Preconception Maternal Nutrition, Offspring DNA Methylation, and InfantGrowth in Low Resource Settings

摘要 与气候变化密切相关的高环境温度和热应力是对环境的一个迫在眉睫的威胁。 全球母亲和儿童的健康。长期的营养不良已经导致了 许多发展中国家的胎儿和产后生长。这一行政补充的目的是 研究产妇营养不良和热暴露的双重负担， 压力指标人体测量和表观遗传学来自多国随机对照试验的数据 （妇女第一，NCT 01883193）显示，在怀孕的头三个月，过度的热量对分娩有不利影响。 在四个试验地点之一的巴基斯坦，婴儿的身长和头围。这项试验， 全面营养补充剂（CNS）的效果揭示了热量对出生长度的影响 在随机分配至CNS的女性中减轻，表明热与母体之间存在潜在的相互作用 营养状况本行政补充文件将对所有国家的热应力指数进行分析。 WF试验的研究中心（3大洲4个国家）将通用热气候指数（UTCI）与 现有的纵向人体测量数据（从出生到24个月）和新生成的表观遗传数据， WF试验。具体目标1中的研究将检查母子二人中UTCI与 从出生到2岁的新生儿/儿童结局以及CNS补充的效果调整。 使用新开发的来自ERA 5-Land再分析的UTCI高分辨率时空图 （HiTiSEA），这些研究将检查1）在所有地点母体热应激和胎儿生长之间的关联 (DRC，危地马拉，印度和巴基斯坦，n= 2，442）从WF试验; 2）热暴露之间的关联 和儿童生长在生命的头两年;和3）检查热和母体中枢神经系统之间的相互作用 补充。在具体目标2中，我们将研究UTCI和营养状况之间的相互作用， 胎盘（N = 463）和新生儿DNA甲基化（颊，3个月，N = 391）。利用DNA数据 在母体R 01中产生，我们将研究母体热暴露（UTCImax）与 每个三个月和靶向DNAme（亚稳定表观等位基因和表观遗传年龄加速）和一个 表观基因组关联分析总的来说，拟议的工作将弥合我们目前的关键差距， 了解气候和环境变化如何对孕妇和儿童产生不利影响， 以及营养减轻这一负担的潜力。

ABSTRACT High ambient temperature and heat stress, closely linked to climate change are an imminent threat to the health of mothers and children globally. Chronic nutritional impoverishments already contribute to inadequate fetal and postnatal growth in many developing countries. The goal of this administrative supplement is to examine the double-burden of poor maternal nutrition and heat exposure by linking state-of-the-art thermal stress indicators, anthropometry, and epigenetics. Data from a multi-country randomized controlled trial (Women First, NCT01883193) revealed detrimental impact of excessive heat in the first trimester on birth length and head circumference of the infant in Pakistan, one of the four trial sites. This trial, which compared the effects of a comprehensive nutritional supplement (CNS) uncovered that impacts of heat on birth length were mitigated in women randomized to CNS suggesting potential interactions between heat and maternal nutritional status. This administrative supplement will conduct analysis of thermal stress indices among all sites of the WF trial (4 countries on 3 continents) integrating universal thermal climate index (UTCI) with existing longitudinal anthropometric data (from birth to 24 mo) and newly generated epigenetic data from the WF trial. Studies in Specific Aim 1 will examine associations between UTCI in mother-child dyads and neonatal/child outcomes from birth through 2 y of age and effect-modification by CNS supplementation. Using newly developed high-resolution spatiotemporal maps of UTCI derived from the ERA5-Land reanalysis (HiTiSEA), the studies will examine 1) associations between maternal heat stress and fetal growth in all sites (DRC, Guatemala, India and Pakistan, n= 2,442) from the WF trial; 2) associations between heat exposure and child growth in the first two years of life; and 3) examine interactions between heat and maternal CNS supplementation. In Specific Aim 2, we will examine the interaction between UTCI and nutritional status on placental (N = 463) and neonatal DNA methylation (buccal, 3 months, N = 391). Leveraging DNAme data generated in the parent R01, we will investigate associations between maternal heat exposure (UTCImax) in each trimester and targeted DNAme (metastable epialleles & epigenetic age acceleration) and an epigenome-wide association analysis. Collectively the proposed work will bridge critical gaps in our current understanding of how climate and environmental change adversely impact pregnant women and children, and the potential for nutrition to mitigate this burden.