Maternal One Carbon Metabolism and Low Birth Weight Infant

描述（由申请人提供）：由于宫内生长迟缓（IUGR）导致的婴儿低出生体重（LBW），定义为足月妊娠体重< 2500g，仍然是发展中国家的一个严重问题，也是导致发病率和死亡率的主要原因。据估计，发展中国家所有活产婴儿中有近30%是低体重婴儿。在成年期，体重过低与非传染性疾病（如2型糖尿病、高血压和冠心病）之间存在密切关联。来自微量营养素或蛋白质/能量补充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碳代谢的扰动会影响胎儿的生长和婴儿代谢的“编程”，并最终导致所观察到的表型。我们已经报道了健康妇女和人类新生儿中蛋氨酸代谢的特定妊娠相关变化。啮齿动物在怀孕期间限制等热量蛋白，会导致IUGR、代谢重编程和后代的长期发病率。在人类中，已经观察到母亲B12和叶酸水平与6岁儿童胰岛素抵抗之间的显著相关性。我们假设，边际蛋白质摄入和微量营养素状态的改变，不足以引起“经典”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，吡哆醇状态和胰岛素抵抗的测量相关联。蛋氨酸代谢、转甲基化和转硫化将在妊娠早期和晚期使用一种新型的稳定同位素标记的蛋氨酸负荷试验进行测量。这些数据将与母亲的宏量和微量营养素状况有关，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况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组成进行评估，以及脐带血中的代谢和激素评估。这些研究将确定IUGR的机制，并在确定的妊娠关键时期使用各种甲基供体制定战略建议，目的是防止新生儿立即和婴儿长期的“编程”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.