Chemoprevention of colon cancer via neonatal imprinting

通过新生儿印记化学预防结肠癌

基本信息

批准号：
7321591
负责人：
Aramandla Ramesh
金额：
$ 7.33万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-20 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7321591
关键词：
Adult Affect American Animals Aromatic Polycyclic Hydrocarbons Attenuated Benzo(a)pyrene Bioavailable Breast CYP1A1 gene Cancer Etiology Characteristics Chemical Agents Chemicals Chemoprevention Chemopreventive Agent Chronic Colon Colon Carcinoma Colon, Rectum Colonic Neoplasms Colorectal Colorectal Cancer Cytochrome P450 DNA DNA Adduction DNA Adducts DNA Modification Process Data Development Diet Dose End Point Environment Environmental Exposure Enzymes Epoxide hydrolase Esophagus Etiology Exposure to Family Fibrinogen Food Fruit Genus Cola Glutathione S-Transferase Goals Histologic Human Intervention Kinetics Life Life Style Location Longevity Lung Malignant Neoplasms Measures Mediating Metabolic Biotransformation Metabolic Pathway Mus Neonatal Neoplasm Metastasis Numbers Nutritional Organ Phytochemical Pilot Projects Plants Plasma Preventive Principal Investigator Process Quality of life Range Rattus Resveratrol Risk Role Severities Staging Stomach Surveys Testing Time Tissues Toxic Environmental Substances Toxic effect Transgenic Mice Translating Treatment Cost adduct adenoma base benzo(a)pyrene-DNA adduct cancer therapy carcinogenesis chemical group chemotherapeutic agent colon carcinogenesis cyclooxygenase 2 day dihydrodiol dehydrogenases environmental chemical human study imprint improved indexing insight male men neonatal exposure novel prenatal prevent prophylactic size trans-1,2-dihydrobenzene-1,2-diol dehydrogenase

项目摘要

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.

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，会对多种器官造成毒性和癌症。我们的初步研究表明，新生大鼠服用白藜芦醇 (RVT) 可减少成年大鼠暴露于 BaP 后的细胞色素 P450 (CYP) 家族酶的 BaP 诱导，同时减少大鼠体内反应性代谢物的形成和分布。血浆和靶组织。我们提出的研究将检验 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。我们的研究将检验的一个相关假设是，在生命周期中导致毒性/癌症的 BaP 生物可利用剂量可以通过新生儿期 RVT 治疗的“印记”来改变，并且这种作用如果最终转化为进入人类研究中，一般来说，可能会对生命质量甚至生命范围产生重大影响，特别是减少结直肠癌的发病率。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，美国每年的治疗费用估计为 84 亿美元，因为据估计饮食导致 80已知结直肠癌病例的百分比，并且由于工业排放导致多环芳烃在食品和环境中普遍存在，因此将环境暴露视为引发或发生结直肠癌的因素之一并非没有道理。结直肠癌病例加速增长。我们将在成年雄性转基因小鼠中测试我们的假设，具体目的如下： 1. 研究新生白藜芦醇对成年 ApcMin 小鼠 BaP-DNA 加合物形成、持久性以及 BaP 诱导的结肠和直肠腺瘤的化学预防作用； 2. 确定新生儿接触白藜芦醇是否会改变成年 ApcMin 小鼠 BaP 生物转化酶的表达和活性以及代谢物谱。该试点项目将提供有关 RVT 等植物化学物质对延缓或预防结直肠癌发生发展的贡献的重要新信息。此外，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，作为预防成年后癌症发展的一种手段，从而提高生活质量。