Conserved DNA Methylation Signatures in The Prefrontal Cortex of Newborn and Juvenile Guinea Pigs Following Antenatal Corticosteroid Exposure

Abstract

Antenatal corticosteroids (ACS) are provided to improve perinatal survival when there is risk of preterm birth. Though evidence suggests increased risk of developing neurobehavioural disorders in exposed offspring, the mechanisms that mediate this relationship remain largely unknown. Here, we investigated the DNA methylation patterns in the prefrontal cortex (PFC) of exposed offspring. We hypothesized that differential methylation will be evident at both newborn and juvenile ages. Pregnant guinea pigs were administered saline or betamethasone (1mg/kg) on gestational days 50/51 to mimic a single course of ACS. gDNA was isolated from the PFC of term-born offspring on postnatal day 1 (PND1) and PND14 to identify differentially methylated CpG sites (DMCs) using reduced representative bisulfite sequencing. In the PND1 PFC, 1521 DMCs, annotating to 145 genes were identified following ACS. Identified genes were involved in pathways regulating developmental cellular process. In the PND14 PFC, 776 DMCs representing 46 genes were identified, and were enriched in synaptic signalling pathways. Though no individual DMCs were identified at both PND1 and PND14, differential methylation was consistently observed at the binding sites of transcription factors PLAGL1, TFAP2C, ZNF263, and SP1 at both ages. In this study, we identified an altered DNA methylome in the PFC of ACS-exposed guinea pig offspring at both newborn and juvenile ages. Notably, a unique methylation signature was consistently observed at four key transcription factor binding sites at multiple post-natal time points, indicating a persistent change which may predispose the development of altered neurobehavioural phenotypes that have been described in exposed offspring.