Methylation changes at<i>NR3C1</i>in newborns associate with maternal prenatal stress exposure and newborn birth weight

Mulligan, Connie J.; D'Errico, Nicole C.; Stees, Jared; Hughes, David A.

doi:10.4161/epi.21180

Cited by 312 publications

(253 citation statements)

References 16 publications

(21 reference statements)

Supporting

Mentioning

230

Contrasting

Unclassified

Order By: Relevance

“…Our findings suggested that maternal PTSD could delay the physical and behavioral development of offsprings, with evidence of lowered body weight and poorer performance in OFT testing, consistent with a previous report (Zhang et al, 2012). Mulligan et al (2012) reported that extreme maternal psychosocial stress stimulation could alter locus-specific epigenetic marks in neonate and found significant correlations among maternal prenatal stress, birth weight, and promoter methylation of the glucocorticoid receptor NR3C1.…”

Section: Discussionsupporting

confidence: 91%

“…A growing body of evidence has suggested that maternal PTSD and other stressors also influence the behavioral development and hormone levels of offsprings (Mulligan et al, 2012). Maternal PTSD contributes to alterations in the stress-induced responsivity of the HPA axis; the transportation and distribution of regulatory neurotransmitters, such as dopamine, acetylcholine, and serotonin; the modification of key limbic structures; and the retardation of intrauterine growth (Kofman, 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

X-G

Zhang

et al. 2016

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Maternal post-traumatic stress disorder (PTSD) increases the risk of adverse neurodevelopmental outcomes in the child. Epigenetic alternations may play an essential role in the negative effects of PTSD. This study was aimed to investigate the possible epigenetic alterations of maternal PTSD, which underpins the developmental and behavioral impact. 24 pregnant Sprague-Dawley (SD) rats were randomly grouped into PTSD and control groups. Open-field tests (OFTs), elevated pull maze (EPM) assays, gene expression profile chip tests, and methylated DNA immunoprecipitation sequencing (MeDIPSeq) were performed on the offsprings 30 days after birth. The results 2 X.G. Zhang et al. Genetics and Molecular Research 15 (3): gmr.15039009 showed that PTSD offsprings had lower body weights and OFT scores than control offsprings. Enzyme-linked immunosorbent assays showed that serotonin receptor (5-HT) and dopamine levels were significantly lower in PTSD offsprings than in control offsprings. In contrast, corticosterone levels were higher in the PTSD group than in the control group. In a comparison of the PTSD group versus the control group, 4,160 significantly differentially methylated loci containing 30,657 CpGs were identified; 2,487 genes, including 13 dysmethylated genes, were validated by gene expression profiling, showing a negative correlation between methylation and gene expression (R = -0.617, P = 0.043). In conclusion, maternal PTSD could delay the physical and behavioral development of offsprings, and the underlying mechanism could contribute to changes in neurotransmitters and gene expression, owing to dysregulation of wholegenome methylation. These findings could support further clinical research on appropriate interventions for maternal PTSD to prevent methylation dysregulation and developmental retardation.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

X-G

Zhang

et al. 2016

Genet. Mol. Res.

View full text Add to dashboard Cite

show abstract

“…Gestational dysregulation of the HPA axis, and of NR3C1 in particular, has been implicated in the pathophysiology of major neurobehavioral disorders. 36 Most studies considering gestational influences for NR3C1 methylation have focused on maternal psychosocial factors, such as depression, 37 stress 5 and trauma 38 during pregnancy, given the potential for such exposures to directly overload and disrupt developing stress-response systems. No human studies have considered the role of neurotoxic metals as similarly disrupting NR3C1, despite the evidence linking prenatal metals exposure to a similar set of at-risk neurobehavioral phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

2017

View full text Add to dashboard Cite

Epigenetic alterations related to prenatal neurotoxic metals exposure may be key in understanding the origins of cognitive and neurobehavioral problems in children. Placental glucocorticoid receptor (NR3C1) methylation has been linked to neurobehavioral risk in early life, but has not been examined in response to neurotoxic metals exposure despite parallel lines of research showing metals exposure and NR3C1 methylation each contribute to a similar set of neurobehavioral phenotypes. Thus, we conducted a study of prenatal neurotoxic metals exposure and placental NR3C1 methylation in a cohort of healthy term singleton pregnancies from Rhode Island, USA (n D 222). Concentrations of arsenic (As; median 0.02 ug/g), cadmium (Cd; median 0.03 mg/g), lead (Pb; median 0.40 mg/g), manganese (Mn; median 0.56 mg/g), mercury (Hg; median 0.02 mg/g), and zinc (Zn; 145.18 mg/g) measured in infant toenails were categorized as tertiles. Multivariable linear regression models tested the independent associations for each metal with NR3C1 methylation, as well as the cumulative risk of exposure to multiple metals simultaneously. Compared to the lowest exposure tertiles, higher levels of As, Cd, Pb, Mn, and Hg were each associated with increased placental NR3C1 methylation (all P<0.02). Coefficients for these associations corresponded with a 0.71-1.41 percent increase in NR3C1 methylation per tertile increase in metals concentrations. For Zn, the lowest exposure tertile compared with the highest tertile was associated with 1.26 percent increase in NR3C1 methylation (PD0.01). Higher cumulative metal risk scores were marginally associated with greater NR3C1 methylation. Taken together, these results indicate that prenatal exposure to neurotoxic metals may affect the offspring's NR3C1 activity, which may help explain cognitive and neurodevelopmental risk later in life.

show abstract

“…For example, DNA methylation levels at the IGF2 gene were reported to be significantly lower in adults who were in utero during the Dutch Hunger Winter Famine (1944Famine ( -1945) when compared to same-sex siblings in utero unexposed to famine (Heijmans et al, 2008). Other candidate gene studies have also reported birth weight related methylation differences in imprinted genes that play a role in fetal growth, such as IGF2 and H19 (Hoyo et al, 2012;Steegers-Theunissen et al, 2009) and in nonimprinted genes such as the glucocorticoid receptor NR3C1 (Filiberto et al, 2011;Mulligan et al, 2012). More recently, epigenome-wide association studies (EWAS) have been performed for birth weight using the Infinium HumanMethylation27 BeadChip (Infinium 27K; Adkins et al, 2012;Banister et al, 2011;Fryer et al, 2011;Straughen et al, 2015) and the Infinium HumanMethylation450 BeadChip (Infinium 450K; Engel et al, 2014;Simpkin et al, 2015) methylation platforms (Illumina Inc, San Diego, CA).…”

mentioning

confidence: 99%

DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

et al. 2015

View full text Add to dashboard Cite

Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to predisposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10 −8 ), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (randomeffects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.

show abstract

Methylation changes atNR3C1in newborns associate with maternal prenatal stress exposure and newborn birth weight

Cited by 312 publications

References 16 publications

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

Contact Info

Product

Resources

About