Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS ONE 5, e12201

Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver, Canada.
PLoS ONE (Impact Factor: 3.23). 08/2010; 5(8):e12201. DOI: 10.1371/journal.pone.0012201
Source: PubMed


Prenatal and early postnatal exposure to maternal depression may "program" childhood behavior via epigenetic processes such as DNA methylation. Methylenetetrahydro-folate reductase (MTHFR) is an important enzyme in the generation of methyl groups for DNA methylation. The common MTHFR C677T variant is associated with depression in men and non-pregnant women, and with global changes in DNA methylation. This study investigated the effect of maternal MTHFR C677T genotype on antenatal maternal mood, and their impact on the gene-specific methylation in pregnant women and their newborn infants. The methylation status of SLC6A4, which encodes the transmembrane serotonin transporter, and BDNF, which encodes brain derived neurotrophic factor, were assessed because of their potential role in behaviour.
Depressed mood was assessed by the Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale for Depression (HAM-D) in women (n = 82, all taking folate) during the 2(nd) and 3(rd) trimesters of pregnancy. The methylation status of SLC6A4 and BDNF were assessed in 3rd trimester maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth. Women with the MTHFR 677TT genotype had greater 2(nd) trimester depressed mood (p<0.05). Increased 2(nd) trimester maternal depressed mood (EPDS scores) was associated with decreased maternal and infant SLC6A4 promoter methylation (p<0.05), but had no effect on BDNF promoter methylation.
These findings show that the MTHFR C677T variant is associated with greater depressed mood during pregnancy. We further showed that prenatal exposure to maternal depressed mood affects gene-specific DNA methylation patterns. These findings support the concept that alterations in epigenetic processes may contribute to developmental programming of behaviour by maternal depression.

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    • "| assessed the association between levels of pain - related stress and SLC6A4 methylation status at NICU discharge in VPT infants , no specific hypotheses were formulated . Nonetheless , consis - tently with previous literature on epigenetic correlates of early adverse experiences in infancy ( Devlin et al . , 2010 ) , we specu - lated that infants exposed to higher pain - related stress would exhibit greater changes in SLC6A4 methylation . Furthermore , given that SLC6A4 methylation variations were expected to be associated with pain - related stress , we hypothesized no difference in methylation status at birth between VPT and full - term infant"
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    ABSTRACT: Very preterm (VPT) infants need long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU) during which they are daily exposed to pain-related stress. Alterations of DNA methylation at the promoter region of the SLC6A4 have been associated with early adverse experiences in infants. The main aim of the present work was to investigate the association between level of exposure to pain-related stress during hospitalization and changes in SLC6A4 DNA methylation at NICU discharge in VPT infants. In order to exclude the potential effect of birth status (i.e., preterm vs. full-term birth) on SLC6A4 methylation, we preliminarily assessed SLC6A4 epigenetic differences between VPT and full-term (FT) infants at birth. Fifty-six VPT and thirty-two FT infants participated in the study. The level of exposure to pain-related stress was quantified on the basis of the amount of skin-breaking procedures to which they were exposed. VPT infants were divided in two subgroups: low-pain exposure (LPE, N = 25) and high-pain exposure (HPE, N = 31). DNA methylation was evaluated at birth for both VPT and FT infants, assessing 20 CpG sites within the SLC6A4 promoter region. The same CpG sites were re-evaluated for variations in DNA methylation at NICU discharge in LPE and HPE VPT infants. No differences in SLC6A4 CpG sites' methylation emerged between FT and VPT infants at birth. Methylation at CpG sites 5 and 6 significantly increased from birth to NICU discharge only for HPE VPT infants. Findings show that preterm birth per se is not associated with epigenetic alterations of the SLC6A4, whereas higher levels of pain-related stress exposure during NICU stay might alter the transcriptional functionality of the serotonin transporter gene.
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    • "This region of the SLC6A4 promoter has been reported to be differentially methylated and associated with changes in SLC6A4 mRNA expression (Philibert et al., 2007, 2008; Devlin et al., 2010). Briefly, we have analyzed a region of the SLC6A4 promoter between −479 and −350, relative to the transcriptional start site, which contains 10 CpG sites and is adjacent to exon 1a (Devlin et al., 2010). Genomic DNA was bisulfite-treated using the EZ DNA Methylation Gold Kit (Zymo Research) following the manufacturer's instructions and stored at −20 • C until further analyzed. "
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    ABSTRACT: Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter. We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behavior problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype) (p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children at 7 years (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population.
    Full-text · Article · Dec 2014 · Frontiers in Behavioral Neuroscience
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    • "In the study by Devlin et al. (2010), the exposure to maternal depressed mood during the second trimester of gestational development was shown to be associated with decreased levels of methylation in promoter of SLC6A4 gene, encoding the serotonin transporter, in maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth, while no such effects on BDNF gene have been revealed (Devlin et al., 2010). Radtke et al. (2011) also demonstrated that mother's experience of intimate partner violence "
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    ABSTRACT: Background: A substantial body of experimental and epidemiological evidence has been accumulated suggesting that stressful events in early life including acute perinatal stress, maternal deprivation or separation, and variation in maternal care may lead to neuroendocrine perturbations thereby affecting reproductive performance, cognitive functions, and stress responses as well as the risk for infectious, cardio-metabolic and psychiatric diseases in later life. Results: Findings from recent studies based on both genome-wide and candidate gene approaches highlighted the importance of mechanisms that are involved in epigenetic regulation of gene expression, such as DNA methylation, histone modifications, and non-coding RNAs, in the long-term effects of exposure to stress in early life. Conclusions: This review is focused on the findings from human studies indicating the role of epigenetic mechanisms in the causal link between early-life stress and later-life health outcomes.
    Full-text · Article · Oct 2014 · Developmental Dynamics
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