Article

Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta

Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 5.11). 05/2011; 6(5):566-72. DOI: 10.4161/epi.6.5.15236
Source: PubMed

ABSTRACT 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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    • "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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    • "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 · 4.23 Impact Factor
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    • "Methylation status of both coding and non-coding regions of the genome from cord blood is associated with low birthweight (Fryer et al., 2009; Fryer et al., 2011). Gene specific changes in methylation have also been reported in human placenta from SGA infants (Ferreira et al., 2011; Filiberto et al., 2011). Factors which contribute to reduced birthweight, such as maternal stress and depression, have also been associated with gene-specific promoter methylation patterns (Liu et al., 2012; Mulligan et al., 2012). "
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