Prenatal Glucocorticoid Exposure Results in Changes in Gene Transcription and DNA Methylation in the Female Juvenile Guinea Pig Hippocampus Across Three Generations

Andrea Constantinof,Lisa Boureau,Stephen G Matthews,Vasilis G Moisiadis,Moshe Szyf,Alisa Kostaki

doi:10.1038/s41598-019-54456-9

Abstract

Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery, to mature the fetal lung and decrease neonatal morbidity. sGC also profoundly affect the fetal brain. The hippocampus expresses high levels of glucocorticoid (GR) and mineralocorticoid receptor (MR), and its development is affected by elevated fetal glucocorticoid levels. Antenatal sGC results in neuroendocrine and behavioral changes that persist in three generations of female guinea pig offspring of the paternal lineage. We hypothesized that antenatal sGC results in transgenerational changes in gene expression that correlate with changes in DNA methylation. We used RNASeq and capture probe bisulfite sequencing to investigate the transcriptomic and epigenomic effects of antenatal sGC exposure in the hippocampus of three generations of juvenile female offspring from the paternal lineage. Antenatal sGC exposure (F0 pregnancy) resulted in generation-specific changes in hippocampal gene transcription and DNA methylation. Significant changes in individual CpG methylation occurred in RNApol II binding regions of small non-coding RNA (snRNA) genes, which implicates alternative splicing as a mechanism involved in transgenerational transmission of the effects of antenatal sGC. This study provides novel perspectives on the mechanisms involved in transgenerational transmission and highlights the importance of human studies to determine the longer-term effects of antenatal sGC on hippocampal-related function.

Highlights

Fetal plasma glucocorticoid is maintained at low levels through the majority of pregnancy; there is a natural ‘surge’ in fetal glucocorticoid levels at the end of gestation in most mammalian species
We have recently shown that antenatal synthetic glucocorticoids (sGC) exposure results in transgenerational changes in behavior and gene expression in the paraventricular nucleus (PVN) of the hypothalamus and medial prefrontal cortex (PFC)[21,26], transgenerational epigenetic signatures of exposure have yet to be investigated
This study demonstrates transgenerational changes in transcription and DNA methylation following antenatal sGC exposure over the paternal lineage

Summary

Introduction

Fetal plasma glucocorticoid is maintained at low levels through the majority of pregnancy; there is a natural ‘surge’ in fetal glucocorticoid levels at the end of gestation in most mammalian species. This surge is important for maturation of fetal organs, including the lung, kidney and brain[17]. The fetus can be exposed to synthetic glucocorticoids (sGC), which are administered to pregnant women at risk for pre-term delivery (~11% of all pregnancies). This treatment promotes lung maturation and reduces morbidity and mortality associated with respiratory distress syndrome in preterm infants[20]. Several studies have demonstrated that exposure of the fetus to high levels of glucocorticoid, prior to the natural glucocorticoid surge, can lead to long-term programming effects on neurocognitive, behavioural, endocrine, and cardiometabolic function[5,8,17,21,22,23]

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Conclusion