A preliminary investigation of epigenome-wide DNA methylation and temperament during infancy.

This study provides preliminary evidence for an epigenetic architecture of infant temperament. At 12 months of age, blood was collected and assayed for DNA methylation and maternally reported infant temperament was assessed using the Infant Behavior Questionnaire in 67 mother-infant dyads. Epigenome-wide analyses showed that the higher order temperament dimensions Surgency and Negative Affect were associated with DNA methylation. The epigenetic signatures of Surgency and Negative Affect were situated at genes involved in synaptic signaling and plasticity. Although replication is required, these results are consistent with a biologically based model of temperament, create new avenues for hypothesis-driven research into epigenetic pathways that underlie individual differences in temperament, and demonstrate that infant temperament has a widespread epigenetic signature in the methylome.

The Social Environment Matters for Telomere Length and Internalizing Problems During Adolescence.

Depression and anxiety symptoms are on the rise among adolescents. With increasing evidence that cellular aging may be associated with depressive and anxiety symptoms, there is an urgent need to identify the social environment context that may moderate this link. This study addresses this research gap by investigating the moderating role of the social environment on the relation between telomere length and emotional health among adolescents. Participants were 411 non-Hispanic (88.56%) Black (100%) adolescents (M = 14.23 years, SD = 1.85, female = 54%) in a major metropolitan city. Youth and parents reported on an array of social risk and protective factors, and youth provided DNA samples for telomere length measurement. Results demonstrated that the association of telomere length and anxiety symptoms was stronger among youth with higher perceived stress or lower school belongingness, and the association of telomere length with depressive symptoms was stronger under conditions of higher parent inter-partner psychological aggression. The results enhance our understanding of the complex associations between biological aging, the social environment, and mental health in adolescence.

Pet ownership is associated with harmful alcohol use among a cohort of people with HIV: a brief research report.

Research suggests that people with HIV (PWH), who are at high risk for alcohol and substance use, may rely on relationships with pets for companionship and stress relief. There may be common mechanisms underlying both substance use and attachment to pets. The purpose of this brief research report was to compare alcohol and substance use behaviors between pet owners and non-owners among a cohort of PWH. Participants (n = 735) in a survey study of PWH in Florida were asked about their alcohol and substance use behaviors, whether they owned a pet, and their sociodemographic characteristics. We used bivariate analyses and logistic regression to examine differences in alcohol and substance use behaviors between pet owners and non-owners. Pet owners had higher mean AUDIT scores than non-owners (Mpet = 5, Mnopet = 4, z = -3.07, p = 0.002). Pet owners were more likely than non-owners to use alcohol in a harmful or hazardous way (AUDIT score ≥ 8), above and beyond sociodemographic characteristics (OR = 1.65, p = 0.052). Pet owners were more likely to have ever used most substances than non-owners, and more likely to currently use alcohol (X2(1) = 12.97, p = 0.000), marijuana or hashish (X2(1) = 6.82, p = 0.009), and amyl nitrate/poppers (X2(1) = 11.18, p = 0.001). Pet owners may be more likely to use alcohol and other substances at higher rates than non-owners. Reasons for owning a pet and using substances may be similar, such as coping with stress.

Associations of depression and anxiety and adolescent telomere length.

BACKGROUND: Telomere length (TL), a biomarker of cellular aging, is influenced by adverse life experiences. Although depression and anxiety are associated with shorter TL in adults, the relationship in younger ages has received little attention. We examined relationships between depression and anxiety diagnoses and symptomatology and TL in adolescence, an important developmental window for early intervention. Sex differences in relationships were also examined. METHODS: Wave 1 survey and TL data from the Adolescent Health and Development in Context study were analyzed (N = 995). Depression and anxiety diagnosis were parent-reported measures categorized as: current diagnosis, prior diagnosis, and never diagnosed (reference category). Depressive symptoms were measured via adolescent-report using nine items from the Center for Epidemiologic Studies-Depression scale, short form. Anxiety symptoms were measured via adolescent-report using eight items from the pediatric anxiety scale obtained from the Patient-Reported Outcomes Measurement Information System. Genomic DNA was isolated from 500 µL saliva via ethanol precipitation. Genomic DNA TL was assessed using monoplexed quantitative polymerase chain reactions. Relative T/S quantities were calculated in accordance with established procedures. Covariates included sociodemographic factors (sex, age, race/ethnicity, caregiver marital status and education level, and household income), pubertal development, and season of collection. Descriptive and multivariable linear regression analyses were conducted, including an examination of sex as a moderator in the relationships between depression, anxiety, and TL. RESULTS: In multivariable analysis, adolescents with a current depression diagnosis (b = -0.26, p < .05), but not a prior diagnosis (b =0.05, p > .05) had shorter TL than those who were never diagnosed; higher depressive symptom scores were associated with shorter TL (b = -0.12, p < .05). No significant associations were found between anxiety diagnosis and TL; however, higher anxiety symptom scores were associated with shorter TL (b = -0.14, p < .01). Sex did not significantly moderate any of the relationships between depression, anxiety and TL. CONCLUSIONS: Depression and anxiety were associated with shorter TL in this diverse community sample of adolescents and the findings highlight the potential for impaired mental health to contribute to cellular senescence as early as adolescence. Prospective research on the long-term effect of depression and anxiety occurring earlier in the life span on TL over time is needed, including examination of potential mechanisms that may accelerate or buffer the negative effects of impaired mental health on TL.

Everyday perceptions of safety and racial disparities in hair cortisol concentration.

OBJECTIVE: Black-White disparities in physiological stress during adolescence are increasingly evident but remain incompletely understood. We examine the role of real-time perceptions of safety in the context of everyday routines to gain insight into the sources of observed adolescent racial differences in chronic stress as measured by hair cortisol concentration (HCC). METHOD: We combined social survey, ecological momentary assessment (EMA), and hair cortisol data on 690 Black and White youth ages 11-17 from wave 1 of the Adolescent Health and Development in Context (AHDC) study to investigate racial differences in physiological stress. Individual-level, reliability-adjusted measures of perceived unsafety outside the home were drawn from a week-long smartphone-based EMA and tested for association with hair cortisol concentration. RESULTS: We observed a statistically significant interaction (p < .05) between race and perceptions of unsafety. For Black youth, perceived unsafety was associated with higher HCC (p < .05). We observed no evidence of an association between perceptions of safety and expected HCC for White youth. For youth who perceive their out-of-home activity locations to be consistently safe, the racial difference in expected HCC was not statistically significant. At the high end of perceived unsafety, however, Black-White differences in HCC were pronounced (0.75 standard deviations at the 95th percentile on perceived unsafety; p < .001). DISCUSSION: These findings call attention to the role of everyday perceptions of safety across non-home routine activity contexts in explaining race differences in chronic stress as assessed by hair cortisol concentrations. Future research may benefit from data on in situ experiences to capture disparities in psychological and physiological stress.

Demographic and health predictors of telomere length during adolescence.

Telomere length (TL) is proposed to play a mechanistic role in how the exposome affects health outcomes. Little is known about TL during adolescence, a developmental period during which precursors of adult-onset health problems often emerge. We examined health and demographic sources of variation in TL in 899 youth aged 11-17. Demographic and health information included age, sex, race, household income, caregiver age and marital status, youth tobacco exposure, body mass index, pubertal status, health problems, medication use, and season of data collection. Genomic DNA was extracted from saliva, and T/S ratios were computed following qPCR. Age, race, season of data collection, and household income were associated with the telomere to single copy (T/S) ratio. We found that T/S ratios were larger at younger ages, among Black youth, for saliva collected during autumn and winter, and among households with higher income. Analyses stratified by race revealed that the association between age and T/S ratio was present for Black youth, that season of collection was present across races, but that family demographic associations with T/S ratio varied by race. The results provide information for future telomere research and highlight adolescence as a potentially important developmental phase for racial disparities in telomere shortening and health.

Racial and Economic Adversity Differences in Stress Markers and Immune Function Among Urban Adolescents.

BACKGROUND: Exposure to racism and associated adversities, such as poverty, is hypothesized to contribute to racial inequities in health via stress and immune pathways. Furthermore, the effects of adversity may be more salient during sensitive developmental periods. Our study examined racial differences in stress and immune biomarkers during adolescence and the effects of exposure to economic adversity at distinct developmental time periods and cumulatively in accounting for potential racial differences. METHODS: Secondary analysis of the Adolescent Health and Development in Context study was conducted. Data were derived from self-administered surveys; interviews; smartphone-based, geographic-explicit ecological momentary assessment; stress biomarkers (evening salivary cortisol over six nights and hair cortisol); and immune biomarkers (salivary shedding of Epstein-Barr virus [EBV] DNA among EBV-positive adolescents). Current socioeconomic status measures included annual household income and caregiver education. Caregivers also reported experiences of bankruptcy, difficulty paying bills, receipt of food stamps/Supplemental Nutrition Assistance Program/electronic benefit transfer, and job loss when the child was of ages birth-5 years, 6-10 years, and 11 years or older. An affirmative response to any item was defined as exposure to economic adversity for that developmental time period (yes/no). A cumulative economic adversity measure was calculated as the sum of exposures across developmental periods (0 = never exposed to 3 = exposed across all time periods). Descriptive and multivariable regression analyses were conducted, accounting for covariates. RESULTS: Black/African American adolescents had higher salivary cortisol concentration, higher hair cortisol concentration, and an increased odd of salivary shedding of EBV DNA compared to White adolescents. Racial differences were not attenuated by the current socioeconomic status or economic adversity (developmental period or cumulatively). DISCUSSION: Our study provides evidence that stress and immune biomarkers differ by race as early as adolescence and may be one pathway through which racism and associated adversities contribute to racial health inequities. Further research on the contribution of multiple adversities beyond poverty to racial inequities in physiological stress and health is critical for informing effective prevention and intervention efforts.

Dehydroepiandrosterone at birth: Response to stress and relation to demographic, pregnancy and delivery factors.

Enhanced production of dehydroepiandrosterone (DHEA) by the foetal hypothalamic-pituitary-adrenal (HPA) axis enables maturational events critical for labour induction and neonatal adaptation. Despite knowledge of the interconnected nature of maternal and foetal physiology and dramatic changes in DHEA production after birth, few studies have examined DHEA levels in newborns and none have examined DHEA's response to acute stress. Understanding normative patterns of early DHEA activity is needed to accurately assess functioning of the biological stress system with relevance for health and development. The present study analysed DHEA concentrations and change after stress among 93 newborns and associations with pregnancy, delivery and demographic risk factors. Three saliva samples, collected prior to and following a blood draw stressor, were used to determine baseline and stress reactive DHEA levels. Mothers self-reported on health behaviours during pregnancy. Data on obstetric factors were obtained from medical records. DHEA levels declined from pre- to post-stressor assessments. Results also showed that post-stressor DHEA change was significantly associated with administration of medications used to treat pain and accelerate labour. However, there was no significant variation in DHEA pre-stress levels or change after stress as a function of time after birth. By capturing DHEA levels after birth, the present study provides a window into prenatal health of the HPA system. The study also advances knowledge of DHEA in newborns by providing data on reference levels and important covariates. This information on basic adrenal physiology provides a foundation that can be expanded on to enhance understanding of early hypothalamic-pituitary-adrenal axis activity.

The impact of maternal stress on infant alpha-amylase is buffered by high infant regulation and low infant negative reactivity.

This study examined the main and interactive effects of maternal perceived stress and infant temperament-surgency, negative affectivity, and orienting/regulation-on infant salivary alpha-amylase (sAA) responses to stress. Saliva samples were collected prior to and following two naturalistic stressors: maternal separation conducted at 9 months and blood draw/immunizations conducted at 12 months. sAA area under the curve (AUC) was computed to determine response of the sympathetic nervous system to each stressor. Results revealed significant interactions of maternal stress and infant negative affectivity and orienting/regulation with sAA AUC. Relations between maternal stress and infant sAA AUC were stronger among infants with higher levels of negative affectivity and lower levels of orienting/regulation. These results highlight the need to examine both infant characteristics and environmental factors when investigating the development of stress response systems.

Protective Factors Buffer Life Stress and Behavioral Health Outcomes among High-Risk Youth.

This study investigated internalizing problems, externalizing problems, and polydrug use among African-American youth residing in high-poverty neighborhoods, and tested the potential protective effects of religiosity, parental monitoring, and neighborhood collective efficacy on life stress and behavioral health outcomes (N = 576; 307 females; Mage = 16 years, SD = 1.44 years). A cumulative risk index reflected the combined effects of past year exposure to stressful life events, racial discrimination, and exposure to violence along with poor neighborhood ecology. Structural equation modeling revealed that cumulative risk significantly predicted internalizing problems, externalizing problems, and polydrug use. Interaction tests showed that the association of cumulative risk with internalizing problems was buffered by adolescent religiosity and neighborhood collective efficacy. The association of cumulative risk with externalizing problems was buffered by parental monitoring and collective efficacy. Adolescent sex further moderated these effects. The findings of the present study collectively highlight potential for protective factors to buffer effects of cumulative risk on behavioral health outcomes among youth residing in high-risk neighborhoods.

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.

Children's Relationship With Their Pet Dogs and OXTR Genotype Predict Child-Pet Interaction in an Experimental Setting.

Human-animal interaction (HAI) research has increasingly documented the important role of pet dogs in children's lives. The quality of interaction between children and their pet dogs, however, is likely influenced by individual differences among children as well as their perceived relationship with their pet dog. Ninety-seven children aged 7-12 years and their pet dogs participated in a laboratory protocol during which the child solicited interaction with their dog, from which time petting and gazing were recorded. Children reported on their perceived relationship with the pet dog via interview. Children provided saliva samples, from which a polymorphism in the oxytocin receptor, OXTR rs53576, which has long been implicated in social behavior, was genotyped. The results showed that OXTR genotype and children's perceived antagonism with the pet dog predicted the amount of petting, but not gazing, between children and their pet dogs. This research adds to the growing body of HAI research by documenting individual differences that may influence children's interactions with animals, which is key to research related to pet ownership and understanding factors that may impact therapeutic interventions involving HAI.

Putting a finger on the problem: Finger stick blood draw and immunization at the well-child exam elicit a cortisol response to stress among one-year-old children.

Research examining stress reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis in young children has historically been hampered by a lack of reliable methods to invoke a cortisol stress response. This report details an effective method of eliciting a cortisol rise in one-year-old children (N = 83) by modifying and combining two naturalistic stressors previously used with infants and children. Salivary cortisol levels were collected from children before and after a finger stick blood draw and immunizations performed during their one year well-child checkup at their pediatrician's office. Results indicated that the stressor was successful at eliciting a significant cortisol response. An extensive set of potential demographic and clinical confounds were also assessed in order to identify methodological considerations important in studies of infant cortisol. The stress paradigm presented here provides a promising alternative for studies of infant HPA activity to enable investigators to more effectively evaluate early functioning of the biological stress system during this developmentally important life stage.

DNA methylation of methylation complex genes in relation to stress and genome-wide methylation in mother-newborn dyads.

OBJECTIVES: Early life stress is known to have enduring biological effects, particularly with respect to health. Epigenetic modifications, such as DNA methylation, are a possible mechanism to mediate the biological effect of stress. We previously found correlations between maternal stress, newborn birthweight, and genome-wide measures of DNA methylation. Here we investigate ten genes related to the methylation/demethylation complex in order to better understand the impact of stress on health. MATERIALS AND METHODS: DNA methylation and genetic variants at methylation/demethylation genes were assayed. Mean methylation measures were constructed for each gene and tested, in addition to genetic variants, for association with maternal stress measures based on interview and survey data (chronic stress and war trauma), maternal venous, and newborn cord genome-wide mean methylation (GMM), and birthweight. RESULTS: After cell type correction, we found multiple pairwise associations between war trauma, maternal GMM, maternal methylation at DNMT1, DNMT3A, TET3, and MBD2, and birthweight. CONCLUSIONS: The association of maternal GMM and maternal methylation at DNMT1, DNMT3A, TET3, and MBD2 is consistent with the role of these genes in establishing, maintaining and altering genome-wide methylation patterns, in some cases in response to stress. DNMT1 produces one of the primary enzymes that reproduces methylation patterns during DNA replication. DNMT3A and TET3 have been implicated in genome-wide hypomethylation in response to glucocorticoid hormones. Although we cannot determine the directionality of the genic and genome-wide changes in methylation, our results suggest that altered methylation of specific methylation genes may be part of the molecular mechanism underlying the human biological response to stress.

BNDF methylation in mothers and newborns is associated with maternal exposure to war trauma.

BACKGROUND: The BDNF gene codes for brain-derived neurotrophic factor, a growth factor involved in neural development, cell differentiation, and synaptic plasticity. Present in both the brain and periphery, BDNF plays critical roles throughout the body and is essential for placental and fetal development. Rodent studies show that early life stress, including prenatal stress, broadly alters BDNF methylation, with presumed changes in gene expression. No studies have assessed prenatal exposure to maternal traumatic stress and BDNF methylation in humans. This study examined associations of prenatal exposure to maternal stress and BDNF methylation at CpG sites across the BDNF gene. RESULTS: Among 24 mothers and newborns in the eastern Democratic Republic of Congo, a region with extreme conflict and violence to women, maternal experiences of war trauma and chronic stress were associated with BDNF methylation in umbilical cord blood, placental tissue, and maternal venous blood. Associations of maternal stress and BDNF methylation showed high tissue specificity. The majority of significant associations were observed in putative transcription factor binding regions. CONCLUSIONS: This is the first study in humans to examine BDNF methylation in relation to prenatal exposure to maternal stress in three tissues simultaneously and the first in any mammalian species to report associations of prenatal stress and BDNF methylation in placental tissue. The findings add to the growing body of evidence highlighting the importance of considering epigenetic effects when examining the impacts of trauma and stress, not only for adults but also for offspring exposed via effects transmitted before birth.

Effect of Pet Dogs on Children's Perceived Stress and Cortisol Stress Response.

The present study tested whether pet dogs have stress-buffering effects for children during a validated laboratory-based protocol, the Trier Social Stress Test for Children (TSST-C). Participants were 101 children aged 7-12 years with their primary caregivers and pet dogs. Children were randomly assigned in the TSST-C to a pet present condition or one of two comparison conditions: parent present or no support figure present. Baseline, response, and recovery indices of perceived stress and cortisol levels were computed based on children's self-reported feelings of stress and salivary cortisol. Results indicated that in the alone (no social support) condition, children showed the expected rise for both perceived stress and cortisol response to stress. Pet dog presence significantly buffered the perceived stress response in comparison to children in the alone and parent present conditions. No main condition effect was observed for cortisol; however, for children experiencing the stressor with their pet present, lower cortisol response to stress was associated with more child-initiated petting and less dog proximity-seeking behavior. The results support the notion that pet dogs can provide socio-emotional benefits for children via stress buffering.

Risk and protective factors for comorbid internalizing and externalizing problems among economically disadvantaged African American youth.

Comorbidity of internalizing and externalizing problems and its risk and protective factors have not been well incorporated into developmental research, especially among racial minority youth from high-poverty neighborhoods. The present study identified a latent comorbid factor as well as specific factors underlying internalizing and externalizing problems among 592 African American adolescents living in economically disadvantaged neighborhoods (291 male; M age = 15.9 years, SD = 1.43 years). Stressful life events and racial discrimination were associated with higher comorbid problems, whereas stressful life events and exposure to violence were associated with higher specific externalizing problems. Collective efficacy was associated with both lower specific externalizing problems and lower comorbid problems. Moreover, high collective efficacy buffered the risk effects of stressful life events and racial discrimination on comorbid problems. Our results demonstrated the advantages of latent variable modeling to understanding comorbidity by articulating impacts of risk factors on comorbid and specific components underlying internalizing and externalizing problems. They also highlighted the protective effect of collective efficacy in mitigating risks for these problems. These findings broadly call for more studies on comorbidities in developmental psychopathology among youth from diverse sociocultural backgrounds.

Cortisol and DHEA in development and psychopathology.

Dehydroepiandrosterone (DHEA) and cortisol are the most abundant hormones of the human fetal and adult adrenals released as end products of a tightly coordinated endocrine response to stress. Together, they mediate short- and long-term stress responses and enable physiological and behavioral adjustments necessary for maintaining homeostasis. Detrimental effects of chronic or repeated elevations in cortisol on behavioral and emotional health are well documented. Evidence for actions of DHEA that offset or oppose those of cortisol has stimulated interest in examining their levels as a ratio, as an alternate index of adrenocortical activity and the net effects of cortisol. Such research necessitates a thorough understanding of the co-actions of these hormones on physiological functioning and in association with developmental outcomes. This review addresses the state of the science in understanding the role of DHEA, cortisol, and their ratio in typical development and developmental psychopathology. A rationale for studying DHEA and cortisol in concert is supported by physiological data on the coordinated synthesis and release of these hormones in the adrenal and by their opposing physiological actions. We then present evidence that researching cortisol and DHEA necessitates a developmental perspective. Age-related changes in DHEA and cortisol are described from the perinatal period through adolescence, along with observed associations of these hormones with developmental psychopathology. Along the way, we identify several major knowledge gaps in the role of DHEA in modulating cortisol in typical development and developmental psychopathology with implications for future research.

Effect of Environmental Risk and Externalizing Comorbidity on Internalizing Problems Among Economically Disadvantaged African American Youth.

This study examined effects of racial discrimination, community violence, and stressful life events on internalizing problems among African American youth from high poverty neighborhoods (N = 607; 293 boys; Mage = 16.0 years, SD = 1.44 years). Mediated effects via externalizing problems on these relations were also examined, given the high comorbidity rate between internalizing and externalizing problems. Externalizing problems partially mediated the effect of stressful life events on internalizing problems and fully mediated the effect of racial discrimination for boys but not for girls. Exposure to violence had a significant indirect effect on internalizing problems via externalizing problems. The findings call for greater attention to internalizing problems among African American youth and pathways to internalizing problems via externalizing problems.

Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo.

Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. BW data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding (TFB) sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at TFB sites, was associated with BW. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes.