Maternal One Carbon Metabolism and Low Birth Weight Infant

描述(由申请人提供)：由于胎儿宫内发育迟缓(IUGR)导致的婴儿低出生体重(LBW)，定义为足月妊娠时的体重&2500克，在发展中国家仍然是一个严重的问题，是发病率和死亡率的主要贡献者。据估计，发展中国家几乎30%的活产婴儿是LBW。在成年期，LBW与非传染性疾病，如2型糖尿病、高血压和冠心病之间有很强的相关性。来自微量营养素或蛋白质/能量补充剂的干预研究的间接证据表明，没有一种营养素本身对IUGR负责。对人类和实验动物的研究表明，母体和胎儿体内蛋氨酸和一种碳代谢的扰动会影响胎儿的生长和婴儿新陈代谢的“编程”，最终导致观察到的表型。我们已经报道了健康妇女和人类新生儿蛋氨酸代谢与妊娠相关的特定变化。在怀孕期间限制啮齿动物的等卡路里蛋白，会导致IUGR、代谢重新编程和子代的长期发病率。在人类中，观察到母亲的B12与6岁时孩子的叶酸状况和胰岛素抵抗之间存在显著的相关性。我们假设，边际蛋白质摄入和微量营养素状态的改变，不足以导致“经典的”缺乏综合征，将影响母亲和胎儿的碳代谢和甲基转移，从而改变胎儿的生长。具体目的是纵向记录母体蛋氨酸、同型半胱氨酸代谢，将其与营养(蛋白质)摄入量、叶酸、B12、吡哆醇状态以及胰岛素抵抗的措施联系起来。蛋氨酸代谢，转甲基化和转硫化，将使用一种新颖和创新的稳定同位素标记的蛋氨酸负荷试验在妊娠早期和后期进行测量。这些数据将与母亲的宏观和微量营养状况有关，通过饮食回忆、血浆B12、甲基丙二酸、吡哆醇和红细胞叶酸水平来估计。蛋氨酸代谢的生理测量将使我们能够确定营养状态的亚临床变化对母亲一碳代谢的影响。这些生理数据将与胎儿生长有关，通过出生体重和身体成分以及脐带血中的代谢和激素评估进行评估。这些研究将确定IUGR的机制，并利用各种甲基捐赠者在已确定的怀孕关键时期制定战略建议，目的是防止新生儿直接和长期的“规划”后果。当人们考虑到LBW的巨大规模、相关的临床问题和对社会的经济负担时，这项研究具有重大的公共卫生和经济影响。

DESCRIPTION (provided by applicant): Low birth weight (LBW) in infants, due to intrauterine growth retardation (IUGR), defined as weight < 2500gms at term gestation, remains a critical problem in the developing countries and is a major contributor to the morbidity and mortality. It is estimated that almost 30% of all live births in developing countries are LBW. A strong association has been shown in adulthood between LBW and non-communicable diseases, such as type 2 diabetes, hypertension and coronary heart disease. Indirect evidence from intervention studies of micronutrient or protein/energy supplement suggests that no single nutrient is itself responsible for the IUGR. Studies with humans and experimental animals have shown that perturbation in the methionine and one carbon metabolism in the mother and possibly in the fetus, impacts fetal growth and "programming" of the metabolism of the infant and ultimately causes the observed phenotype. We have reported specific gestational-related changes in methionine metabolism in healthy women and in the human newborn infant. Isocaloric protein restriction in rodents during pregnancy, results in IUGR, metabolic re-programming, and long term morbidity in the off spring. In humans, a significant correlation between maternal B12 and folate status and insulin resistance in their children at age 6 years has been observed. We hypothesize that marginal protein intake and altered micronutrient status, insufficient to cause "classical" deficiency syndrome, will impact one carbon metabolism and methyl transfers in the mother and the fetus and thereby alter fetal growth. The specific aims are to longitudinally document maternal methionine, homocysteine metabolism, relate it to nutrient (protein) intake, folate, B12, pyridoxine status, and measures of insulin resistance. Methionine metabolism, transmethylation and transsulfuration, will be measured using a novel and innovative stable isotope labeled methionine loading test early and late in gestation. These data will be related to the macro and micronutrient status of the mother estimated by dietary recall, plasma B12, methylmalonic acid, pyridoxine and red blood cell folate levels. The physiological measurements of methionine metabolism will allow us to identify the effect of subclinical changes in nutrient status on the one carbon metabolism of the mother. These physiological data will be related to fetal growth as assessed by birth weight and body composition, and metabolic and hormonal assessments in the cord blood. These studies will identify the mechanism of IUGR and lead to the development of strategic recommendations at the identified critical periods in pregnancy using various methyl donors with the goal of preventing both immediate neonatal and long term "programming" consequences in the baby. There are major public health and economic implications for this study, when one considers the enormous magnitude of the LBW, the associated clinical problems and the economic burden to the society.