Effect of paternal B vitamin intake on intestinal tumorigenesis in offspring

描述（由申请人提供）：父母的饮食和接触越来越多地被认为是后代疾病风险的决定因素。我们的贡献是证明母体补充维生素B2，B6，B12和叶酸可以抑制，而轻度缺乏可以促进小鼠后代的肠道肿瘤发生。我们认为，调节父亲的饮食将对后代的肿瘤发生产生类似的影响。这个问题很重要，因为可能存在一个机会，利用以前被忽视的手段来降低我们社会中的癌症发病率。与孕妇的情况不同，在怀孕前没有针对男性的饮食建议，在美国，维生素B2，B6和B12轻度缺乏的发生率仍然很高（10-50%）。此外，尽管叶酸缺乏症在美国很少见，但我们在母亲中的数据表明，摄入量超过被认为足够的摄入量是最大限度地抑制后代肠道肿瘤发生所必需的，并且认为“足够”的摄入量与后代肿瘤发病率升高相关。我们的长期目标是通过优化整个生命周期（包括父母双方）的饮食，最大限度地降低后代患癌症的风险。本申请的目的是确定父亲补充和消耗维生素B2，B6，B12和叶酸是否可以改变后代的肿瘤发病率，并了解所涉及的机制。我们假设，补充量的维生素B2，B6，B12和叶酸在父亲的饮食将抑制，而结合轻度缺乏将促进后代的肿瘤发生。此外，这种作用将与预防或促进“Wnt”信号通路成员的有害启动子甲基化和基因表达变化相关，该信号通路调节细胞分裂和死亡，并且通常在结直肠癌中被破坏。本提案的主要具体目的是确定父亲补充维生素B2、B6、B12和叶酸的轻度耗竭是否会改变后代肠道肿瘤的发病率。第二个目的是确定观察到的肿瘤发生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相关。这一贡献是重要的，因为了解B族维生素如何调节个体及其后代癌症的发展对于开发智能构建和有效的措施将利用这些维生素预防癌症是必不可少的。 公共卫生相关性：母亲补充维生素B2，B6，B12和叶酸可以显著抑制小鼠后代的肠癌;然而，调节父亲的摄入量是否具有类似的效果尚不清楚。我们的目的是确定父亲补充和消耗B族维生素是否可以改变后代肠道肿瘤的发病率。这些知识的获得是为父母双方制定旨在降低后代癌症发病率的智能饮食干预措施的基石。我们的研究特别涉及结直肠癌，这是一种在美国每年导致约60，000人死亡的疾病，但所涉及的机制可能在各种癌症中共享。

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.