accomplish the objective of this study in the following specific aims:
Aim 1 : To investigate the effect of dietary fat on BaP-induced adenomas in colon and rectum of the adult Ape Min mouse. After sub chronic exposure (60 days) of the mice to BaP, the size, number and histological features of the adenomas in the colon will be studied. The influence of dietary lipid type, consumption and the BaP dose on adenoma characteristics will be the focus of this aim.
Aim 2 : To determine the dietary fat induced alteration of BaP toxicokinetics and biotransformation enzyme expression in adult Ape Min mice. The applicant will determine how BaP is metabolized when given in a saturated lipid- based meal, an unsaturated lipid-based meal, and a lipid-free meal. The expression of cytochrome P450 family of enzymes (CYP1A1 and 1B1), and glutatione-S-transferase, the generation of reactive metabolites of BaP, their distribution, and accumulation in target tissues will be analyzed in this aim.
Aim 3 : To assess the contribution of dietary fat to BaP-DNA adduct formation and persistence in the Ape Min mouse. The applicant will investigate the severity of BaP-induced damage by measuring the endpoints of DNA modification (DNA adducts) in target organs. The role of different lipid based diets causing cellular damage and the length of the time the affected DNA stays in the tissues will be the focus of this specific aim. This study will indicate the extent to which chemicals in the environment contaminate diet causing colon cancer. The amount of fat in the diet may worsen the toxic effect of these contaminants. Findings of this study will enhance our understanding of the steps involved in the causation of colon cancer by toxic chemicals found in the environment.
