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Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program.

ABSTRACT: Prepregnancy 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 IL-6/TNF-? response to TLR 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 prepregnancy maternal body mass index. We show that UCB monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared with those born to lean mothers, at the level of secreted immune mediators and transcription. Because 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 and regulatory regions of genes involved in TLR signaling in resting UCB monocytes. Interestingly, the DNA methylation status of resting cells was highly predictive of transcriptional changes post-LPS stimulation, suggesting that cytosine methylation is 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-associated epigenetic changes in influencing the function of an 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 prepregnancy body mass index.

SUBMITTER: Sureshchandra S

PROVIDER: S-EPMC7384891 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program.

Sureshchandra Suhas S Wilson Randall M RM Rais Maham M Marshall Nicole E NE Purnell Jonathan Q JQ Thornburg Kent L KL Messaoudi Ilhem I

Journal of immunology (Baltimore, Md. : 1950) 20170908 8

Prepregnancy 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 IL-6/TNF-α response to TLR 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 dysregulate ...[more]

PMID: 28887432

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Project description:Pre-pregnancy (pregravid) obesity has been linked to several adverse health outcomes for both mother and offspring. Complications during pregnancy include increased risk for gestational diabetes, hypertension, preeclampsia, placental abruption, and difficulties during delivery. Several studies suggest that these negative outcomes are mediated by heightened systemic inflammation as well as changes in placental development and function. However, the molecular mechanisms by which pregravid obesity affects these processes are poorly understood. In this study, we aimed to address this question by carrying out a comprehensive analysis of the systemic maternal immune system coupled with placental gene expression and microbial profiling at term delivery (11 lean and 14 obese). Specifically, we examined the impact of pregravid obesity on circulating cytokines, chemokine, adipokines, and growth factors using multiplex Luminex assay. Innate and adaptive immune cell frequencies and their cytokine production in response to stimuli were measured using flow cytometry. Finally, changes in placental transcriptome and microbiome were profiled using RNA- and 16S-sequencing, respectively. Pregravid obesity is characterized by insulin and leptin resistance, high levels of circulating inflammatory markers IL-6 and CRP, in addition to chemokine IL-8 (p < 0.01). Moreover, pregravid obesity was associated with lower frequency of naïve CD4+ T-cells (p < 0.05), increased frequency of memory CD4+ T-cells (p < 0.01), and a shift towards Th2 cytokine production (p = 0.05). Myeloid cells from the obese cohort produced higher levels of pro-inflammatory cytokines but lower levels of chemokines following TLR stimulation (p < 0.05). Lastly, pregravid obesity is associated with increased abundance of Bacteroides and changes in the expression of genes important for nutrient transport and immunity (FDR < 0.05). Collectively, these data indicate that pregravid obesity is associated with heightened systemic inflammation and of dysregulated nutrient transport in the placenta and provide insight into the basis of fetal reprogramming.

Dataset Information

Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program.

Publications

Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program.

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