Table_2_Maternal Intake of n-3 Polyunsaturated Fatty Acids During Pregnancy Is Associated With Differential Methylation Profiles in Cord Blood White Cells.xlsx

A healthy diet during pregnancy is pivotal for the offspring health at birth and later in life. N-3 polyunsaturated fatty acids (n-3 PUFAs) are not endogenously produced in humans and are exclusively derived from the diet. They are pivotal for the fetus growth and neuronal development and seem beneficial in reducing the risk of cardiometabolic diseases and preventing later allergic disorders in the offspring by modulating the inflammatory immune response. In the present study, we investigated the association between maternal intakes of n-3PUFAs, profiled on maternal erythrocyte membranes at pregnancy term, and offspring DNA methylation on cord blood mononuclear cells in a sample of 118 mother–newborn pairs randomly drawn from the “Feeding fetus’ low-grade inflammation and insulin-resistance” study cohort. N-3 PUFA content on erythrocyte membranes is a validated biomarker to measure objectively medium term intake of n-3 PUFAs. Based on distribution of n-3 PUFA in the whole cohort of mothers, we identified mothers with low (n-3 PUFA concentration <25th percentile), medium (n-3 PUFAs between 25th and 75th percentiles), and high n-3 PUFA content (>75th percentile). The HumanMethylation450 BeadChip (Illumina) was used for the epigenome-wide association study using the Infinium Methylation Assay. The overall DNA methylation level was not different between the three groups while there was significant difference in methylation levels at certain sites. Indeed, 8,503 sites had significantly different methylations between low and high n-3 PUFA groups, 12,716 between low and medium n-3 PUFA groups, and 18,148 between high and medium n-3 PUFA groups. We found differentially methylated genes that belong prevalently to pathways of signal transduction, metabolism, downstream signaling of G protein-coupled receptors, and gene expression. Within these pathways, we identified four differentially methylated genes, namely, MSTN, IFNA13, ATP8B3, and GABBR2, that are involved in the onset of insulin resistance and adiposity, innate immune response, phospholipid translocation across cell membranes, and mechanisms of addiction to high fat diet, alcohol, and sweet taste. In conclusion, findings of this preliminary investigation suggest that maternal intake of n-3 PUFAs during pregnancy has potential to influence the offspring DNA methylation. Validation of results in a larger cohort and investigation of biological significance and impact on the phenotype are warranted.

妊娠期健康饮食对子代出生时及终身健康均至关重要。N-3多不饱和脂肪酸（N-3 polyunsaturated fatty acids, n-3 PUFAs）无法在人体内内源合成，仅能通过膳食获取。其对胎儿生长与神经发育具有关键作用，且可通过调节炎症性免疫应答，降低子代心血管代谢疾病风险，并预防其日后发生过敏性疾病。本研究在从“胎儿轻度炎症与胰岛素抵抗膳食调控”研究队列中随机抽取的118对母婴样本中，分析了妊娠末期母体红细胞膜所表征的n-3 PUFAs摄入水平，与子代脐血单个核细胞DNA甲基化之间的关联。红细胞膜中的n-3 PUFAs含量是一种经过验证的生物标志物，可客观反映中期n-3 PUFAs摄入情况。基于全部母亲队列的n-3 PUFAs分布情况，我们将母体分为n-3 PUFAs含量低（浓度<第25百分位数）、中等（浓度介于第25~75百分位数）与高（浓度>第75百分位数）三组。本研究采用Infinium甲基化检测技术，借助人类甲基化450芯片（HumanMethylation450 BeadChip，Illumina）开展全表观基因组关联分析。三组整体DNA甲基化水平无显著差异，但部分位点的甲基化水平存在显著差异。具体而言，低与高n-3 PUFAs组间存在8503个差异甲基化位点，低与中等组间为12716个，高与中等组间则为18148个。本研究鉴定到的差异甲基化基因主要富集于信号转导、代谢、G蛋白偶联受体下游信号通路以及基因表达调控等通路。在这些通路中，我们鉴定到4个差异甲基化基因，即MSTN、IFNA13、ATP8B3与GABBR2，它们分别参与胰岛素抵抗与肥胖发生、天然免疫应答、磷脂跨细胞膜转运，以及高脂饮食、酒精与甜味成瘾的相关机制。综上，本初步研究结果表明，妊娠期母体n-3 PUFAs摄入水平可能对子代DNA甲基化产生影响。未来需在更大规模队列中验证本研究结果，并探究其生物学意义以及对表型的影响。