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1. Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birth Weight Identified by Investigating Methylation at Individual, Regional, and Genome Levels

   https://doi.org/10.13110  

   Clukay, Chris J ; Hughes, David A ; Kertes, Darlene A ; Mulligan, Connie J ( April 2019 , Human biology)

   null (Ed.)

   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. 

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2. DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort

   https://doi.org/10.1186/s13148-023-01480-2  

   Bozack, Anne K. ; Rifas-Shiman, Sheryl L. ; Gold, Diane R. ; Laubach, Zachary M. ; Perng, Wei ; Hivert, Marie-France ; Cardenas, Andres ( December 2023 , Clinical Epigenetics)

   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.

   Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGAr = 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.

   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.

    

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3. Epigenetics, gene expression, and stress in mothers and offspring in the Democratic Republic of Congo: A biocultural investigation of the intergenerational effects of stress

   Mulligan CJ, Maisha FM ( January 2019 , American journal of physical anthropology)

   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. 

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4. Maternal distress, DNA methylation, and fetal programing of stress physiology in Brazilian mother–infant pairs

   https://doi.org/10.1002/dev.22352  

   Wiley, Kyle S. ; Camilo, Caroline ; Gouveia, Gisele ; Euclydes, Verônica ; Panter‐Brick, Catherine ; Matijasevich, Alicia ; Ferraro, Alexandre Archanjo ; Fracolli, Lislaine Aparecida ; Chiesa, Anna Maria ; Miguel, Euripedes Constantino ; et al ( December 2022 , Developmental Psychobiology)

   Maternal prenatal psychosocial stress is associated with adverse hypothalamic–pituitary–adrenal axis (HPAA) function among infants. Although the biological mechanisms influencing this process remain unknown, altered DNA methylation is considered to be one potential mechanism. We investigated associations between maternal prenatal psychological distress, infant salivary DNA methylation, and stress physiology at 12 months. Mother's distress was measured via depression and anxiety in early and late pregnancy in a cohort of 80 pregnant adolescents. Maternal hair cortisol was collected during pregnancy. Saliva samples were collected from infants at 12 months to quantify DNA methylation of three stress‐related genes (FKBP5,NR3C1,OXTR) (n = 62) and diurnal cortisol (n = 29). Multivariable linear regression was used to test for associations between prenatal psychological distress, and infant DNA methylation and cortisol. Hair cortisol concentrations in late pregnancy were negatively associated with two sites ofFKBP5(site 1:B = −22.33,p = .003; site 2:B = −15.60,p = .012). Infants of mothers with elevated anxiety symptoms in late pregnancy had lower levels ofOXTR2CpG2 methylation (B = −2.17,p = .03) and higher evening salivary cortisol (B = 0.41,p = .03). Furthermore,OXTR2methylation was inversely associated with evening cortisol (B = −0.14,p‐value ≤ .001). Our results are, to our knowledge, the first evidence that the methylation of the oxytocin receptor may contribute to the regulation of HPAA during infancy.

    

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5. Maternal epigenetic clocks measured during pregnancy do not predict gestational age at delivery or offspring birth outcomes: a replication study in metropolitan Cebu, Philippines

   https://doi.org/10.1186/s13148-022-01296-6  

   Ryan, Calen P. ; Rege, Raviraj J. ; Lee, Nanette R. ; Carba, Delia B. ; Kobor, Michael S. ; MacIsaac, Julie L. ; Lin, David S. ; Atashzay, Parmida ; Kuzawa, Christopher W. ( June 2022 , Clinical Epigenetics)

   Adverse birth outcomes, such as early gestational age and low birth weight, can have lasting effects on morbidity and mortality, with impacts that persist into adulthood. Identifying the maternal factors that contribute to adverse birth outcomes in the next generation is thus a priority. Epigenetic clocks, which have emerged as powerful tools for quantifying biological aging and various dimensions of physiological dysregulation, hold promise for clarifying relationships between maternal biology and infant health, including the maternal factors or states that predict birth outcomes. Nevertheless, studies exploring the relationship between maternal epigenetic age and birth outcomes remain few. Here, we attempt to replicate a series of analyses previously reported in a US-based sample, using a larger similarly aged sample (n = 296) of participants of a long-running study in the Philippines. New pregnancies were identified prospectively, dried blood spot samples were collected during the third trimester, and information was obtained on gestational age at delivery and offspring weight after birth. Genome-wide DNA methylation was assessed with the Infinium EPIC array. Using a suite of 15 epigenetic clocks, we only found one significant relationship: advanced age on the epigenetic clock trained on leptin predicted a significantly earlier gestational age at delivery (β = − 0.15,p = 0.009). Of the other 29 relationships tested predicting gestational age and offspring birth weight, none were statistically significant. In this sample of Filipino women, epigenetic clocks capturing multiple dimensions of biology and health do not predict birth outcomes in offspring.

    

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