Maternal stress has been linked to low birth weight in newborns. One potential pathway involves epigenetic changes at candidate genes that may mediate the effects of prenatal maternal stress on birth weight. This relationship has been documented in stress-related genes, such as NR3C1 . There is less literature exploring the effect of stress on growth-related genes. IGF1 and IGF2 have been implicated in fetal growth and development, though via different mechanisms as IGF2 is under imprinting control. In this study, we tested for associations between prenatal stress, methylation of IGF1 and IGF2 , and birth weight. A total of 24 mother–newborn dyads in the Democratic Republic of Congo were enrolled. Ethnographic interviews were conducted with mothers at delivery to gather culturally relevant war-related and chronic stressors. DNA methylation data were generated from maternal venous, cord blood and placental tissue samples. Multivariate regressions were used to test for associations between stress measures, DNA methylation and birth weight in each of the three tissue types. We found an association between IGF2 methylation in maternal blood and birth weight. Previous literature on the relationship between IGF2 methylation and birth weight has focused on methylation at known differentially methylated regions in cord blood or placental samples. Our findings indicate there may be links between the maternal epigenome and low birth weight that rely on mechanisms outside known imprinting pathways. It thus may be important to consider the effect of maternal exposures and epigenetic profiles on birth weight even in the setting of maternally imprinted genes such as IGF2 .
more »
« less
Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birth Weight Identified by Investigating Methylation at Individual, Regional, and Genome Levels
Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood (n = 24 and 22, respectively) were assayed for methylation at ∼450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures using genome-wide mean methylation (GMM), Horvath's epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight (p < 1.95 × 10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction. However, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p = 1.95 × 10-7 and 8.3 × 10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p = 0.025) and was suggestively associated with sexual violence (p = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM.
more »
« less
- Award ID(s):
- 1719866
- NSF-PAR ID:
- 10229607
- Date Published:
- Journal Name:
- Human biology
- Volume:
- 91
- Issue:
- 2
- ISSN:
- 0018-7143
- Page Range / eLocation ID:
- 117-131
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
The field of social and behavioral epigenetics examines how social and behavioral experiences can cause epigenetically-driven changes in gene expression that in turn influence health and well-being. We work in the eastern Democratic Republic of Congo, where 20 years of conflict and post-conflict violence have subjected women to extreme stress and sexual violence. We collected blood samples from mothers and their offspring at birth, plus follow-up samples from offspring up to five years of age, in three cohorts (2010 cohort, n=25; 2013 cohort , n=103, 2015 cohort, n=77). Using DNA extracted from blood and placental samples, we assayed methylation using Illumina’s 450K and EPIC chips, telomere length, and gene expression using the ClariomS chip. We also collected ethnographic and survey data on maternal stress, newborn health outcomes, and cortisol from offspring saliva and hair samples. Using these data, we tested for associations among maternal stress, DNA methylation, gene expression, and offspring health outcomes. We find that epigenetic aging is accelerated in mothers relative to chronological age, but newborn epigenetic age appears unchanged. In contrast, telomere length is significantly shorter in offspring born to mothers with high levels of war stress, but this effect only emerges after birth. Analyses of epigenome and gene expression data are ongoing. Our study takes a biocultural perspective to understand the molecular, biological, and health effects of stress and violence, particularly from an intergenerational perspective.more » « less
-
more » « less
Abstract Objectives Maternal stress has long been associated with lower birthweight, which is associated with adverse health outcomes including many adult diseases. The underlying mechanisms remain elusive although changes in gene expression may play a role. Studies are only beginning to test how maternal stress impacts gene expression as reflected in the transcriptome.
Materials and Methods In a cohort of mothers and newborns in the eastern Democratic Republic of Congo (
n = 93), we studied the effects of four maternal stress measures (chronic stress, war trauma, sexual trauma, and general trauma) on the transcriptomes of maternal venous blood, newborn venous blood, and placental tissues, and on newborn birthweight. Maternal stress was investigated as independent measures, principal components, and clusters identified through machine learning. The transcriptome was assayed using the ClariomD chip. Multiple regression models were used to test for associations between maternal stress measures, the transcriptome, and newborn birthweight.Results None of the maternal stress measures showed an association with the expression of individual genes. In contrast, when testing global gene expression, war trauma was significantly associated with the placental transcriptome. War trauma was also significantly associated with birthweight in multiple models. Mediation analysis indicated that ~14% of the effect of war trauma on birthweight was mediated by a placental gene expression component.
Discussion Our results suggest that gene expression in the placenta, which represents the interface between mother and developing fetus, may partially mediate the negative impact of maternal stress on newborn birthweight.
-
more » « less
Abstract Objectives Candidate gene methylation studies of NR3C1 have identified associations with psychosocial adversity, including war trauma. This pilot study (sample sizes from 22 to 45 for primary analyses) examined NR3C1 methylation in a group of Kenyan pastoralist young men in relation to culturally relevant traumatic experiences, including participation in coalitional lethal gun violence.
Methods Adolescent and young adult Samburu men (“warriors”) were recruited for participation. DNA was obtained from whole saliva and methylation analyses performed using mass spectrometry. We performed a data reduction of variables from a standardized instrument of lifetime stress using a factor analysis and we assessed the association between the extracted factors with culturally relevant and cross‐culturally comparative experiences.
Results Cumulative lifetime trauma exposure and forms of violence to which warriors are particularly susceptible were associated with DNA methylation changes in the NR3C1 1Fpromoter region but not in the NR3C1 1Dpromoter region. However, sensitivity analyses revealed significant associations between individual CpG sites in both regions and cumulative stress exposures, war exposure timing, and war fatalities.
Conclusions This study supports the importance of NR3C1 methylation changes in response to challenging life circumstances, including in a global south cultural context that contrasts in notable ways from global north contexts and from the starkly tragic examples of the Rwandan genocide and war‐associated rape explored in recent studies. Timing of traumatic exposure and culturally salient means to measure enduring symptoms of trauma remain important considerations for DNA methylation studies.
-
more » « less
Abstract Background Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA.
Results Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA
r = 0.82,p < 0.001). Horvath and skin & blood EA were weakly correlated with gestational age, but moderately correlated with chronological age in childhood (r = 0.45–0.65). Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [B (95% CI) = 1.17 weeks (− 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [− 0.17 weeks (− 0.30, − 0.04)] and Horvath EAA at birth [B (95% CI) = − 2.88 weeks (− 4.41, − 1.35)] and in childhood [early childhood: − 0.3 years (− 0.60, 0.01); mid-childhood: − 0.48 years (− 0.77, − 0.18)] than males. When comparing self-reported Asian, Black, Hispanic, and more than one race or other racial/ethnic groups to White, we identified significant differences in EGAA and EAA at birth and in mid-childhood, but associations varied across clocks. Horvath EA at birth was positively associated with childhood Horvath and skin & blood EAA.Conclusions Maternal smoking during pregnancy and child sex were associated with EGAA and EAA at multiple timepoints. Further research may provide insight into the relationship between perinatal factors, pediatric epigenetic aging, and health and development across the lifespan.
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.13110
