Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta. [Research Support, N.I.H., Extramural]

Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 05/2011; 6(5):566-72. DOI: 10.4161/epi.6.5.15236
Source: PubMed


Birthweight has been associated with a number of health outcomes throughout life. Crucial to proper infant growth and development is the placenta, and alterations to placental gene function may reflect differences in the intrauterine environment which functionally contribute to infant growth and may ultimately affect the child's health. To examine if epigenetic alteration to the glucocorticoid receptor (GR) gene was linked to infant growth, we analyzed 480 human placentas for differential methylation of the GR gene exon 1F and examined how this variation in methylation extent was associated with fetal growth. Multivariable linear regression revealed a significant association (p < 0.0001) between differential methylation of the GR gene and large for gestational age (LGA) status. Our work is one of the first to link infant growth as a measure of the intrauterine environment and epigenetic alterations to the GR and suggests that DNA methylation may be a critical determinant of placental function.

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    • "Although SEPP1 is expressed and active in the placenta (Kasik and Rice 1995), there have been no examinations of SEPP1 methylation or its relationship to Hg in the placenta. The placenta is active during development, and variation in placental methylation at various genes has been associated with fetal growth and development and neuro behavior (Banister et al. 2011; Bromer et al. 2012; Filiberto et al. 2011; Marsit et al. 2012a, 2012b; Wilhelm-Benartzi et al. 2012). Thus, Hg-associated placental alterations may mediate exposure-associated neurobehavioral outcomes, even at exposure levels commonly identified in the population. "
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    ABSTRACT: Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. As Hg can interfere with placental functioning, and cross the placenta to target fetal brain, prenatal Hg exposure can negatively impact fetal growth and development directly and indirectly. To examine potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes. The methylation status of >485,000 CpG loci was interrogated in 192 placental samples using Illumina's Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants. 339 loci were identified with an average methylation difference >0.125 between any two toenail Hg tertiles. Variation amongst these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value=0.007) characterized by the NNNS. Ten loci had p<0.01 for the association between methylation and the high-risk NNNS profile. Six of ten loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants' placentas. Methylation at these loci was moderately correlated (correlation coefficients range -0.33 to -0.45) with EMID2 expression. EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes.
    Environmental Health Perspectives 03/2015; 123(7). DOI:10.1289/ehp.1408561 · 7.98 Impact Factor
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    • "Because certain classes of epigenetic marks, notably DNA and histone methylation, are stably maintained in mitotic and postmitotic cells, this " environmental epigenetic " hypothesis provides a candidate mechanism for the enduring influences of the social environment on neurodevelopment and mental health (Bateson et al., 2004; Feil & Fraga, 2011; Jirtle & Skinner, 2007; Meaney & Ferguson-Smith, 2010; Zhang & Meaney, 2010). Support for this hypothesis is derived from studies of the methylation of a glucocorticoid receptor gene promoter that reveal stable associations between levels of DNA methylation and both pre-and postnatal adversity (Bromer , Marsit, Armstrong, Padbury, & Lester, 2013; Filiberto et al., 2011; Hompes et al., 2013; Labonte et al., 2012; Mc- Gowan et al., 2009; Mulligan, D'Errico, Stees, & Hughes, 2012; Oberlander et al., 2008; Perroud et al., 2011, 2014; Radtke et al., 2011; Steiger, Labonte, Groleau, Turecki, & Israel , 2013; Tyrka, Price, Marsit, Walters, & Carpenter, 2012). These findings emerge from studies using cells obtained from blood sampling as well as those involving postmortem human hippocampus, suggesting that environmental influences on epigenetic states of at least certain genomic regions are apparent across multiple tissues. "
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    ABSTRACT: Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.
    Development and Psychopathology 02/2015; 27(1):137-50. DOI:10.1017/S0954579414001357 · 4.89 Impact Factor
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    • "In the light of this hypothesis, Mulligan et al. (Mulligan et al. 2012) recently showed that extreme maternal psychosocial stressors, as observed in the Democratic Republic of Congo, modifi ed locus specifi c epigenetic marks in the newborn resulting in altered health outcomes. If the in utero environment appears to be an important factor related to alteration of methylation of NR3C1 in newborns and appears to mediate neurobehavioral measures assessed at birth (Oberlander et al. 2008; Filiberto et al. 2012; Bromer et al. 2013), the impact of these altered methylation processes on later neurobehavioral outcomes remains poorly addressed. "
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    ABSTRACT: Objectives. Transmission of parental post-traumatic stress disorder (PTSD) to offspring might be explained by transmission of epigenetic processes such as methylation status of the glucocorticoid receptor (GR) gene (NR3C1). Methods. We investigated PTSD and depression severity, plasma cortisol, GR and mineralocorticoid receptor (MR) levels, and methylation status of NR3C1 and NR3C2 promoter regions in 25 women exposed to the Tutsi genocide during pregnancy and their children, and 25 women from the same ethnicity, pregnant during the same period but not exposed to the genocide, and their children. Results. Transmission of PTSD to the offspring was associated with transmission of biological alterations of the HPA axis. Mothers exposed to the genocide as well as their children had lower cortisol and GR levels and higher MR levels than non-exposed mothers and their children. Moreover, exposed mothers and their children had higher methylation of the NR3C1 exon 1F than non-exposed groups. Finally, exposed mothers showed higher methylation of CpGs located within the NR3C2 coding sequence than non-exposed mothers. Conclusions. PTSD was associated with NR3C1 epigenetic modifications that were similarly found in the mothers and their offspring, modifications that may underlie the possible transmission of biological alterations of the HPA axis.
    The World Journal of Biological Psychiatry 04/2014; 15(4). DOI:10.3109/15622975.2013.866693 · 4.18 Impact Factor
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