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

• 批准号: 7898060
• 负责人: Aramandla Ramesh
• 金额: $ 30.4万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-10 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898060
• 关键词: 8-Oxo-2' -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; Figs - dietary; Food; Generations; Genomics; Genus Cola; 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; body system; carcinogenesis; colon carcinogenesis; cooking; food consumption; genotoxicity; indexing; jejunum; mouse model; novel; oxidative damage; prevent; public health relevance; saturated fat; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project looks into how environmental toxicants such as benzo(a)pyrene [B(a)P] cause colorectal cancer. This project also focuses on how consumption of foods rich in fat accelerates the development of environmentally-induced (sporadic) colorectal cancer.

描述（由申请人提供）：苯并（a）pyrene [b（a）p]是一种亲脂性环境毒物，广泛分布在食品和空气中。已知该化学物质在各种器官系统中引起癌症。我们的初步研究表明，通过饱和脂肪将小鼠饮食暴露于B（a）P导致结肠息肉的发生率增加，与接受B（a）P通过不饱和脂肪接收B（a）P的小鼠相比，其中一些是侵入性的。与通过不饱和脂肪接收B（a）P的酶相比，小鼠通过饱和脂肪暴露于B（a）P导致细胞色素P450酶家族的诱导，导致反应性代谢产物的浓度增加。类似地，小鼠通过饱和脂肪暴露于B（a）p也导致了小鼠结肠中的氧化应激，这表明了小鼠结肠中F2-异丙烷（氧化应激的标记）浓度升高。我们的中心假设是，饮食脂肪通过增强B（a）P的生物利用度增强了B（a）P诱导的结肠致癌作用，并可能在组织中B（a）P的积累更大，而B（a）P代谢物的水平更高。链接的假设是B（a）P效应继发于环氧化物或喹酮的生产，其中一些形成引起遗传毒性的DNA加合物。我们将通过以下具体目的研究成年APCMIN小鼠在饱和脂肪与非饱和脂肪中的口服暴露对B（a）P中的口服暴露的影响来检验假设：1。表征饱和饮食脂肪对B（a）P（A）P（A）P（A）P（A）P（A）P（A）P（A）P（A）P（A）P（A）P（A）P（a）诱导的小直肠和Colon apcmin apcmin op apcmin; apcmin; 2。评估饮食脂肪类型对B（a）P诱导的生物转化酶表达，其活性和B（a）P代谢物在APCMIN小鼠中的影响； 3。测试B（a）P诱导的结肠癌是通过环氧（基因组DNA加合物）还是喹酮（奎诺酮，8-氧和乙烯加合物）介导的，或两者兼有APCMIN小鼠。该项目与人类健康的相关性每年有56,000人死亡归因于美国的结直肠癌（CRC），在大多数案件中。富含良好的红肉和其他饱和脂肪的食用，富含B（a）P是可能的病因。我们的方法是新颖的，因为它使用了复制人类CRC场景的鼠标模型系统。我们提案的另一个新方面是，它将评估B（a）P代谢途径 - 特异性生物转化事件在CRC的因果关系中的作用。我们的发现将成为进行CRC化学预防研究的序幕，并有助于合成药物以防止或延迟结肠癌的发作。 公共卫生相关性：该项目探讨了诸如苯并（a）pyrene [b（a）p]等环境有毒物质如何引起大肠癌。该项目还着重于富含脂肪的食物的消费如何加速环保（零星）结直肠癌的发展。