Western diet as a modifier of benzo(a)pyrene-induced colon carcinogenesis

项目总结 苯并(A)芘[B(A)P]是一种普遍存在的环境毒物，是多环芳烃中的一员。 碳氢化合物(PAH)是一类化合物，与结直肠癌(CRC)的病因有关。 此外，食用红肉、饱和脂肪和多环芳烃等有毒物质也被认为与 散发性结肠癌的危险因素之一。我们的初步研究不仅表明B(A)P导致 结肠癌，但西方饮食对B(A)P治疗的大鼠结肠息肉病(PIRC)的影响 增加结肠腺瘤的发展。我们提议的研究将检验这一假设 西方饮食通过改变生物转化和DNA加重B(A)P引发的结肠癌 损坏。我们将在成年雄性转基因PIRC大鼠身上验证我们的假设，具体目的如下：1. 将PIRC大鼠作为研究西方饮食如何增强B(A)P诱导的结肠的模型并进行验证 2.测定饮食诱导的苯并(A)磷生物转化酶活性、表达、 和代谢产物在PIRC大鼠中的分布；以及3.评估常规饮食和西式饮食对 B(A)P-DNA加合物的形成和持续与PIRC大鼠的DNA氧化损伤这个项目将 提供新的有趣的信息，说明西方饮食对增加 大肠息肉的发生。这个应用程序的目标也是提供智力环境 和资源，让申请者在她选择的研究领域通过 培训计划包括：1)有指导的研究活动；2)积极参与和展示 会议、研讨会和期刊俱乐部；3)与来访的科学家互动；4)定期评估申请者的 通过个人发展计划取得研究进展；5)在同行评议中发表研究成果 日记；以及6)参与职业发展活动。预计到培训结束时， 期间，申请者将在她所选择的研究努力中取得成功，并为促进 研究人员，Ruth L.Kirschstein博士前研究员的目标之一。 本项目与人类健康的相关性 在美国，结直肠癌造成了巨大的死亡率，每年有50,000人死亡。 食用被B(A)P污染的高脂肪食物被认为是致病因素。三分之一的成年人 美国有17%的青少年患有肥胖症。肥胖的人患结肠癌的风险更高 从西方饮食中摄取过多的能量。我们计划使用大鼠模型来研究结直肠癌的进展。 这反映了人类CRC的情景。我们还建议使用西方饮食，(&gt；58%脂肪)作为一种促进剂 CRC。我们的发现将有助于确定饮食对B(A)P引发的启动的机制影响， 促进和发展儿童权利公约。

PROJECT SUMMARY Benzo(a)pyrene [B(a)P], an ubiquitous environmental toxicant, is a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds and has been implicated in the causation of colorectal cancer (CRC). Additionally, consumption of red meat and saturated fats, toxicants such as PAHs has also been implicated as one of the risk factors for sporadic colon cancer. Our preliminary studies not only show that B(a)P causes colon cancer, but that administration of Western diet to B(a)P-treated Polyposis in Rat Coli (PIRC) rats increases the development of adenomas in the colon. Our proposed studies will test the hypothesis that Western diet exacerbates B(a)P-initiated colon carcinogenesis through altered biotransformation and DNA damage. We will test our hypothesis in adult male transgenic PIRC rats with the following specific aims: 1. Characterize and validate the PIRC rat as a model to study how Western diet potentiates B(a)P-induced colon carcinogenesis; 2. Determine diet-induced alteration of B(a)P biotransformation enzyme activities, expression, and metabolite disposition in the PIRC rat; and 3. Assess the contribution of regular and Western diet in the formation and persistence of B(a)P-DNA adducts and oxidative DNA damage in the PIRC rat. This project will provide new and interesting information with regard to the contribution of Western diet towards increasing the development of colorectal polyps. The goals of this application are also to provide the intellectual environment and resources for the applicant to enrich herself in various approaches in her chosen area of research via a training plan that incorporates: 1) Mentored research activity; 2) Active participation & presentation in meetings, seminars and journal clubs; 3) Interaction with visiting scientists; 4) Periodic evaluation of applicant's research progress through individual development plan; 5) Publishing research findings in peer-reviewed journals; and 6) Participation in career development activities. It is expected that by the end of the training period, the applicant will be successful in her chosen research endeavor and contribute to the diversity of the research workforce, a goal of the Ruth L. Kirschstein predoctoral fellowship. Relevance of this project to human health Colorectal cancer contributes to significant mortalities in the United States, with 50,000 deaths per year. Consumption of fatty foods contaminated with B(a)P was implicated as a causative factor. One-third of adults and 17% of adolescents in the United State are obese. Obese people have a higher risk for colon cancer due to the excess energy intake from Western diet. We plan to study the progression of CRC, using a rat model that mirrors the human CRC scenario. We also propose to use Western diet, (>58% fat), as an accelerator of CRC. Our findings will be of use to determining the mechanistic effects of diet on B(a)P-caused initiation, promotion and progression of CRC.