Chemoprevention of colon cancer via neonatal imprinting

描述（由申请人提供）： 苯并（a）芘（BaP）是一种普遍存在的环境毒物，属于多环芳烃（PAH）化合物家族，对多种器官造成毒性和癌症。我们的初步研究表明，新生大鼠白藜芦醇（RVT）的管理减少BaP诱导的细胞色素P450（P450）家族的酶在成年大鼠暴露于BaP后，伴随着减少的形成和分布的反应性代谢产物在血浆和靶组织。我们提出的研究将验证RVT通过细胞色素P450（CYP）介导的代谢途径调节BaP诱导的结肠癌发生的假设。将在我们的研究中测试的一个相关假设是，在生命周期中导致毒性/癌症的BaP的生物可利用剂量可以通过在新生儿期间使用RVT治疗的"印记"来改变，并且这种作用如果最终转化为人类研究，可能对生命的质量甚至可能对生命的程度产生重大影响。特别是减少结肠直肠癌的发病。超过9000万美国人-其中58%是男性-患有结肠癌和直肠癌或有患结肠癌和直肠癌的风险，并且在美国每年的治疗费用估计为84亿美元。由于据估计饮食导致80%的已知结肠直肠癌病例，并且由于PAH在食物和环境中的普遍存在（由于工业排放），将环境暴露作为引发或加速结直肠癌病例的因素之一并非不合理。我们将在成年雄性转基因小鼠中测试我们的假设，具体目标如下：1。研究新生儿白藜芦醇对成年ApcMin小鼠BaP-DNA加合物形成、持久性和BaP诱导的结肠和直肠腺瘤的化学预防作用;确定新生儿暴露于白藜芦醇是否会改变成年ApcMin小鼠BaP生物转化酶和代谢产物谱的表达和活性。该试点项目将提供有关植物化学物质（如RVT）对延迟或预防结直肠癌发生的贡献的重要新信息。此外，所获得的数据将有助于评估和/或合成其他天然存在的植物化学品，这些化学品可以在生命早期进行测试，作为预防成年癌症发展的一种手段，从而提高生活质量。

DESCRIPTION (provided by applicant): Benzo(a)pyrene (BaP) is an ubiquitous environmental toxicant that belongs to the polycyclic aromatic hydrocarbon (PAH) family of compounds and causes toxicity and cancer to a variety of organs. Our preliminary studies have demonstrated that neonatal administration of rats with resveratrol (RVT) reduces BaP induction of the cytochrome P450 (CYP) family of enzymes in adult rats subsequent to exposure to BaP, with a concomitant reduction in the formation and distribution of reactive metabolites in plasma and target tissues. Our proposed studies will test the hypothesis that RVT modulates BaP-induced colon carcinogenesis through cytochrome P450 (CYP) mediated metabolic pathways. A related hypothesis that will be tested in our studies is that the bioavailable dose of BaP that contributes to toxicity/cancer during a lifespan can be altered by "imprinting" with RVT treatment during the neonatal period, and that such an action, if ultimately translated into human studies, could have a significant effect on the quality and perhaps even the extent of life, in general, and in reducing the onset of colorectal cancer, in particular. More than 90 million Americans - 58 % of whom are men -- have or are at risk of developing cancer of colon and rectum, and the treatment costs are estimated to be $8.4 billion annually in the U.S. Since it is estimated that diet contributes to 80% of the known colorectal cancer cases, and because of PAH's ubiquity in foods and in environment due to industrial emissions, it is not unreasonable to attribute environmental exposure serving as one of the factors in initiating or accelerating colorectal cancer cases. We will test our hypotheses in adult male transgenic mice with the following specific aims: 1. Investigate the chemopreventive effect of neonatal resveratrol on BaP-DNA adduct formation, persistence and BaP-induced adenomas in colon and rectum of adult ApcMin mice; and 2. Determine whether neonatal exposure to resveratrol alters the expression and activities of BaP biotransformation enzymes and metabolite profile in adult ApcMin mice. This pilot project will provide important new information regarding the contribution of phytochemicals such as RVT towards delaying or preventing the development of colorectal carcinogenesis. Also, the data obtained will be useful for assessment and/or synthesis of other naturally occurring plant-based chemicals that could be tested in the early life as a means of preventing the development of cancer in adult life, thus improving the quality of life.