Effect of paternal B vitamin intake on intestinal tumorigenesis in offspring

父本 B 族维生素摄入量对子代肠道肿瘤发生的影响

• 批准号: 8202420
• 负责人: Jimmy W Crott
• 金额: $ 7.9万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202420
• 关键词: Apoptosis; Awareness; Biometry; Cell Death; Cell division; Cessation of life; Chronic Disease; Collaborations; Colorectal Cancer; Conceptions; Consumption; Core Facility; Country; DNA; Data; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Elements; Environment; Epigenetic Process; Evaluation; Fathers; Folate; Folic Acid Deficiency; Foundations; Funding; Gene Expression; Genes; Genomics; Goals; Guidelines; Histologic; Hypermethylation; Incidence; Individual; Inhibition of Apoptosis; Intake; Intestinal Cancer; Intestinal Mucosa; Intestinal Neoplasms; Intestines; Knowledge; Life Cycle Stages; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Methylation; Mothers; Mucous Membrane; Mus; Nuclear; Nutritional Biochemistry; Obesity; Outcome; Parents; Pathway interactions; Pattern; Prevention; Recommendation; Recurrence; Reporting; Repression; Research; Research Personnel; Riboflavin; Signal Pathway; Small Intestines; Small intestine mucous membrane; Societies; Solid; Supplementation; Testing; Time; United States National Institutes of Health; Vitamin B Complex; Vitamins; Work; animal facility; base; cancer prevention; cancer risk; disorder risk; in utero; inhibitor/antagonist; innovation; killings; laboratory facility; member; men; mouse model; nutrition; offspring; prevent; promoter; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Parental diet and exposures are increasingly recognized as determinants of disease risk in offspring. Our contribution here has been to demonstrate that maternal supplementation with vitamins B2, B6, B12 and folate can suppress, while mild deficiency can promote, intestinal tumorigenesis in mouse offspring. We propose that modulating paternal diet will have similar effect on tumorigenesis in offspring. This issue is of importance because there may exist an opportunity to exploit a previously ignored means to lower the incidence of cancer in our society. Unlike the situation for expectant mothers, there are no dietary recommendations for men prior to conception and the incidence of mild deficiencies of vitamins B2, B6 and B12 remains high in the US (10-50%). Furthermore, despite the rarity of folate deficiency in the US, our data in mothers indicates that intakes above and beyond those considered adequate are required to maximally suppress intestinal tumorigenesis in offspring and that intakes considered 'adequate' are associated with elevated tumor incidence in offspring. Our long term goal is to minimize the risk of cancer in offspring by optimizing diet throughout the life cycle, including that of both parents. The objectives of this application are to determine whether paternal supplementation and depletion with vitamins B2, B6, B12 and folate can alter tumor incidence in offspring and to gain an understanding of the mechanisms involved. We hypothesize that supplemental quantities of vitamins B2, B6, B12 and folate in the paternal diet will suppress, while combined mild deficiency will promote tumorigenesis in offspring. Furthermore, that such effects will be associated with the prevention or promotion of deleterious promoter methylation and gene expression changes of members of the "Wnt" signaling pathway, a pathway that regulates cell division and death and is commonly disrupted in colorectal cancer. The primary Specific Aim of this proposal is to determine whether paternal supplementation of mild depletion of vitamins B2, B6, B12 and folate alters the incidence of intestinal tumors in offspring. A secondary aim is to determine whether observed changes in tumor incidence are associated with changes in the expression and methylation of Wnt pathway genes in the normal intestinal mucosa. This contribution is significant because understanding how B vitamins modulate the development of cancer in individuals and their offspring is essential for developing intelligently-constructed and effective measures that will utilize these vitamins in the prevention of cancer. PUBLIC HEALTH RELEVANCE: Maternal supplementation with vitamins B2, B6, B12 and folate dramatically suppresses intestinal cancer in the offspring of mice; however it is unknown whether modulating paternal intake has a similar effect. We aim to determine whether paternal B vitamin supplementation and depletion can alter the incidence of intestinal tumors in offspring. The acquisition of such knowledge is a cornerstone of developing intelligently-constructed dietary interventions for both parents aimed at reducing the incidence of cancer in offspring. Our study specifically pertains to colorectal cancer, a disease which kills approximately 60,000 people per year in the US, however the mechanisms involved may be shared amongst a variety of cancers.

描述（由申请人提供）：父母饮食和暴露越来越被认为是后代疾病风险的决定因素。我们在这里做出的贡献是证明，对维生素B2，B6，B12和叶酸的孕产妇补充可以抑制，而轻度缺乏可以促进小鼠后代中的肠道肿瘤发生。我们建议调节父亲饮食对后代的肿瘤发生相似。这个问题很重要，因为可能有机会利用先前忽略的手段来降低我们社会中癌症的发生率。与准妈妈的情况不同，在受孕之前，没有针对男性的饮食建议，在美国，维生素B2，B6和B12的轻度缺乏症的发生率在美国仍然很高（10-50％）。此外，尽管美国的叶酸缺乏症稀有，但我们的母亲数据表明，在被认为是足够的摄入量以上和超出了足够的摄入量才能最大程度地抑制后代的肠道肿瘤发生，并且被认为“适当的进气口”与升高的肿瘤发生率升高有关。我们的长期目标是通过在整个生命周期（包括父母双方的饮食）中优化饮食，从而最大程度地降低后代癌症的风险。该应用的目标是确定父亲补充维生素B2，B6，B12和叶酸是否可以改变后代的肿瘤发生率，并了解所涉及的机制。我们假设父亲饮食中补充量的维生素B2，B6，B12和叶酸将抑制，而轻度缺乏症的组合将促进后代的肿瘤发生。此外，这种影响将与“ Wnt”信号通路成员的预防或促进有害启动子甲基化和基因表达变化有关，这是一种调节细胞分裂和死亡的途径，通常在结直肠癌中受到干扰。该提案的主要目的是确定对维生素B2，B6，B12和叶酸的轻度耗尽的父亲补充是否会改变后代肠道肿瘤的发生率。第二个目的是确定观察到的肿瘤发病率的变化是否与正常肠粘膜中Wnt途径基因的表达和甲基化的变化有关。这项贡献很重要，因为了解B族维生素如何调节个体及其后代的癌症发展对于开发智能结构和有效的措施至关重要，这些措施将利用这些维生素来预防癌症。 公共卫生相关性：补充维生素B2，B6，B12和叶酸的孕产妇在小鼠的后代中大大抑制肠道癌；但是，尚不清楚调节父亲摄入是否具有相似的作用。我们旨在确定父亲B维生素补充和耗竭是否可以改变后代肠肿瘤的发生率。获得此类知识的获取是为旨在减少后代癌症发生率的父母开发智能饮食干预措施的基石。我们的研究特别与大肠癌有关，这种疾病在美国每年约60,000人丧生，但是涉及的机制可能会在各种癌症中共享。