Epigenetic Alterations in Childhood Reflect Prenatal Exposure to Maternal Infection
Objectives: We sought to explore the potential biological consequences of prenatal exposure to maternal infections.
Methods: We examined 929 children, aged 2-5 years, in the Study to Explore Early Development, phase I (SEED I) with both genome-scale whole blood DNA methylation data, from the Illumina 450K array, and in utero infection exposure data, ascertained via structured maternal phone interview. We used linear models, adjusted for cell type composition, sex, ancestry, and other unwanted variation via estimated surrogate variables, to identify differentially methylated loci associated with prenatal exposure to any infection, at any time in pregnancy or during a specific trimester.
Results: We found one site in an intergenic region on chromosome 5 that was significantly (q-value = 0.005) hypomethylated in children whose mothers had an infection during the preconception period. We also identified 2 genomic loci, within the IQSEC1 and EPS8L3 genes, showing significant decreases in DNA methylation (q-value=0.014 for IQSEC1 and q-value = 0.036 for EPS8L3) among children whose mother had an infection during her third trimester. The differences in percent methylation increased in magnitude when comparing children whose mothers reported infections in every trimester of pregnancy (n=56) to those whose mothers reported no infections during pregnancy (n=589). This may reflect a dose-response relationship between a cumulative prenatal infection exposure and methylation at the identified sites. Although we detected these differences in blood, reference datasets indicate that methylation at the intergenic locus on chromosome 5 is strongly correlated across blood and brain. This site is also predicted to be near an enhancer-like region in human astrocytes. IQSEC1 is thought to be involved in synaptic transmission, as both a scaffolding and signaling protein. It is highly expressed in brain tissues, particularly the frontal cortex, as well as whole blood. EPS8LS is not well studied but is likely involved in actin regulation, which is important in neuronal structures like the postsynaptic density and dendritic spine.
Conclusions: Our findings suggest that epigenetic changes related to prenatal infection exposure can present in childhood samples, and can provide candidate loci for studies examining potential epigenetic mediation of prenatal MIA exposure and atypical neurodevelopment.