Placental transcriptomic signatures of prenatal and preconceptional maternal stress.

Prenatal exposure to maternal psychological stress is associated with increased risk for adverse birth and child health outcomes. Accumulating evidence suggests that preconceptional maternal stress may also be transmitted intergenerationally to negatively impact offspring. However, understanding of mechanisms linking these exposures to offspring outcomes, particularly those related to placenta, is limited. Using RNA sequencing, we identified placental transcriptomic signatures associated with maternal prenatal stressful life events (SLEs) and childhood traumatic events (CTEs) in 1 029 mother-child pairs in two birth cohorts from Washington state and Memphis, Tennessee. We evaluated individual gene-SLE/CTE associations and performed an ensemble of gene set enrichment analyses combing across 11 popular enrichment methods. Higher number of prenatal SLEs was significantly (FDR < 0.05) associated with increased expression of ADGRG6, a placental tissue-specific gene critical in placental remodeling, and decreased expression of RAB11FIP3, an endocytosis and endocytic recycling gene, and SMYD5, a histone methyltransferase. Prenatal SLEs and maternal CTEs were associated with gene sets related to several biological pathways, including upregulation of protein processing in the endoplasmic reticulum, protein secretion, and ubiquitin mediated proteolysis, and down regulation of ribosome, epithelial mesenchymal transition, DNA repair, MYC targets, and amino acid-related pathways. The directional associations in these pathways corroborate prior non-transcriptomic mechanistic studies of psychological stress and mental health disorders, and have previously been implicated in pregnancy complications and adverse birth outcomes. Accordingly, our findings suggest that maternal exposure to psychosocial stressors during pregnancy as well as the mother's childhood may disrupt placental function, which may ultimately contribute to adverse pregnancy, birth, and child health outcomes.

Air Pollution Exposures and Child Executive Function: A U.S. Multi-Cohort Study.

BACKGROUND: Executive function, which develops rapidly in childhood, enables problem solving, focused attention, and planning. Animal models describe executive function decrements associated with ambient air pollution exposure, but epidemiologic studies are limited. METHODS: We examined associations between early childhood air pollution exposure and school-aged executive function in 1,235 children from three U.S. pregnancy cohorts in the ECHO-PATHWAYS Consortium. We derived point-based residential exposures to ambient particulate matter ≤2.5µm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2), and ozone (O3) at ages 0-4 years from spatiotemporal models with a 2-week resolution. We assessed executive function across three domains -- cognitive flexibility, working memory, and inhibitory control -- using performance-based measures and calculated a composite score quantifying overall performance. We fitted linear regressions to assess air pollution - child executive function associations, adjusting for sociodemographic characteristics, maternal mental health, and health behaviors, and examined modification by child sex, maternal education, and neighborhood educational opportunity. RESULTS: In the overall sample, we found hypothesized inverse associations in crude but not adjusted models. Modified associations between NO2 exposure and working memory by neighborhood education opportunity were present (P interaction = 0.05), with inverse associations more pronounced in the "High" and "Very high" categories. Associations of interest did not differ by child sex or maternal education. CONCLUSIONS: This work contributes to the evolving science regarding early-life environmental exposures and child development. There remains a need for continued exploration in future research endeavors, to elucidate the complex interplay between natural environment and social determinants influencing child neurodevelopment.

Associations Between Early-Life Adversity, Ambient Air Pollution, and Telomere Length in Children.

OBJECTIVE: Examine the independent associations and interaction between early-life adversity and residential ambient air pollution exposure on relative buccal telomere length (rBTL). METHODS: Experiences of abuse, neglect, household challenges, and related life events were identified in a cross-sectional sample of children aged 1 to 11 years ( n = 197) using the 17-item Pediatric ACEs and Related Life Event Screener (PEARLS) tool. The PEARLS tool was analyzed both as a total score and across established domains (Maltreatment, Household Challenges, and Social Context). Ground-level fine particulate matter (PM 2.5 ) concentrations were matched to residential locations for the 1 and 12 months before biospecimen collection. We used multivariable linear regression models to examine for independent associations between continuous PM 2.5 exposure and PEARLS score/domains with rBTL. In addition, effect modification by PEARLS scores and domains on associations between PM 2.5 exposure and rBTL was examined. RESULTS: Study participants were 47% girls, with mean (standard deviation) age of 5.9 (3.4) years, median reported PEARLS score of 2 (interquartile range [IQR], 4), median 12-month prior PM 2.5 concentrations of 11.8 µg/m 3 (IQR, 2.7 µg/m 3 ), median 1-month prior PM 2.5 concentrations of 10.9 µg/m 3 (IQR, 5.8 µg/m 3 ), and rBTL of 0.1 (IQR, 0.03). Mean 12-month prior PM 2.5 exposure was inversely associated with rBTL ( ß = -0.02, 95% confidence interval = -0.04 to -0.01). Although reported PEARLS scores and domains were not independently associated with rBTL, we observed a greater decrement in rBTL with increment of average annual PM 2.5 as reported Social Context domain items increased ( p -interaction < .05). CONCLUSIONS: Our results suggest that adverse Social Context factors may accelerate the association between chronic PM 2.5 exposure on telomere shortening during childhood.

Maternal stressful life events during pregnancy and childhood asthma and wheeze.

BACKGROUND: Studies have linked prenatal maternal psychosocial stress to childhood wheeze/asthma but have rarely investigated factors that may mitigate risks. OBJECTIVE: To investigate associations between prenatal stress and childhood wheeze/asthma, evaluating factors that may modify stress effects. METHODS: Participants included 2056 mother-child dyads from Environmental influences on Child Health Outcomes (ECHO)-PATHWAYS, a consortium of 3 prospective pregnancy cohorts (the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study, The Infant Development and Environment Study, and a subset of the Global Alliance to Prevent Prematurity and Stillbirth study) from 6 cities. Maternal stressful life events experienced during pregnancy (PSLEs) were reported using the Pregnancy Risk Assessment Monitoring System Stressful Life Events questionnaire. Parents reported child wheeze/asthma outcomes at age 4 to 6 years using standardized questionnaires. We defined outcomes as ever asthma, current wheeze, current asthma, and strict asthma. We used modified Poisson regression with robust standard errors (SEs) to estimate risk ratios (RRs) and 95% CI per 1-unit increase in PSLE, adjusting for confounders. We evaluated effect modification by child sex, maternal history of asthma, maternal childhood traumatic life events, neighborhood-level resources, and breastfeeding. RESULTS: Overall, we observed significantly elevated risk for current wheeze with increasing PSLE (RR, 1.09 [95% CI, 1.03-1.14]), but not for other outcomes. We observed significant effect modification by child sex for strict asthma (P interaction = .03), in which risks were elevated in boys (RR, 1.10 [95% CI, 1.02-1.19]) but not in girls. For all other outcomes, risks were significantly elevated in boys and not in girls, although there was no statistically significant evidence of effect modification. We observed no evidence of effect modification by other factors (P interactions > .05). CONCLUSION: Risk of adverse childhood respiratory outcomes is higher with increasing maternal PSLEs, particularly in boys.

Individual and Neighborhood Level Predictors of Children's Exposure to Residential Greenspace.

Inequities in urban greenspace have been identified, though patterns by race and socioeconomic status vary across US settings. We estimated the magnitude of the relationship between a broad mixture of neighborhood-level factors and residential greenspace using weighted quantile sum (WQS) regression, and compared predictive models of greenspace using only neighborhood-level, only individual-level, or multi-level predictors. Greenspace measures included the Normalized Difference Vegetation Index (NDVI), tree canopy, and proximity of the nearest park, for residential locations in Shelby County, Tennessee of children in the CANDLE cohort. Neighborhood measures include socioeconomic and education resources, as well as racial composition and racial residential segregation. In this sample of 1012 mother-child dyads, neighborhood factors were associated with higher NDVI and tree canopy (0.021 unit higher NDVI [95% CI: 0.014, 0.028] per quintile increase in WQS index); homeownership rate, proximity of and enrollment at early childhood education centers, and racial composition, were highly weighted in the WQS index. In models constrained in the opposite direction (0.028 unit lower NDVI [95% CI: - 0.036, - 0.020]), high school graduation rate and teacher experience were highly weighted. In prediction models, adding individual-level predictors to the suite of neighborhood characteristics did not meaningfully improve prediction accuracy for greenspace measures. Our findings highlight disparities in greenspace for families by neighborhood socioeconomic and early education factors, and by race, suggesting several neighborhood indicators for consideration both as potential confounders in studies of greenspace and pediatric health as well as in the development of policies and programs to improve equity in greenspace access.

Associations of residential green space with internalizing and externalizing behavior in early childhood.

BACKGROUND: Green space exposures may promote child mental health and well-being across multiple domains and stages of development. The aim of this study was to investigate associations between residential green space exposures and child mental and behavioral health at age 4-6 years. METHODS: Children's internalizing and externalizing behaviors in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort in Shelby County, Tennessee, were parent-reported on the Child Behavior Checklist (CBCL). We examined three exposures-residential surrounding greenness calculated as the Normalized Difference Vegetation Index (NDVI), tree cover, and park proximity-averaged across the residential history for the year prior to outcome assessment. Linear regression models were adjusted for individual, household, and neighborhood-level confounders across multiple domains. Effect modification by neighborhood socioeconomic conditions was explored using multiplicative interaction terms. RESULTS: Children were on average 4.2 years (range 3.8-6.0) at outcome assessment. Among CANDLE mothers, 65% self-identified as Black, 29% as White, and 6% as another or multiple races; 41% had at least a college degree. Higher residential surrounding greenness was associated with lower internalizing behavior scores (-0.66 per 0.1 unit higher NDVI; 95% CI: -1.26, -0.07) in fully-adjusted models. The association between tree cover and internalizing behavior was in the hypothesized direction but confidence intervals included the null (-0.29 per 10% higher tree cover; 95% CI: -0.62, 0.04). No associations were observed between park proximity and internalizing behavior. We did not find any associations with externalizing behaviors or the attention problems subscale. Estimates were larger in neighborhoods with lower socioeconomic opportunity, but interaction terms were not statistically significant. CONCLUSIONS: Our findings add to the accumulating evidence of the importance of residential green space for the prevention of internalizing problems among young children. This research suggests the prioritization of urban green spaces as a resource for child mental health.

Prenatal polycyclic aromatic hydrocarbon exposure and asthma at age 8-9 years in a multi-site longitudinal study.

BACKGROUND AND AIM: Studies suggest prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may influence wheezing or asthma in preschool-aged children. However, the impact of prenatal PAH exposure on asthma and wheeze in middle childhood remain unclear. We investigated these associations in socio-demographically diverse participants from the ECHO PATHWAYS multi-cohort consortium. METHODS: We included 1,081 birth parent-child dyads across five U.S. cities. Maternal urinary mono-hydroxylated PAH metabolite concentrations (OH-PAH) were measured during mid-pregnancy. Asthma at age 8-9 years and wheezing trajectory across childhood were characterized by caregiver reported asthma diagnosis and asthma/wheeze symptoms. We used logistic and multinomial regression to estimate odds ratios of asthma and childhood wheezing trajectories associated with five individual OH-PAHs, adjusting for urine specific gravity, various maternal and child characteristics, study site, prenatal and postnatal smoke exposure, and birth year and season in single metabolite and mutually adjusted models. We used multiplicative interaction terms to evaluate effect modification by child sex and explored OH-PAH mixture effects through Weighted Quantile Sum regression. RESULTS: The prevalence of asthma in the study population was 10%. We found limited evidence of adverse associations between pregnancy OH-PAH concentrations and asthma or wheezing trajectories. We observed adverse associations between 1/9-hydroxyphenanthrene and asthma and persistent wheeze among girls, and evidence of inverse associations with asthma for 1-hydroxynathpthalene, which was stronger among boys, though tests for effect modification by child sex were not statistically significant. CONCLUSIONS: In a large, multi-site cohort, we did not find strong evidence of an association between prenatal exposure to PAHs and child asthma at age 8-9 years, though some adverse associations were observed among girls.

Programming the next generation of prenatal programming of stress research: A review and suggestions for the future of the field.

In this article, I highlight core ideas, empirical findings, and advances in the study of how stress during pregnancy may prenatally program child neurodevelopmental, psychopathological, and health outcomes, emphasizing reviews, metanalyses, and recent contributions of conceptual and empirical work. The article offers a perspective on the history of this area of science, the underrecognized contributions of influential scholars from diverse fields of study, what we know from the evidence to date, the persistent challenges in sorting through what is left to learn, and suggestions for future research. I include sections focused on promoting resilience, pregnancy interventions that demonstrate positive effects across two generations, and the translational implications of the accruing data for practice and policy, highlighting opportunities for integrating across a range of fields and sectors. In the concluding sections, I discuss lessons learned from conducting this work and provide a closing summary of progress and future directions. The goal of this writing was to provide a viewpoint on some ways that emerging intergenerational transmission scholars might responsibly contribute to the future of the field of developmental psychopathology.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

Role of Air Pollution in the Development of Asthma Among Children with a History of Bronchiolitis in Infancy.

BACKGROUND: Infants experiencing bronchiolitis are at increased risk for asthma, but few studies have identified modifiable risk factors. We assessed whether early life air pollution influenced child asthma and wheeze at age 4-6 years among children with a history of bronchiolitis in the first postnatal year. METHODS: Children with caregiver-reported physician-diagnosed bronchiolitis were drawn from ECHO-PATHWAYS, a pooled longitudinal cohort from six US cities. We estimated their air pollution exposure from age 1 to 3 years from validated spatiotemporal models of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ). Caregivers reported children's current wheeze and asthma at age 4-6 years. We used modified Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI), adjusting for child, maternal, and home environmental factors. We assessed effect modification by child sex and maternal history of asthma with interaction models. RESULTS: A total of 224 children had caregiver-reported bronchiolitis. Median (interquartile range) 2-year pollutant concentrations were 9.3 (7.8-9.9) µg/m 3 PM 2.5 , 8.5 (6.4-9.9) ppb NO 2 , and 26.6 (25.6-27.7) ppb O 3 . RRs (CI) for current wheeze per 2-ppb higher O 3 were 1.3 (1.0-1.7) and 1.4 (1.1-1.8) for asthma. NO 2 was inversely associated with wheeze and asthma whereas associations with PM 2.5 were null. We observed interactions between NO 2 and PM 2.5 and maternal history of asthma, with lower risks observed among children with a maternal history of asthma. CONCLUSION: Our results are consistent with the hypothesis that exposure to modest postnatal O 3 concentrations increases the risk of asthma and wheeze among the vulnerable subpopulation of infants experiencing bronchiolitis.

Biological Burden of Adverse Childhood Experiences in Children.

OBJECTIVE: This study aimed to examine relationships between adverse childhood experiences (ACEs) and related life events and allostatic load (AL)-"wear and tear" from chronic stress-in a pediatric population. METHODS: Children were screened with the PEdiatric ACEs and Related Life Event Screener (PEARLS) tool, a 17-item questionnaire capturing experiences of abuse, neglect, household challenges, and related life events. Biological data were available for 207 participants, and AL was operationalized using clinical or empirical cutoff points across 4 physiological systems (i.e., cardiac, metabolic, inflammatory, neurologic). Covariate-adjusted multivariable regression models were used to examine associations between AL with adversity and health. RESULTS: Children (mean age = 6.5 years, range = 1-11 years) had an average AL score of 1.9 (standard deviation = 1.7), and a U-shaped relationship was observed with child's age. Continuous PEARLS and original ACE scores were not associated with AL. However, children with a reported PEARLS score of 1 to 2 or original ACEs score of 1 to 3 had 1.5 (incidence rate ratio [IRR] = 1.50, 95% confidence interval [CI] = 1.09-2.08) and 1.4 (IRR = 1.41, 95% CI = 1.08-1.84) times greater AL, respectively, compared with participants with none reported. In secondary analyses, caregiver mental illness was associated with higher child AL (adjusted IRR = 1.27, 95% CI = 1.01-1.58). AL was also associated with poorer perceived child general health (adjusted ß = -0.87, 95% CI = -1.58 to -0.15) and greater odds of child obesity (adjusted odds ratio = 1.51, 95% CI = 1.23-1.89). CONCLUSIONS: Measuring AL in a pediatric population requires careful consideration of age. Higher AL was associated with a greater number of reported adversities and worse child health.

A path model examination: maternal anxiety and parenting mediate the association between maternal adverse childhood experiences and children's internalizing behaviors.

BACKGROUND: Children of mothers with adverse childhood experiences (ACEs) are at increased risk for developmental problems. However, the mechanisms through which a mother's experience of ACEs are transmitted to her offspring are understudied. The current study investigates potential modifiable mediators (maternal psychopathology and parenting) of the association between maternal ACEs and children's behavioral problems. METHODS: We utilized data from a pregnancy cohort study (N = 1030; CANDLE study) to investigate longitudinal associations between maternal ACEs, postpartum anxiety, observed parenting behavior, and child internalizing behaviors (meanage = 4.31 years, s.d. age = 0.38) in a racially diverse (67% Black; 33% White/Other) sample. We used structural equation modeling to test for direct associations between maternal ACEs and children's internalizing behaviors, as well as indirect associations via two simple mediations (maternal anxiety and parenting), and one serial mediation (sequence of maternal anxiety to parenting). RESULTS: Simple mediation results indicated that maternal anxiety and cognitive growth fostering behaviors independently mediated the association between maternal ACEs and child internalizing. We observed no evidence of a serial mediation from ACEs to internalizing via the effects of maternal anxiety on parenting. CONCLUSIONS: This study supports and refines extant literature by confirming the intergenerational association between maternal ACEs and child internalizing behaviors in a large, diverse sample, and identifies potential modifiable mediators: maternal anxiety and parenting behaviors related to fostering cognitive development. Findings may inform interventions targeting mothers who have experienced ACEs and suggest that providing support around specific parenting behaviors and addressing maternal anxiety may reduce internalizing behaviors in children.

Placental transcriptomic signatures of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. RESULTS: In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. CONCLUSION: This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Urinary oxidative stress biomarkers are associated with preterm birth: an Environmental Influences on Child Health Outcomes program study.

BACKGROUND: Preterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States. OBJECTIVE: We leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin. STUDY DESIGN: This study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F2α, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F2α (F2-IsoP-M; the major 8-iso-prostaglandin-F2α metabolite), and prostaglandin-F2α were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models. RESULTS: Approximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11-1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16-1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F2α was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94-1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis. CONCLUSION: Here, oxidative stress, as measured by 8-iso-prostaglandin-F2α, F2-IsoP-M, and prostaglandin-F2α in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

Linking specific biological signatures to different childhood adversities: findings from the HERO project.

BACKGROUND: Although investigations have begun to differentiate biological and neurobiological responses to a variety of adversities, studies considering both endocrine and immune function in the same datasets are limited. METHODS: Associations between proximal (family functioning, caregiver depression, and anxiety) and distal (SES-D; socioeconomic disadvantage) early-life adversities with salivary inflammatory biomarkers (IL-1ß, IL-6, IL-8, and TNF-α) and hair HPA markers (cortisol, cortisone, and dehydroepiandrosterone) were examined in two samples of young U.S. children (N = 142; N = 145). RESULTS: Children exposed to higher SES-D had higher levels of TNF-α (B = 0.13, p = 0.011), IL-1ß (B = 0.10, p = 0.033), and DHEA (B = 0.16, p = 0.011). Higher family dysfunction was associated with higher cortisol (B = 0.08, p = 0.033) and cortisone (B = 0.05, p = 0.003). An interaction between SES-D and family dysfunction was observed for cortisol levels (p = 0.020) whereby children exposed to lower/average levels of SES-D exhibited a positive association between family dysfunction and cortisol levels, whereas children exposed to high levels of SES-D did not. These findings were partially replicated in the second sample. CONCLUSIONS: Our results indicate that these biological response systems may react differently to different forms of early-life adversity. IMPACT: Different forms of early-life adversity have varied stress signatures, and investigations of early-life adversities with inflammation and HPA markers are lacking. Children with higher socioeconomic disadvantage had higher TNF-α, IL-1ß, and DHEA. Higher family dysfunction was associated with higher hair cortisol and cortisone levels, and the association between family dysfunction and cortisol was moderated by socioeconomic disadvantage. Biological response systems (immune and endocrine) were differentially associated with distinct forms of early-life adversities.

Prenatal bisphenol A and S exposure and atopic disease phenotypes at age 6.

BACKGROUND: Atopic disease may be influenced by prenatal and early life exposure to endocrine disrupting chemicals, including bisphenols, but results from epidemiological studies have been mixed. This study aimed to extend the epidemiological literature, hypothesizing that children with higher prenatal bisphenol exposure are more likely to have childhood atopic disease. METHODS: Urinary bisphenol A (BPA) and S (BPS) concentrations were measured in each trimester from 501 pregnant women in a multi-center, prospective pregnancy cohort. Ever asthma, current asthma, wheeze, and food allergy) were assessed at age six via standardized ISAAC questionnaire. We constructed generalized estimating equations to examine BPA and BPS exposure jointly at each trimester for each atopy phenotype. BPA was modeled as a log-transformed continuous variable, whereas BPS was modeled as detected versus not detected. We also modeled pregnancy-averaged BPA values and a categorical indicator for number of detectable BPS values over pregnancy (0-3) in logistic regression models. RESULTS: First trimester BPA was associated with inverse odds of food allergy among the entire study sample (OR = 0.78, 95% CI = 0.64-0.95, p = 0.01) and females only (OR = 0.69, 95% CI = 0.52-0.90, p = 0.006). The inverse relationship persisted in pregnancy-averaged models of BPA among females (OR = 0.56, 95% CI = 0.35-0.90, p = 0.006). Second trimester BPA was associated with greater odds of food allergy in the entire sample (OR = 1.27, 95% CI = 1.02-1.58, p = 0.03) and among males only (OR = 1.48, 95% CI = 1.02-2.14, p = 0.04). Odds of current asthma increased among males in the pregnancy-averaged BPS models (OR = 1.65, 95% CI = 1.01-2.69, p = 0.045). CONCLUSION: We saw opposite effects of BPA on food allergy that were trimester- and sex-specific. These divergent associations warrant further investigation. There is some evidence to suggest that prenatal BPS is associated with asthma among males, but further research is required in cohorts with a greater proportion of prenatal urine samples with detectable BPS to validate these results.

Prenatal exposure to polycyclic aromatic hydrocarbons is not associated with behavior problems in preschool and early school-aged children: A prospective multi-cohort study.

BACKGROUND: Epidemiological study findings are inconsistent regarding associations between prenatal polycyclic aromatic hydrocarbon (PAH) exposures and childhood behavior. This study examined associations of prenatal PAH exposure with behavior at age 4-6 years in a large, diverse, multi-region prospective cohort. Secondary aims included examination of PAH mixtures and effect modification by child sex, breastfeeding, and child neighborhood opportunity. METHODS: The ECHO PATHWAYS Consortium pooled 1118 mother-child dyads from three prospective pregnancy cohorts in six U.S. cities. Seven PAH metabolites were measured in prenatal urine. Child behavior was assessed at age 4-6 using the Total Problems score from the Child Behavior Checklist (CBCL). Neighborhood opportunity was assessed using the socioeconomic and educational scales of the Child Opportunity Index. Multivariable linear regression was used to estimate associations per 2-fold increase in each PAH metabolite, adjusted for demographic, prenatal, and maternal factors and using interaction terms for effect modifiers. Associations with PAH mixtures were estimated using Weighted Quantile Sum Regression (WQSR). RESULTS: The sample was racially and sociodemographically diverse (38% Black, 49% White, 7% Other; household-adjusted income range $2651-$221,102). In fully adjusted models, each 2-fold increase in 2-hydroxynaphthalene was associated with a lower Total Problems score, contrary to hypotheses (b = -0.80, 95% CI = -1.51, -0.08). Associations were notable in boys (b = -1.10, 95% CI = -2.11, -0.08) and among children breastfed 6+ months (b = -1.31, 95% CI = -2.25, -0.37), although there was no statistically significant evidence for interaction by child sex, breastfeeding, or neighborhood child opportunity. Associations were null for other PAH metabolites; there was no evidence of associations with PAH mixtures from WQSR. CONCLUSION: In this large, well-characterized, prospective study of mother-child pairs, prenatal PAH exposure was not associated with child behavior problems. Future studies characterizing the magnitude of prenatal PAH exposure and studies in older childhood are needed.

Association between maternal eating and young child feeding in a community sample.

BACKGROUND: Early childhood is a pivotal period for the development of healthy eating practices. One way to promote child health is to identify early modifiable factors that affect child eating and weight. Given the intergenerational transmission of eating behaviors, this study examined how mothers' eating behaviors were associated with child feeding practices, and whether child weight-for-length (z-WFL) moderated this relation, in a community sample. METHODS: Participants were 72 mother-child dyads. Maternal eating behaviors-emotional, external and restrained-were assessed 9-months postpartum, using the Dutch Eating Behavior Questionnaire. Child feeding-restrictive, pressure, and concern about overeating/overweight or undereating/underweight-was measured using the Infant Feeding Questionnaire, and child z-WFL were assessed 18-months postpartum. Linear regressions were used to test the main effect of maternal eating and the interaction effect of maternal eating and child z-WFL, on child feeding practices. RESULTS: Maternal restrained eating was associated with child pressure feeding, and contrarily with concerns about overeating/overweight. However, a significant interaction between child z-WFL and both maternal emotional and external eating were found with regard to concern about child undereating/underweight. Paradoxically, among children who weighed more, greater maternal emotional and greater external eating were associated with greater concern about child undereating/underweight. CONCLUSIONS: In this community sample, mothers were more likely to report contradictory feeding practices and concerns, suggesting complicated relations among a mother's own eating behavior, her child's weight, and her perceptions of child eating and weight. This may indicate a need for better communication and support of infant feeding practices. TRIAL REGISTRATION: Data was collected as part of two grants (MAMAS Grant ID: HL097973-01; SEED Grant ID: HL116511-02) conducted at the University of California, San Francisco (UCSF). All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by institutional review board at UCSF.

Intergenerational transmission of stress: Multi-domain stressors from maternal childhood and pregnancy predict children's mental health in a racially and socioeconomically diverse, multi-site cohort.

PURPOSE: Despite growing recognition that unfortunately common maternal stress exposures in childhood and pregnancy may have intergenerational impacts on children's psychiatric health, studies rarely take a life course approach. With child psychopathology on the rise, the identification of modifiable risk factors is needed to promote maternal and child well-being. In this study, we examined associations of maternal exposure to childhood traumatic events (CTE) and pregnancy stressful life events (PSLE) with child mental health problems in a large, sociodemographically diverse sample. METHODS: Participants were mother-child dyads in the ECHO-PATHWAYS consortium's harmonized data across three U.S. pregnancy cohorts. Women completed questionnaires regarding their own exposure to CTE and PSLE, and their 4-6-year-old child's mental health problems using the Child Behavior Checklist (CBCL). Regression analyses estimated associations between stressors and child total behavior problems, adjusting for confounders. RESULTS: Among 1948 dyads (child age M = 5.13 (SD = 1.02) years; 38% Black, 44% White; 8.5% Hispanic), maternal history of CTE and PSLE were independently associated with children's psychopathology: higher CTE and PSLE counts were related to higher total problems ([ßCTE = 0.11, 95% CI [.06, .16]; ßSLE = 0.21, 95% CI [.14, 0.27]) and greater odds of clinical levels of problems (ORCTE = 1.41; 95% CI [1.12, 1.78]; ORPSLE = 1.36; 95% CI [1.23, 1.51]). Tests of interaction showed PSLEs were more strongly associated with child problems for each additional CTE experienced. CONCLUSION: Findings confirm that maternal exposure to CTE and PSLE are independently associated with child mental health, and history of CTE exacerbates the risk associated with PSLE, highlighting intergenerational risk pathways for early psychopathology. Given the prevalence of these exposures, prevention and intervention programs that reduce childhood trauma and stress during pregnancy will likely positively impact women's and their children's health.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.