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激是对 全球母亲和儿童的健康。长期的营养贫乏已经造成了营养不足 许多发展中国家的胎儿和出生后发育。本行政副刊的目标是 通过将最先进的热暴露与母亲营养不良的双重负担联系起来，检查母亲营养不良和高温暴露的双重负担 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 (女性优先，NCT01883193)揭示了怀孕早期过热对分娩的有害影响 四个试验点之一的巴基斯坦婴儿的身长和头围。这场审判，它比较了 一种综合营养补充剂(CNS)的效果发现，高温对出生长度有影响 在被随机分配到中枢神经系统的女性中得到缓解，这表明高温和母体之间可能存在相互作用 营养状况。本行政副刊将对各地区的热应力指标进行分析 WF试验地点(三大洲4个国家)将全球热气候指数(UTCI)与 现有的纵向人体测量数据(从出生到24个月)和新产生的表观遗传学数据 WF审判。具体目标1的研究将检验母子二胎的UTCI和 新生儿/儿童从出生到2岁的结局和中枢神经系统补充剂的效果调整。 利用来自ERA5-LAND再分析的新开发的UTCI高分辨率时空图 (HiTiSEA)，这项研究将在所有地点检查1)母亲热应激与胎儿生长之间的关系 (刚果民主共和国、危地马拉、印度和巴基斯坦，n=2,442)来自WF试验的；2)热暴露之间的关联 和婴儿出生前两年的发育；以及3)研究高温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(口腔，3个月，N=391)。利用DNAME数据 在亲本R01中生成，我们将调查母体热暴露(UTCImax)与 每个三个月和目标DNAME(亚稳态表观等位基因和表观遗传年龄加速)和一个 表观基因组范围的关联分析。总的来说，拟议的工作将弥合我们目前 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.