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

说明(申请人提供)：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。众所周知，这种化学物质会导致各种器官系统的癌症。我们的初步研究表明，小鼠通过饱和脂肪饮食暴露于B(A)P会导致结肠息肉发生率增加，其中一些是侵袭性的，与通过不饱和脂肪接受B(A)P的小鼠相比。与通过不饱和脂肪接受B(A)P的小鼠相比，通过饱和脂肪暴露于B(A)P的小鼠可诱导细胞色素P450家族酶，从而导致反应性代谢物浓度增加。同样，通过饱和脂肪暴露于B(A)P的小鼠也促进了小鼠结肠的氧化应激，表现为小鼠结肠中F2-异前列腺素(氧化应激的标志)浓度增加。我们的中心假设是，膳食脂肪通过提高B(A)P的生物利用度、可能在组织中更大程度地积累B(A)P以及更高水平的B(A)P代谢物来增强B(A)P诱导的结肠癌发生。一个相关的假设是，苯并(A)磷的影响是次要的，环氧化物或苯二酚的产生，其中一些形成DNA加合物，导致遗传毒性。我们将通过研究成年ApcMin小鼠口服饱和脂肪和不饱和脂肪对B(A)P的影响来验证我们的假设，具体目的如下：1.表征饱和和不饱和饮食脂肪对B(A)P诱发ApcMin小鼠小肠和结肠癌的增强作用；2.评估饮食脂肪类型对B(A)P诱导的ApcMin小鼠生物转换酶的表达、它们的活性和B(A)P代谢物在ApcMin小鼠中的分布的影响；3.检测在ApcMin小鼠中，苯并(A)P诱发的结肠癌是通过环氧化物(基因组DNA加合物)或苯醌(苯醌、8-氧-DG和乙烯加合物)途径，还是两者都有。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)，在调查的绝大多数病例中；食用熟红肉和其他富含B(A)P的饱和脂肪可能是致病因素。我们的方法是新颖的，因为它使用了一个复制人类CRC场景的老鼠模型系统。我们建议的另一个新的方面是，它将评估B(A)P代谢途径特异性生物转化事件在结直肠癌病因中的作用。我们的发现将作为开展结直肠癌化学预防研究的前奏，并有助于合成预防或延缓结肠癌发病的药物。 公共卫生相关性：该项目研究环境毒物，如苯并(A)芘[B(A)P]如何导致结直肠癌。该项目还重点研究了食用富含脂肪的食物如何加速环境诱发(散发性)结直肠癌的发展。

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.