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: 8296488
• 负责人: Jimmy W Crott
• 金额: $ 15.35万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296488
• 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.

描述（由申请人提供）：父母的饮食和接触越来越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。

项目成果

Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring.

父本 B 族维生素摄入量是雌性 Apc1638N 小鼠后代生长、肝脂质代谢和肠肿瘤体积的决定因素。

• DOI: 10.1371/journal.pone.0151579
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sabet,JuliaA;Park,LaraK;Iyer,LakshmananK;Tai,AlbertK;Koh,GarYee;Pfalzer,AnnaC;Parnell,LaurenceD;Mason,JoelB;Liu,Zhenhua;Byun,AlexanderJ;Crott,JimmyW
• 通讯作者: Crott,JimmyW