170 - Characterizing the Impact of Fetal Congenital Heart Disease on the Neonatal Epigenome

With a reported prevalence of 6-13 per 1,000 newborns, congenital heart disease (CHD) is the most common and severe spectrum of developmental anomalies. The presence of CHD is known to expose the fetus to stressful stimuli, including cerebral hypoxia, during critical developmental periods in utero. The impact of these adverse intrauterine exposures on the epigenome, and potential impact on neurodevelopmental outcomes is not well described.

Objective: To elucidate differences in DNA methylation profiles at birth between healthy and CHD newborns.

Design/Methods:

We prospectively recruited healthy pregnancies and those complicated by fetal CHD to characterize the impact of stressful insults in utero on newborns. A methylation array approach was utilized to globally assess differences in methylation between newborns with cyanotic CHD and healthy term control newborns. We leveraged the MethylationEPIC array for this study and DNA was extracted from buccal swabs collected at birth as part of a comprehensive, longitudinal phenotypic study, including the collection of fetal and post-natal brain MRIs, maternal blood, and behavioral questionnaires. Unsupervised hierarchical clustering showed appropriate clustering by tissue type, no gender bias, and gross appropriate clustering of cohort samples. Exceptions to this clustering will be further studied to uncover phenotypic associations. Differentially methylated probes (DMPs) were determined using linear regression analysis and a significance threshold of FDR p-value < 0.05.

Results:

We found that there were over 400 differences in DNA methylation that are observable as biomarkers of exposure to in utero stress, potentially driven by prenatal exposure to hypoxemia, between healthy newborn controls and newborns with cyanotic CHD during pregnancy. There was noted differential methylation within the gene HIF1A, which codes for hypoxia-inducible factor 1α (HIF1α), as well as EPO, which codes for erythropoietin, is also disrupted within the theoretical hypoxia-inducible factor, “brain-sparing effect” cascade.

Conclusion(s): Together, these data may provide critical insight into the molecular underpinnings of the pathobiology associated with hypoxemia exposure and reduced brain growth in newborns with CHD and serve as a critical prenatal biomarker to be studied and validated in future experiments. Defining these signatures in newborns is critical for establishing a baseline impact on the neonatal epigenome so that future studies can elucidate early markers of long-term neurodevelopmental impairment.
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