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

项目总结 苯并(A)芘[B(A)P]是一种广泛存在于食品和空气中的亲脂性环境毒物。这 众所周知，化学物质会在各种器官系统中引起癌症。我们的初步研究表明，饮食 通过饱和脂肪暴露于B(A)P的小鼠导致结肠息肉发生率增加，其中一些 与通过不饱和脂肪摄入B(A)P的小鼠相比，这些小鼠具有侵入性。小鼠对苯并(A)磷的暴露 通过饱和脂肪引起细胞色素P450家族酶的诱导，导致 反应性代谢物的浓度，与通过不饱和脂肪接受B(A)P的人相比。 同样，小鼠通过饱和脂肪暴露于B(A)P也会导致小鼠结肠的氧化应激， 表现为小鼠结肠中F2-异前列腺素(氧化应激标志物)浓度增加。我们的 中心假说是膳食脂肪通过促进B(A)P诱导的结肠癌 B(A)P的生物利用度，可能在组织中积累更多的B(A)P，以及更高的水平 B(A)P代谢物。一个相关的假设是，B(A)P的影响是次要的，环氧化物或 喹酮类化合物，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验证我们的假设 研究成年ApcMin小鼠口服饱和脂肪和不饱和脂肪中苯并(A)磷的影响。 具体目标如下：1.描述饱和与不饱和膳食脂肪对人体健康的促进作用 B(A)P诱发ApcMin小鼠小肠和结肠癌的腺瘤和癌；2.评估 膳食脂肪类型对苯并(A)磷诱导的生物转化酶表达及其活性的影响 苯并(A)磷代谢产物在ApcMin小鼠体内的分布3.检测苯并(A)磷诱发的结肠癌是否 通过环氧化物-(基因组DNA加合物)或醌(醌，8-氧-DG和乙烯加合物)途径介导， 或者两者兼而有之，在ApcMin鼠标中。 本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)，而且绝大多数病例 调查显示，食用熟红肉和其他富含B(A)P的饱和脂肪可能是一种 可能的致病因素。我们的方法很新颖，因为它使用了一个复制人类的老鼠模型系统 CRC方案。我们建议的另一个新方面是它将评估B(A)P代谢途径的作用- 结直肠癌病因中的特定生物转化事件。我们的发现将作为进行 结肠癌的化学预防研究，并帮助合成药物来预防或延缓结肠癌的发生。

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.