Maternal pregravid obesity remodels the DNA methylation landscape of cord blood monocytes disrupting its inflammatory program

Pre-pregnancy maternal obesity is associated with adverse outcomes for the offspring, including increased incidence of neonatal bacterial sepsis and necrotizing enterocolitis. We recently reported that cord blood monocytes from babies born to obese mothers generate a reduced IL-6/TNFa response to Toll-like receptors 1/2 and 4 ligands compared to those collected from lean mothers. These observations suggest altered intrauterine development of the offspring’s immune system, which in turn results in dysregulated function. We, therefore, investigated transcriptional and epigenetic differences within cord blood monocytes stratified by pre-pregnancy maternal body mass index. We show that cord blood monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared to those born to lean mothers, both at the level of secreted immune effectors and transcriptional activity. Since gene expression profiles of resting cord blood monocytes from both groups were comparable, we next investigated the role of epigenetic differences. Indeed, we detected stark differences in methylation levels within promoters/regulatory regions of genes involved in Toll-like receptor signaling in resting cord blood monocytes. Interestingly, DNA methylation status of resting cells was more predictive of transcriptional changes post stimulation, suggesting cytosine methylation as one of the dominant mechanisms driving functional inadequacy in cord blood monocytes. These data highlight a potentially critical role of maternal obesity-induced epigenetic changes in influencing the function of offspring’s monocytes at birth. These findings further our understanding of mechanisms that explain the increased risk of infection in neonates born to mothers with high pre-gravid body mass index.

孕前母体肥胖与子代不良妊娠结局密切相关，其中包括新生儿细菌性败血症（neonatal bacterial sepsis）及坏死性小肠结肠炎（necrotizing enterocolitis）的发病率升高。我们此前的研究表明，相较于瘦母亲所娩新生儿的脐带血单核细胞（cord blood monocytes），肥胖母亲所娩新生儿的脐带血单核细胞在受到Toll样受体（Toll-like receptor, TLR）1/2及4配体刺激时，产生的白细胞介素6（IL-6）/肿瘤坏死因子α（TNF-α）应答水平显著降低。上述结果提示子代免疫系统的宫内发育发生改变，进而导致其免疫功能失调。因此，我们基于孕前母亲的体质量指数（body mass index, BMI）对脐带血单核细胞进行分层，探究其转录组与表观基因组层面的差异。我们的研究结果显示，相较于瘦母亲所娩新生儿，肥胖母亲所娩新生儿的脐带血单核细胞在受到脂多糖（lipopolysaccharide, LPS）刺激时，其分泌型免疫效应分子产生与转录活性均呈现减弱的应答反应。由于两组静息状态脐带血单核细胞的基因表达谱无显著差异，我们进一步探究了表观遗传差异在此过程中的作用。我们确实在静息脐带血单核细胞中发现，参与Toll样受体信号通路的基因启动子/调控区域的甲基化水平存在显著差异。值得注意的是，静息细胞的DNA甲基化状态更能预测刺激后的转录组变化，这提示胞嘧啶甲基化是导致脐带血单核细胞功能不全的主要机制之一。上述数据表明，母体肥胖诱导的表观遗传改变可能在新生儿出生时子代单核细胞功能异常中发挥关键作用。本研究结果进一步阐明了孕前体质量指数较高的母亲所娩新生儿感染风险升高的潜在分子机制。