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according to the developmental origins of health and disease ( dohad ) hypothesis , events in early development are directly related to disease risk in later life .
the rationale is that fetal tissues are especially sensitive to the intrauterine environment , which results in selection of an optimal fetal phenotype .
if the intrauterine environment is unusually limiting or unrepresentative of the environment in later life , the selected phenotype may be maladaptive in the adult and result in increased risk for a number of diseases . in recent years
, the role of epigenetically determined changes in gene expression during early development has emerged as a possible mechanism by which the most adaptive phenotype is expressed .
early life stress is associated with poor stress adaptation , elevated disease risk and mortality in later life .
glucocorticoids ( gcs ) are associated with stress responses and have been proposed as a primary candidate for fetal programming in part because elevated gc levels during pregnancy are correlated with low birth weight .
specifically , experimental and clinical data in humans and animal models demonstrate that both prenatal stress and prenatal overexposure to gcs are associated with reduced birth weight , possibly via related actions in a shared pathway such as feeding behavior . 

nr3c1 is the gc receptor and is involved in cell proliferation and differentiation and specifically implicated in newborn birth weight , thus providing a biological mechanism by which nr3c1 expression may influence birth weight .
the current study tests the hypothesis that maternal prenatal stress may result in epigenetic changes at nr3c1 in newborns that are related to birth outcomes ( fig .  1 ) .
we measure the effects of maternal stress on newborn birth weight and investigate if any observed correlation is associated with epigenetic modifications at the newborn nr3c1 .
specifically , we assay methylation status at 39 cpg sites in the upstream promoter of nr3c1 , the same region that has been associated with changes in methylation and/or gene expression correlated with childhood abuse - related suicide , prenatal exposure to intimate partner violence and post - traumatic stress disorder . figure  1 . proposed relationship of environmental stress influencing a phenotype via an epigenetic mechanism that alters gene expression .
in the current study , we developed three models of maternal prenatal stress ; specifically , material deprivation intended to reflect availability of financial resources , mundane stressors to reflect daily psychosocial stress , and war stress to measure the influence of war - related events ( see table s1 for a list of questions associated with each maternal stressor ) .
we find a strong correlation between each maternal stressor and our birth outcome phenotype of newborn birth weight ( fig .  2 ) .
war stress has the largest effect and accounts for a notable 35% of the variance in birth weight ( fig . 
2c , pearson s correlation = -0.62 , p = 0.0009 ) . within the war stress variables , personal experience of rape ( past rape , rape resulting in pregnancy , rape during pregnancy )
accounts for 31% of birth weight variance and eclipses the effect of other war stressors ( refugee status , family member killed , past kidnapping , parents or self a result of rape ) , which can then account for only an additional 4% of the variance in birth weight .
this association between maternal stress and newborn birth weight provides the foundation upon which to test a possible epigenetic mechanism that mediates the stressful effects of the intrauterine environment to the newborn ( fig .  1 ) .
pearson s correlation , associated p value and percent explained variation in birth weight are reported in each figure for each maternal stressor .
preterm birth is associated with both the predictor maternal stressor variables and the outcome birth weight variable .
since our data include only three preterm births and since preterm birth is involved as both predictor and outcome , we focus on maternal stressors and birth weight . for the methylation data , we performed a principal component analysis ( pca ) of the percent methylation at all 39 cpg sites .
this method allows the identification of independent components that explain observed , complex variation from across the entire data set and may reflect different environmental , genetic or biological influences on methylation .
each principle component is driven by variation at a subset of the data allowing the creation of a data driven summary statistic as opposed to testing each site separately or devising a simple summary statistic .
our methylation results reveal several important aspects of methylation profiles and mother - to - newborn transmission of epigenetic information .
first , we find no identically methylated sequences between mothers and their newborns , implying that all maternal methylation marks at the nr3c1 promoter have been removed from the newborn s genomes and new marks generated .
lack of identical methylation marks between mother and newborn suggests that methylation marks are not strongly genetically determined at this locus and , thus , may be more susceptible to environmental influences , perhaps providing the nr3c1 gene with an increased capacity for rapid change and adaptation .
second , previous studies have shown a high degree of tissue specificity in methylation profiles , e.g. , between blood and soft tissue samples .
however , our pca of methylation profiles reveals no separation of mother and newborn samples ( fig . 
3 ) , suggesting that maternal venous blood and umbilical cord blood do not display tissue - specific methylation marks at nr3c1 .
thus , differences between maternal and newborn samples are unlikely to be due to tissue specificity .
the first principal component ( pc1 ) of maternal and newborn samples is plotted with pc2 , 3 , 4 and 5 in four graphs .
mothers are indicated by triangles and newborns are indicated by squares . with respect to testing the effect of stress on methylation patterns ,
we see differences in correlation of the nr3c1 methylation data and maternal stressor , but only when mothers and newborns are analyzed separately ( fig .  4 ) .
we see the strongest correlation between war stress and newborn methylation ( when analyzed as the first principal component , i.e. , pc1 ; figure  4a , p = 0.0032 ) .
furthermore , newborn methylation - pc1 is strongly correlated with newborn birth weight ( fig . 
4b , p = 0.024 ) , thus completing the cycle from stress to methylation to phenotype / birth weight outlined in figure  1 .
all three maternal stressors are significantly correlated with each other ( table s2 ) ; consequently , material deprivation and mundane stress are also correlated with newborn methylation - pc1 ( fig .
s1 ; significant correlation of newborn methylation - pc1 with war stress and material deprivation ) .
an exploratory factor analysis was performed to determine which cpg sites are correlated with pc1 and cpg sites 25 , 20 , 23 , 10 , 21 and 24 were each found to have an additive effect ( with loadings of 0.998 , 0.652 , 0.560 , 0.344 , 0.292 and 0.192 , respectively ) .
newborn ( a and b ) and maternal ( c and d ) methylation were analyzed in a principal components analysis ( pca ) and correlation of the first principal component ( pc1 ) with maternal war stress ( a and c ) and newborn birth weight ( b and d ) is shown here .
only newborn methylation - pc1 shows significant correlation with war stress and newborn birth weight .
plot abbreviations are as follows : pc1 var exp = amount of variance in methylation - pc1 explained by war stress ; total var exp = total amount of methylation variance explained by war stress ; bw var exp = amount of variance in birth weight explained by methylation - pc1 .
in contrast to the results with newborn methylation , no correlation is seen between maternal methylation and stress or newborn birth weight ( figs . 
a correlation with newborn methylation , but not maternal methylation , is consistent with the tenets of the dohad hypothesis in which maternal stress modifies offspring biology .
moreover , methylation marks are determined by a combination of environmental , genetic and biological factors , thus a pca may be necessary to separate the various factors that influence methylation .
we see no correlation of newborn methylation with maternal stress or newborn birth weight when total methylation is analyzed , consistent with the idea that multiple factors determine methylation and these factors must be separated in order to evaluate their individual effects .
we also see no correlation of newborn methylation pc2 , 3 or 4 with maternal stress or newborn birth weight suggesting that pc1 may be particularly influenced by , and mediating the effects of , maternal stress . increased methylation that occurs in response to in utero stress may constrain plasticity in expression at stress - related genes in later life and thus restrict the range of stress adaptation responses possible in the affected individuals .
limited stress adaptations may , in turn , increase an individual s risk of developing chronic complex disorders later in life .
kinnally et al . found that increased methylation ( genome - wide and gene - specific ) interacted with early life stress in macaques to predict higher stress reactivity .
specifically , at - risk individuals showed enhanced reactivity to higher intensity stressors , which may be the most comparable factor to stress - related disorders in humans .
it has been shown that glucocorticoid receptors ( grs ) and mineralocorticoid receptors ( mrs ) provide complementary functions in mediating the stress response in humans and that a gr : mr imbalance increases vulnerability to stress - related psychiatric disorders . increased methylation of the gr , as seen in our study ( fig .
s2 , increased infant methylation pc1 is correlated with increased mean methylation ) could , potentially , perturb the gr : mr balance if it were not matched by a similar change in mr methylation and gene expression , thus setting the stage for increased stress reactivity .
the fact that our results are robust to different types of stressors is important given the chronic nature of stress exposure and our ability to deal with stress .
animal models have found that dietary supplements during pregnancy cause a permanent shift in coat color associated with increased methylation upstream of the agouti coat color gene .
these studies suggest we may be able to devise treatments to manipulate environmentally induced epigenetic alterations , which has profound implications for our ability to deal with the increasing prevalence of stress - related disorders in the united states .
maternal venous blood and umbilical cord blood samples were collected from 25 mother - newborn dyads in july  august , 2010 in eastern democratic republic of congo ( drc ) , a region plagued by ongoing war and extreme violence to women .
detailed ethnographic interviews and perinatal trauma surveys were administered to all mothers including questions designed to develop emic , i.e. , culturally relevant , measures of stress .
an additive model was built to capture stress levels in which each stressor was unweighted and/or weighted based on factor and association analyses .
a 321 bp region of the nr3c1 promoter was amplified , agarose gel - purified and cloned .
methylation was analyzed using a principal component analysis ( pca ) of percent methylation across all 39 assayed sites . in pca ,
the first principal component ( pc1 ) accounts for the largest portion of variation in the data set , followed by the second and subsequent pcs . in our case , pc1 accounted for 12.7% and 12.0% of variation in newborn and maternal methylation , respectively .
all statistical analyses including regressions , analyses of variance ( anovas ) and pcas were completed in r. see supplemental materials for more information .
early life experiences , including those in utero , have been linked to increased risk for adult - onset chronic disease . 
 the underlying assumption is that there is a critical period of developmental plasticity in utero when selection of the fetal phenotype that is best adapted to the intrauterine environment occurs . 
 the current study is the first to test the idea that extreme maternal psychosocial stressors , as observed in the democratic republic of congo , may modify locus - specific epigenetic marks in the newborn resulting in altered health outcomes . 
 here we show a significant correlation between culturally relevant measures of maternal prenatal stress , newborn birth weight and newborn methylation in the promoter of the glucocorticoid receptor nr3c1 . 
 increased methylation may constrain plasticity in subsequent gene expression and restrict the range of stress adaptation responses possible in affected individuals , thus increasing their risk for adult - onset diseases .