Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring

Abstract

The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.

Figure 1. Gestational stress disrupts antepartum maternal behaviour.

Time spent engaged in tail chasing behaviours and the number of rotations performed at 19–18 hours prior to delivery (all data transformed to square root). Gestational stress decreased the time spent in tail chasing activities and the number of rotations, indicating reduced maternal preparatory activity (n = 6 non-stress controls, n = 9 gestational stress). *p≤0.05, mean ± SEM.

Figure 2. Gestational stress induces differential miRNA expression in frontal cortex. A,

Schematic overview of miRNA biogenesis pathways. B, Heat map representation of differentially regulated miRNAs, as observed by microarray analysis. C, Table of target genes for miRNAs modulated by gestational stress (miR-329, miR-380, miR-20a, and miR-500; p≤0.05), and their physiological implications. D, Expression ratio group averages of miRNAs as observed by qRT-PCR analysis (p≤0.05). Note that prenatal stress downregulated miR-181 and miR-186 expression in the frontal cortex. miRNA analyses were performed in dams that showed representative behavioural characteristics (n = 3 per group, three repeats per sample). All data are presented as mean ± SEM.

Figure 3. Prenatal stress modulates the brain miRNAome in male newborn offspring. A,

Heat map representation of differentially regulated miRNA as observed by microarray analyses. B, Table of putative target genes for modulated miRNAs (miR-103, miR-151, and miR-219-2-3p; p≤0.05) and their physiological functions. C, Expression ratio group averages of miRNAs as observed by qRT-PCR analysis (p≤0.05). Whole brains of newborns born to dams shown in Figures 1 and 2 (n = 3 per group, three repeats per sample; 1 pup per dam) were used. All data are presented as mean ± SEM.

Figure 4. Prenatal stress alters the brain transcriptome in male newborn offspring.

A, Differential global gene expression in the brains of prenatally stressed newborn rats. Ptplb and Dazap1 are targets for miR-103 and miR-219, respectively. B, Clustering analysis of gene expression showed clusters of stressed and non-stress animals, except for one non-stressed animal. C, Prenatal stress elevated expression of miR-103, which coincides downregulation of its potential target Ptplb (mean ± SEM). Whole brains of newborns born to dams shown in Figures 1 and 2 were analysed (n = 3 per group, three repeats per sample; 1 pup per dam).