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。我们在这里的贡献是证明了母亲补充维生素B2、B6、B12和叶酸可以抑制小鼠后代的肠道肿瘤发生，而轻度缺乏可以促进子代的肠道肿瘤发生。我们认为，调整父亲的饮食对子代的肿瘤发生也有类似的影响。这个问题很重要，因为我们可能有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。与准妈妈的情况不同，在美国，男性在怀孕前没有饮食建议，维生素B2、B6和B12轻度缺乏的发生率仍然很高(10%-50%)。此外，尽管叶酸缺乏在美国很少见，但我们在母亲中的数据表明，要最大限度地抑制后代的肠道肿瘤发生，需要超过被认为充足的摄入量，而被认为“充足”的摄入量与后代肿瘤发病率的增加有关。我们的长期目标是通过优化包括父母双方在内的整个生命周期的饮食，将后代患癌症的风险降至最低。这项应用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子代的肿瘤发病率，并了解其中的机制。我们假设，在父亲的饮食中补充维生素B2、B6、B12和叶酸的数量将受到抑制，而轻度缺乏将促进子代的肿瘤发生。此外，这种作用将与防止或促进有害启动子甲基化和“Wnt”信号通路成员的基因表达变化有关，“Wnt”信号通路是一种调节细胞分裂和死亡的途径，在结直肠癌中通常被破坏。这项建议的主要具体目的是确定父亲补充轻度缺乏维生素B2、B6、B12和叶酸是否会改变子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变化有关。这一贡献意义重大，因为了解维生素B如何调节个体及其后代的癌症发展，对于开发智能构建和有效的措施，利用这些维生素预防癌症至关重要。

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.