Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses

Oberlander, Tim F.; Weinberg, Joanne; Papsdorf, Michael; Grunau, Ruth E.; Misri, Shaila; Devlin, Angela M.

doi:10.4161/epi.3.2.6034

Cited by 1,279 publications

(1,130 citation statements)

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“…Fourth, information on exposure to trauma prior to treatment was not available for this sample. Traumatic experiences in childhood have been demonstrated to have lasting effects on DNA methylation of both the FKBP5 and GR genes 11, 12, 14, 15, 16, 17. Therefore, we are unable to make any conclusions regarding other environmental factors that may have influenced baseline DNA methylation and subsequent changes in DNA methylation during active treatment.…”

Section: Discussionmentioning

confidence: 86%

“…Studies of early experiences in rats found that DNA methylation of the GR promoter region was altered by maternal care, which in turn was associated with GR expression and HPA responses to stress 12. In humans, stressful life events (e.g., trauma and abuse) have been associated with higher DNA methylation at the GR promoter region13, 14, 15, 16, 17, 18 as well as differential GR expression and biological markers of HPA‐axis activity, such as salivary cortisol 13, 14. Furthermore, GR methylation has been implicated in the development of PTSD following trauma 19.…”

Section: Introductionmentioning

confidence: 99%

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Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

et al. 2015

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BackgroundHypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress‐related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT).MethodsChildren with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response).ResultsTreatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response.ConclusionsAllele‐specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype‐dependent manner.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

et al. 2015

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“…Previous studies have shown that hypermethylation of the NR3C1 gene influences cortisol response, infant behavior and self-regulation. 39,40 Interestingly a recent experimental study demonstrated that exposure to arsenic in utero lowers the activity of the glucocorticoid receptor pathway and these changes were maintained into adolescence of the mouse model. 41 However, further studies are needed to confirm whether these biological findings influence behavioral outcomes.…”

Section: Discussionmentioning

confidence: 99%

Inuteroarsenic exposure and epigenome-wide associations in placenta, umbilical artery, and human umbilical vein endothelial cells

et al. 2015

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Exposure to arsenic early in life has been associated with increased risk of several chronic diseases and is believed to alter epigenetic programming in utero. In the present study, we evaluate the epigenome-wide association of arsenic exposure in utero and DNA methylation in placenta (n D 37), umbilical artery (n D 45) and human umbilical vein endothelial cells (HUVEC) (n D 52) in a birth cohort using the Infinium HumanMethylation450 BeadChip array. Unadjusted and cell mixture adjusted associations for each tissue were examined along with enrichment analyses relative to CpG island location and omnibus permutation tests of association among biological pathways. One CpG in artery (cg26587014) and 4 CpGs in placenta (cg12825509; cg20554753; cg23439277; cg21055948) reached a Bonferroni adjusted level of significance. Several CpGs were differentially methylated in artery and placenta when controlling the false discovery rate (q-value<0.05), but none in HUVEC. Enrichment of hypomethylated CpG islands was observed for artery while hypermethylation of open sea regions were present in placenta relative to prenatal arsenic exposure. The melanogenesis pathway was differentially methylated in artery (Max F P < 0.001), placenta (Max F P < 0.001), and HUVEC (Max F P D 0.02). Similarly, the insulin-signaling pathway was differentially methylated in artery (Max F P D 0.02), placenta (Max F P D 0.02), and HUVEC (Max F P D 0.02). Our results show that prenatal arsenic exposure can alter DNA methylation in artery and placenta but not in HUVEC. Further studies are needed to determine if these alterations in DNA methylation mediate the effect of prenatal arsenic exposure and health outcomes later in life.

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“…We selected candidate genes based on the results of prior work in rodents, primates, and humans, which found that exposure to various psychosocial stressors was associated with DNAm in genes related to stress reactivity, including AVP, 19 BDNF, 20,21 CRF, 22 FKBP5, 23 GR, [24][25][26][27][28][29] OXTR, 30 and SLC6A4, [31][32][33][34] and inflammation, including CD1D, CCL1, F8, IL8, KLRG1, LTA4H, NLRP12, PYDC1, SLAMF7, TLR1, and TLR3. 35 Stress reactivity and inflammation have been hypothesized to mediate the impact of social circumstances on health and are therefore reasonable candidates for investigation of SES effects on DNAm processes.…”

Section: Introductionmentioning

confidence: 99%

Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis

et al. 2015

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y Co-first authors. Keywords: DNA methylation, gene expression, inflammation, socioeconomic status, stress reactivityEpigenetic changes, such as DNA methylation, have been hypothesized to provide a link between the social environment and disease development. The purpose of this study was to examine associations between life course measures of socioeconomic status (SES) and DNA methylation (DNAm) in 18 genes related to stress reactivity and inflammation using a multi-level modeling approach that treats DNAm measurements as repeat measures within an individual. DNAm and gene expression were assessed in purified monocytes for a random subsample of 1,264 nonHispanic white, African-American, and Hispanic participants aged 55-94 from the Multi-Ethnic Study of Atherosclerosis (MESA). After correction for multiple testing, we found that low childhood SES was associated with DNAm in 3 stressrelated genes (AVP, FKBP5, OXTR) and 2 inflammation-related genes (CCL1, CD1D), low adult SES was associated with DNAm in one stress-related gene (AVP) and 5 inflammation-related genes (CD1D, F8, KLRG1, NLRP12, TLR3), and social mobility was associated with DNAm in 3 stress-related genes (AVP, FKBP5, OXTR) and 7 inflammation-related genes (CCL1, CD1D, F8, KLRG1, NLRP12, PYDC1, TLR3). In general, low SES was associated with increased DNAm. Expression data was available for 7 genes that showed a significant relationship between SES and DNAm. In 5 of these 7 genes (CD1D, F8, FKBP5, KLRG1, NLRP12), DNAm was associated with gene expression for at least one transcript, providing evidence of the potential functional consequences of alterations in DNAm related to SES. The results of this study reflect the biological complexity of epigenetic data and underscore the need for multi-disciplinary approaches to study how DNAm may contribute to the social patterning of disease.

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Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses

Abstract: Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.

Cited by 1,279 publications

References 50 publications

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

Inuteroarsenic exposure and epigenome-wide associations in placenta, umbilical artery, and human umbilical vein endothelial cells

Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis

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