Mechanisms for Benzo(a)pyrene-Induced Colon Cancer Exacerbation by Dietary Fat

膳食脂肪导致苯并(a)芘诱发结肠癌恶化的机制

基本信息

批准号：
8223305
负责人：
Aramandla Ramesh
金额：
$ 29.49万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223305
关键词：
8-Oxo-2&apos -Deoxyguanosine Adult Affect Air Animal Model Aromatic Polycyclic Hydrocarbons Atherosclerosis Benzo(a)pyrene Biological Availability Biological Models CYP1A1 gene Cancer Etiology Carcinoma Cessation of life Charcoal Chemicals Chemoprevention Colon Colon Carcinoma Colorectal Cancer Colorectal Neoplasms Consumption Control Animal Cytochrome P450 DNA DNA Adduction DNA Adducts DNA Damage DNA Repair Data Developing Countries Development Diet Dietary Fats Dietary Intervention Dose Drug Kinetics Enzymes Epithelial Epoxide hydrolase Epoxy Compounds Etiology Event Exposure to F2-Isoprostanes Family Fatty acid glycerol esters Food Generations Genomics Glutathione Glycols Goals Health Hepatic Human Incidence Individual Intake Intestines Isoprostanes Laboratories Length Life Style Link Lipid Peroxidation Lipids Liver Location Malignant Neoplasms Measures Meat Mediating Metabolic Biotransformation Metabolic Pathway Metabolism Modeling Mucous Membrane Mus Mutation Obesity Oncogenes Oral Organ Oxidative Stress Pathway interactions Pharmaceutical Preparations Polyps Prevention strategy Production Property Quinones Recommendation Risk Role Secondary to Small Intestines Smoking Surveys Testing Time Tissues Toxic Environmental Substances Translating Unsaturated Fats Variant Western World Work absorption adduct adenoma base benzo(a)pyrene-DNA adduct body system carcinogenesis colon carcinogenesis cooking food consumption genotoxicity indexing jejunum mouse model novel oxidative damage prevent saturated fat tumor

项目摘要

PROJECT SUMMARY Benzo(a)pyrene [B(a)P] is a lipophilic environmental toxicant that is widely distributed in foods and air. This chemical is known to cause cancer in various organ systems. Our preliminary studies have shown that dietary exposure of mice to B(a)P via saturated fat results in an increased incidence of polyps in colon, some of which were invasive compared to mice that received B(a)P through unsaturated fat. Exposure of mice to B(a)P through saturated fat causes induction of cytochrome P450 family of enzymes resulting in an increased concentration of reactive metabolites, compared to those that received B(a)P through unsaturated fat. Similarly, exposure of mice to B(a)P via saturated fat also contributed to oxidative stress in mouse colon, shown by an increased concentration of F2-isoprostanes (markers of oxidative stress) in mouse colon. Our central hypothesis is that dietary fat enhances B(a)P-induced colon carcinogenesis through enhanced bioavailability of B(a)P, and possibly a greater accumulation of B(a)P in tissues, and greater levels of B(a)P metabolites. A linked hypothesis is that B(a)P effects are secondary to production of epoxide or quinones some of which form DNA adducts that cause genotoxicity. We will test our hypothesis by studying the effects of oral exposure of adult ApcMin mice to B(a)P in saturated versus unsaturated fat via the following specific aims: 1. Characterize the potentiating effect of saturated vs. unsaturated dietary fat on B(a)P-induced adenomas and carcinomas in the small intestine and colon of the ApcMin mouse; 2. Assess the impact of the type of dietary fat on B(a)P-induced expression of biotransformation enzymes, their activities and disposition of B(a)P metabolites in the ApcMin mouse; 3. Test whether B(a)P- induced colon cancer is mediated via epoxide- (genomic DNA adducts) or quinone (quinone, 8-oxo-dG and etheno adduct) pathways, or both, in the ApcMin mouse. Relevance of this project to human health Every year 56,000 deaths are attributed to colorectal cancer (CRC) in USA and in a great majority of the cases surveyed; consumption of well-done red meat and other saturated fats, rich in B(a)P were implicated as a possible causative factor. Our approach is novel in that it uses a mouse model system that replicates a human CRC scenario. Another novel aspect of our proposal is that it will evaluate the role of B(a)P metabolic pathway- specific biotransformation events in the causation of CRC. Our findings will serve as a prelude to conducting chemoprevention studies for CRC and help to synthesize drugs to prevent or delay the onset of colon cancer.

项目概要苯并(a)芘[B(a)P]是一种亲脂性环境毒物，广泛分布于食品和空气中。这已知化学物质会导致多种器官系统癌症。我们的初步研究表明，饮食小鼠通过饱和脂肪接触 B(a)P 会导致结肠息肉的发生率增加，其中一些息肉与通过不饱和脂肪接受 B(a)P 的小鼠相比，该小鼠具有侵入性。小鼠接触 B(a)P 通过饱和脂肪引起细胞色素 P450 家族酶的诱导，从而导致与通过不饱和脂肪接受 B(a)P 的代谢物相比，反应性代谢物的浓度。同样，小鼠通过饱和脂肪接触 B(a)P 也会导致小鼠结肠氧化应激，小鼠结肠中 F2-异前列腺素（氧化应激标记物）浓度增加表明。我们的中心假设是膳食脂肪通过增强 B(a)P 诱导的结肠癌发生 B(a)P 的生物利用度，并且 B(a)P 在组织中可能积累更多，并且 B(a)P 水平更高 B(a)P 代谢物。一个相关的假设是 B(a)P 效应继发于环氧化物或醌，其中一些形成 DNA 加合物，导致遗传毒性。我们将通过以下方式检验我们的假设研究成年 ApcMin 小鼠口服暴露于饱和脂肪与不饱和脂肪中的 B(a)P 的影响以下具体目标： 1. 表征饱和膳食脂肪与不饱和膳食脂肪对 ApcMin 小鼠小肠和结肠中 B(a)P 诱导的腺瘤和癌； 2. 评估膳食脂肪类型对 B(a)P 诱导的生物转化酶表达及其活性的影响 ApcMin 小鼠体内 B(a)P 代谢物的处置； 3. 测试B(a)P诱导的结肠癌是否是通过环氧化物（基因组 DNA 加合物）或醌（醌、8-oxo-dG 和乙烯加合物）途径介导，或两者都在 ApcMin 鼠标中。该项目与人类健康的相关性在美国，每年有 56,000 人死于结直肠癌 (CRC)，其中绝大多数病例接受调查；食用富含 B(a)P 的熟红肉和其他饱和脂肪被认为是可能的致病因素。我们的方法很新颖，因为它使用复制人类的小鼠模型系统 CRC 场景。我们提案的另一个新颖之处是它将评估 B(a)P 代谢途径的作用 - CRC 病因中的特定生物转化事件。我们的研究结果将作为进行的前奏 CRC 的化学预防研究，并帮助合成预防或延缓结肠癌发病的药物。