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)家族，对多种器官具有毒性和致癌作用。我们的初步研究表明，新生大鼠给予白藜芦醇(RVT)可减少成年大鼠暴露于BaP后BaP对细胞色素P450(CYP)家族的诱导，并伴随着血浆和靶组织中反应性代谢物的形成和分布的减少。我们提出的研究将验证RVT通过细胞色素P450(CYP)介导的代谢途径调控BaP诱导的结肠癌发生的假设。在我们的研究中将测试的一个相关假设是，在生命周期内导致毒性/癌症的BaP的生物可用剂量可以通过在新生儿期使用RVT治疗来改变，如果这种作用最终转化为人体研究，可能会对总体生活质量甚至生活范围产生重大影响，特别是在减少结直肠癌的发病方面。超过9000万美国人--其中58%是男性--有或正在面临患结肠癌和直肠癌的风险，据估计，美国每年的治疗费用为84亿美元。据估计，80%的已知结直肠癌病例是由饮食造成的，而且由于工业排放，多环芳烃在食品和环境中无处不在，因此将环境暴露视为引发或加速结直肠癌病例的因素之一并不是不合理的。我们将在成年雄性转基因小鼠中验证我们的假设，具体目的如下：1.研究新生白藜芦醇对成年ApcMin小鼠结肠和直肠BaP-DNA加合物的形成、持久性和BaP诱导的腺瘤的化学预防作用；2.确定新生白藜芦醇暴露是否改变成年ApcMin小鼠BaP生物转换酶和代谢物的表达和活性。这一试点项目将提供有关植物化学物质(如RVT)对延缓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/或合成其他自然产生的植物性化学物质，这些化学物质可以在生命早期进行测试，作为预防成年生活中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.