Abstract
Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14–20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.
Highlights
In humans, the experience of stress during pregnancy is associated with increased risk of preterm birth, reduced birth weight, and smaller head circumference [1,2,3] and has been implicated in the heightened risk of metabolic and psychiatric disorders [4,5,6,7]
Prenatal stress was associated with a significant decrease in HSD11B2 mRNA in the placenta and no group differences in HSD11B2 mRNA were evident in the fetal hypothalamus or cortex
The stress-induced down-regulation of placental 11bHSD was specific to HSD11B2 as analysis of HSD11B1 mRNA levels indicated no significant effects of stress and no stress by tissue type interactions on the expression of this gene
Summary
The experience of stress during pregnancy is associated with increased risk of preterm birth, reduced birth weight, and smaller head circumference [1,2,3] and has been implicated in the heightened risk of metabolic and psychiatric disorders [4,5,6,7]. Pharmacological inhibition of 11ß–HSD2 during pregnancy or administration of dexamethasone, a synthetic glucocorticoid that is not metabolized by 11ß–HSD2, leads to molecular and neurobiological changes within the HPA axis associated with increased stress responsivity and anxiety-like behavior in adulthood [22,23] These glucocorticoid programming effects may be evident in humans, consequent to prenatal betamethasone exposure or inhibition of 11ß–HSD2 through elevated glycyrrhizin consumption during pregnancy [24,25]. These studies suggest that the regulation of placental 11ß–HSD2 levels may be a mechanistic link between the experience of maternal gestational stress and long-term health outcomes in offspring
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