Epigenetic disruptions in the offspring hypothalamus in response to maternal infection.

DNA methylation is an epigenetic modification that can alter gene expression, and the incidence can vary across developmental stages, inflammatory conditions, and sexes. The effects of viral maternal viral infection and sex on the DNA methylation patterns were studied in the hypothalamus of a pig model of immune activation during development. DNA methylation at single-base resolution in regions of high CpG density was measured on 24 individual hypothalamus samples using reduced representation bisulfite sequencing. Differential over- and under-methylated sites were identified and annotated to proximal genes and corresponding biological processes. A total of 120 sites were differentially methylated (FDR-adjusted p-value < 0.05) between maternal infection or sex groups. Among the 66 sites differentially methylated between groups exposed to inflammatory signals and control, most sites were over-methylated in the challenged group and included sites in the promoter regions of genes SIRT3 and NRBP1. Among the 54 differentially methylated sites between females and males, most sites were over-methylated in females and included sites in the promoter region of genes TNC and EIF4G1. The analysis of the genes proximal to the differentially methylated sites suggested that biological processes potentially impacted include immune response, neuron migration and ensheathment, peptide signaling, adaptive thermogenesis, and tissue development. These results suggest that translational studies should consider that the prolonged effect of maternal infection during gestation may be enacted through epigenetic regulatory mechanisms that may differ between sexes.

Genes Participating in the Ensheathment of Neurons Are Affected by Postnatal Stress and Maternal Immune Activation in the Pituitary Gland.

Immune challenges during gestation are associated with neurodevelopmental disorders and can interact with stress later in life. The pituitary gland participates in endocrine- and immune-related processes that influence development, growth, and reproduction and can modulate physiological and behavioral responses to challenges. The objective of this study was to investigate the effect of stressors at different time points on the molecular mechanisms of the pituitary gland and detect sex differences. RNA sequencing was used to profile the pituitary glands of female and male pigs exposed to weaning stress and virally induced maternal immune activation (MIA), relative to unchallenged groups. Significant effects (FDR-adjusted p-value < 0.05) of MIA and weaning stress were detected in 1829 and 1014 genes, respectively. Of these, 1090 genes presented significant interactions between stressors and sex. The gene ontology biological process of the ensheathment of neurons (GO:0007272), substance abuse, and immuno-related pathways, including the measles disease (ssc05162), encompasses many genes with profiles impacted by MIA and weaning stress. A gene network analysis highlighted the under-expression of myelin protein zero (Mpz) and inhibitors of DNA binding 4 (Id4) among the non-stressed males exposed to MIA, relative to the control and non-MIA males exposed to weaning stress, relative to non-stressed pigs. The detection of changes in the molecular mechanisms of the pituitary gland could advance our understanding of disruptions in the formation of the myelin sheath and the transmission of neuron-to-neuron signals in behavioral disorders associated with maternal immune activation and stress.