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 umbilical cord blood (UCB) monocytes from babies born to obese mothers generate a reduced IL6/TNFα response to Toll-like receptors 1/2 and 4 ligands compared to those collected from lean mothers. These observations suggest altered development of the offspring’s immune system, which in turn results in dysregulated function. We, therefore, investigated transcriptional and epigenetic differences within UCB monocytes stratified by pre-pregnancy maternal body mass index (BMI). We show that UCB monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared to those born to lean mothers, at the level of secreted immune mediators and transcription. Since gene expression profiles of resting UCB 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 UCB monocytes. Interestingly, DNA methylation status of resting cells was highly predictive of transcriptional changes post LPS stimulation, suggesting cytosine methylation as one of the dominant mechanisms driving functional inadequacy in UCB monocytes obtained from babies born to obese mothers. These data highlight a potentially critical role of maternal pregravid 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-pregnancy BMI.