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Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain.

Jensen Peña C, Monk C, Champagne FA - PLoS ONE (2012)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Columbia University, New York, New York, United States of America.

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.

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Tissue-specific expression of HSD11B2 and DNMTs in offspring exposed to prenatal stress.Average (mean ± SEM) mRNA levels of (A) HSD11B2, (B) DNMT1, and (C) DNMT3a in hypothalamus (HYPO), cortex, and placenta in control offspring and offspring exposed to prenatal stress. Relative gene expression levels were determined by the 2ddCT method using cyclophilin-A and beta-actin as internal standards. Relative expression was normalized to control (non-stress) cortex samples. (n = 8/group; † p<0.1; *p<0.05, **p<0.01).
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pone-0039791-g002: Tissue-specific expression of HSD11B2 and DNMTs in offspring exposed to prenatal stress.Average (mean ± SEM) mRNA levels of (A) HSD11B2, (B) DNMT1, and (C) DNMT3a in hypothalamus (HYPO), cortex, and placenta in control offspring and offspring exposed to prenatal stress. Relative gene expression levels were determined by the 2ddCT method using cyclophilin-A and beta-actin as internal standards. Relative expression was normalized to control (non-stress) cortex samples. (n = 8/group; † p<0.1; *p<0.05, **p<0.01).

Mentions: Analysis of HSD11B2 gene expression indicated a main effect of tissue (F(2,40) = 15.37, p<.001), a main effect of stress (F(1,40) = 5.46, p<.05), and a significant tissue by stress interaction (F(2,40) = 6.66, p<.01). Overall, there were significantly higher levels of HSD11B2 mRNA in the placenta (p<.01) compared to fetal hypothalamus and cortex (placenta: M = 28.57±7.38; hypothalamus: M = 5.85±.77; cortex: M = 1.13±.17). Prenatal stress was associated with a significant decrease in HSD11B2 mRNA in the placenta (compared to controls, p<.05; Figure 2a) and no group differences in HSD11B2 mRNA were evident in the fetal hypothalamus or cortex. The stress-induced down-regulation of placental 11β-HSD 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. Based on the tissue-specific effects of stress on HSD11B2 gene expression, we proceeded to determine whether there were tissue specific effects of stress on the expression of genes involved in epigenetic regulation of gene expression (DNMT1 and DNMT3a). Overall, levels of DNMT1 mRNA were found to be significantly higher in the placenta compared the fetal hypothalamus and cortex (p<.001) and levels of DNMT3a mRNA were significantly elevated in the hypothalamus compared to the cortex and placenta (p<.001; see Figure 2). Within the hypothalamus, we found a trend for increases in DNMT1 gene expression amongst prenatally stressed offspring (t(14) = −1.79, p = .09). Within the fetal cortex, DNMT1 expression was significantly increased in stressed offspring (t(14) = −2.24, p<.05; Figure 2b). There were no significant effects of stress on DNMT1 expression in the placenta. Analysis of the de novo methyltransferase DNMT3a, indicated a placenta-specific effect of stress on the expression of this enzyme. Prenatal stress was found to be associated with increased placental DNMT3a mRNA levels (t(14) = −3.71, p<.01; Figure 2c).


Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain.

Jensen Peña C, Monk C, Champagne FA - PLoS ONE (2012)

Tissue-specific expression of HSD11B2 and DNMTs in offspring exposed to prenatal stress.Average (mean ± SEM) mRNA levels of (A) HSD11B2, (B) DNMT1, and (C) DNMT3a in hypothalamus (HYPO), cortex, and placenta in control offspring and offspring exposed to prenatal stress. Relative gene expression levels were determined by the 2ddCT method using cyclophilin-A and beta-actin as internal standards. Relative expression was normalized to control (non-stress) cortex samples. (n = 8/group; † p<0.1; *p<0.05, **p<0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3383683&req=5

pone-0039791-g002: Tissue-specific expression of HSD11B2 and DNMTs in offspring exposed to prenatal stress.Average (mean ± SEM) mRNA levels of (A) HSD11B2, (B) DNMT1, and (C) DNMT3a in hypothalamus (HYPO), cortex, and placenta in control offspring and offspring exposed to prenatal stress. Relative gene expression levels were determined by the 2ddCT method using cyclophilin-A and beta-actin as internal standards. Relative expression was normalized to control (non-stress) cortex samples. (n = 8/group; † p<0.1; *p<0.05, **p<0.01).
Mentions: Analysis of HSD11B2 gene expression indicated a main effect of tissue (F(2,40) = 15.37, p<.001), a main effect of stress (F(1,40) = 5.46, p<.05), and a significant tissue by stress interaction (F(2,40) = 6.66, p<.01). Overall, there were significantly higher levels of HSD11B2 mRNA in the placenta (p<.01) compared to fetal hypothalamus and cortex (placenta: M = 28.57±7.38; hypothalamus: M = 5.85±.77; cortex: M = 1.13±.17). Prenatal stress was associated with a significant decrease in HSD11B2 mRNA in the placenta (compared to controls, p<.05; Figure 2a) and no group differences in HSD11B2 mRNA were evident in the fetal hypothalamus or cortex. The stress-induced down-regulation of placental 11β-HSD 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. Based on the tissue-specific effects of stress on HSD11B2 gene expression, we proceeded to determine whether there were tissue specific effects of stress on the expression of genes involved in epigenetic regulation of gene expression (DNMT1 and DNMT3a). Overall, levels of DNMT1 mRNA were found to be significantly higher in the placenta compared the fetal hypothalamus and cortex (p<.001) and levels of DNMT3a mRNA were significantly elevated in the hypothalamus compared to the cortex and placenta (p<.001; see Figure 2). Within the hypothalamus, we found a trend for increases in DNMT1 gene expression amongst prenatally stressed offspring (t(14) = −1.79, p = .09). Within the fetal cortex, DNMT1 expression was significantly increased in stressed offspring (t(14) = −2.24, p<.05; Figure 2b). There were no significant effects of stress on DNMT1 expression in the placenta. Analysis of the de novo methyltransferase DNMT3a, indicated a placenta-specific effect of stress on the expression of this enzyme. Prenatal stress was found to be associated with increased placental DNMT3a mRNA levels (t(14) = −3.71, p<.01; Figure 2c).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Columbia University, New York, New York, United States of America.

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.

Show MeSH
Related in: MedlinePlus