Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis

Abstract

Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05-0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.

Keywords: DNA methylation; HPA axis; NR3C1 gene; epigenetics; glucocorticoid receptor; maternal stress.

Figure 1.

Flowchart of study selection and inclusion of results. Data from 7 papers were included in the meta-analysis.

Figure 2.

CpG site distribution and overlap among included papers in the meta-analysis. Research groups focused on distinct regions of promoter and exon 1_F. Six out of the 7 papers included in the meta-analysis assessed the DNA methylation of a small cluster of CpG sites located immediately preceding exon 1_F, from 35 to 39; additionally, Murgatroyd et al. limited their analyses to CpG sites 35 and 36 as they had been already pointed out as informative in the previous papers. The whole sequence of this region is displayed in Figure 3.

Figure 3.

Exon 1_F (NR3C1 gene) structure. Exon is underlined. All CpG sites (CG) are numbered, remarked in bold and capital letters. Reviewed CpG sites herein (35 to 39) are highlighted in dark red.

Figure 4.

Results of meta-analyses of prenatal stress exposure influence on methylation of the CpG sites 35 to 39. From left to right, displayed variables consist of: study, sample size (n), a graphical representation of the computed correlations, correlation values between methylation and the assessed prenatal stress variable, their corresponding confidence intervals and the weight of each study in the meta-analysis as determined by a random effects model.