Stable isotope evaluation of the methionine cycle in undernourished pregnancy

营养不良妊娠中蛋氨酸循环的稳定同位素评估

• 批准号: 8445720
• 负责人: PETER W. NATHANIELSZ
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445720
• 关键词: Activity Cycles; Address; Adult; Adverse effects; Affect; Age; Animals; Biological Process; Cardiovascular Diseases; Catheters; Cesarean section; Clinical Medicine; Complication; DNA; Data; Developed Countries; Developing Countries; Development; Developmental Process; Diagnosis; Diagnostic; Diet; Discipline of obstetrics; Dose; Eating; Ensure; Enzymes; Epigenetic Process; Evaluation; Fetal Growth Retardation; Fetal Tissues; Fetus; Folate; Folic Acid; Folic Acid Deficiency; Food; Functional disorder; Gene Expression; General Anesthesia; Genes; Gestational Age; Glucocorticoids; Hand; Health; Hepatic; Homocysteine; Homocystine; Housing; Human; Human Development; Hyperhomocysteinemia; Hypertension; Individual; Infusion procedures; Intake; Isotopes; Kinetics; Lead; Left; Letters; Life; Link; Lipids; Liver; Metabolic; Metabolism; Methionine; Methods; Methylation; Modeling; Mothers; Neural Tube Defects; Nutrient; Nutritional; Papio; Pathway interactions; Perinatal; Phenotype; Physical activity; Pilot Projects; Placenta; Plasma; Polysaccharides; Pregnancy; Pregnant Women; Primates; Production; Proteins; Protocols documentation; Publishing; RNA; Randomized; Rat-1; Rattus; Recruitment Activity; Regimen; Risk; Rodent; S-Adenosylmethionine; Site; System; Techniques; Tetrahydrofolates; Therapeutic; Tissue Sample; Tissues; Tracer; Translating; Translations; United States National Institutes of Health; Vitamin B 12; Weight; base; experience; feeding; fetal; fetal blood; fetus nutrition; gene environment interaction; high risk; innovation; instrument; maternal nutrient restriction; methyl group; nonhuman primate; novel; nutrition; offspring; pregnant; programs; public health relevance; purine/pyrimidine metabolism; research study; response; stable isotope

DESCRIPTION (provided by applicant): The methionine (MET) cycle is central to methylation in developmental processes (e.g. gene-environment interactions). Impaired methyl transfers have structural and metabolic consequences e.g. neural tube defects and high homocysteine (HCYS). Gene methylation is a fundamental mechanism leading to persistent epigenetic changes. Maternal under-nutrition and IUGR results in epigenetic changes in fetal tissues, including decreased methylation that increases gene expression. We have developed a baboon non-human primate (NHP) model of moderate maternal nutrient restriction (MNR) resulting in IUGR. MNR mothers eat 70% of controls (CTR) eating ad lib. In MNR, fetal vitamin B12 is decreased 22% while folate is unchanged. Rat studies show hyperhomocysteinemia is associated with increases in both plasma HCYS inflow and outflow. However NHP data are needed since rat 1-CC function differs from primates. Central to our proposal to develop these techniques in an IUGR NHP model, rat studies in pregnancy show that plasma fluxes under- estimate by >80% absolute tissue HCYS production e.g. little maternal or fetal hepatic HCYS is exported to plasma. Thus, plasma HCYS does not reflect major MET cycle tissue activity. As a consequence, MET cycle dysfunction does not necessarily lead to elevated HCYS and can occur with normal plasma HCYS. B12 is essential for methyl group transfer from 5-methyl-tetrahydrofolate to methylate HCYS to MET. HYPOTHESIS: MNR decreases B12 availability to the fetal MET cycle decreasing 1) overall HCYS methylation 2) contribution of HCYS methylation in maternal and fetal tissues to plasma HCYS. APPROACH: In stable isotope studies at 0.9 gestation in pregnant baboons chronically instrumented with maternal and fetal catheters maintained on a tether system, we use a priming dose followed by constant infusion of the tracers [U-13C] MET and [1-13C] HCYS to determine HCYS methylation and HCYS kinetics in both CTR and MNR pregnancies. Our collaborators methods in pregnant rats are now in Press. INNOVATION: Human studies cannot 1) control and match pre-study maternal phenotype, 2) precisely control nutrient intake; 3) obtain maternal and fetal tissues. Novelty lies in combining a unique NHP model and a pressing developmental question. R03 RESPONSIVENESS: The R03 mechanism encourages novel, high-risk studies. These isotope techniques have never been performed in any precocial species. INVESTIGATORS have many years experience with perinatal baboon studies and have published extensively on this NHP MNR/IUGR fetal phenotype. ENVIRONMENT: Our baboon feeding facility is unique worldwide to produce controlled MNR and IUGR. RELEVANCE: Primate and rodent MET cycle metabolism differs markedly. Identification of alterations in tissue methylation will provide evidence of tissues in which MET cycle dysfunction occurs with resultant epigenetic changes. Information will translate to human pregnancy aiding diagnostic, preventative and therapeutic strategies. B12 has been ignored in comparison to folic acid.

描述（由申请人提供）：蛋氨酸（MET）循环是发育过程（例如基因-环境相互作用）中甲基化的核心。甲基转移受损会产生结构和代谢后果，例如神经管缺陷和高同型半胱氨酸（HCYS）。基因甲基化是导致持久表观遗传变化的基本机制。母亲营养不良和 IUGR 会导致胎儿组织的表观遗传变化，包括甲基化减少，从而增加基因表达。我们开发了一种狒狒非人类灵长类动物 (NHP) 模型，该模型的母亲适度营养限制 (MNR) 会导致 IUGR。 MNR 母亲的饮食是对照组 (CTR) 的 70%。在 MNR 中，胎儿维生素 B12 减少 22%，而叶酸则保持不变。大鼠研究表明高同型半胱氨酸血症与血浆 HCYS 流入和流出的增加有关。然而，由于大鼠 1-CC 功能与灵长类动物不同，因此需要 NHP 数据。我们建议在 IUGR NHP 模型中开发这些技术的核心是，妊娠期大鼠研究表明，血浆通量低估了 >80% 的绝对组织 HCYS 产量，例如很少有母体或胎儿肝脏 HCYS 输出至血浆。因此，血浆 HCYS 并不反映主要的 MET 循环组织活性。因此，MET 循环功能障碍并不一定会导致 HCYS 升高，血浆 HCYS 正常时也可能发生。 B12 对于甲基从 5-甲基四氢叶酸到甲基化 HCYS 到 MET 的转移至关重要。假设：MNR 降低 B12 对胎儿 MET 周期的可用性，从而降低 1) 总体 HCYS 甲基化 2) 母体和胎儿组织中 HCYS 甲基化对血浆 HCYS 的贡献。方法：在妊娠 0.9 周的稳定同位素研究中，对怀孕狒狒长期使用系绳系统上的母体和胎儿导管进行测量，我们使用启动剂量，然后持续输注示踪剂 [U-13C] MET 和 [1-13C] HCYS，以确定 CTR 和 MNR 妊娠中的 HCYS 甲基化和 HCYS 动力学。我们的合作者在怀孕大鼠中的方法现已出版。创新：人类研究无法 1) 控制和匹配研究前的母体表型，2) 精确控制营养摄入； 3) 获取母体和胎儿组织。新奇的谎言 将独特的 NHP 模型与紧迫的发展问题相结合。 R03 响应性：R03 机制鼓励新颖的高风险研究。这些同位素技术从未在任何早成物种中进行过。研究人员在围产期狒狒研究方面拥有多年经验，并发表了大量关于 NHP MNR/IUGR 胎儿表型的文章。环境：我们的狒狒饲养设施在全球范围内是独一无二的，能够生产受控的 MNR 和 IUGR。相关性：灵长类动物和啮齿类动物的 MET 循环代谢显着不同。组织甲基化改变的鉴定将为发生 MET 循环功能障碍并导致表观遗传变化的组织提供证据。信息将转化为人类妊娠辅助诊断、预防和治疗策略。与叶酸相比，维生素 B12 被忽略了。