Children born extremely preterm (< 28 weeks gestation) are at increased risk for neurodevelopmental disorders and reduced brain volumes. This study examined whether neonatal inflammation predicts adolescent brain volume and whether associations differ by sex or presence of major neurologic disorders. Data were drawn from the Extremely Low Gestational Age Newborns (ELGAN) Study. Inflammatory protein levels measured during the first two postnatal weeks were used to classify neonates into low, moderate, or high inflammation groups. At age 15, participants underwent 3T MRI, and total and regional brain volumes were quantified using FreeSurfer. Neurologic status was assessed at ages 2, 10, and 15. Higher neonatal inflammation was associated with reduced volumes in the cerebellum cortex, brainstem, and subcortical gray matter, including the ventral diencephalon, thalamus, and amygdala. Sex-specific effects were observed: females with moderate inflammation showed reduced volumes in total brain, cerebellum cortex and white matter, ventral diencephalon, and thalamus, while males with moderate or high inflammation had reductions in the cerebellum cortex, corpus callosum, and brainstem. Among adolescents with major neurologic disorders, higher inflammation was linked to smaller cerebellum cortex, cerebellum white matter, and brainstem volumes. These findings suggest lasting effects of neonatal inflammation on brain development in extremely preterm individuals.

Birth defects are a leading cause of infant mortality in the United States, but little is known about causes of many types of birth defects. Spatiotemporal disease mapping to identify high-prevalence areas is a potential strategy to narrow the search for potential environmental and other causes that aggregate over space and time. We described the spatial and temporal trends of the prevalence of birth defects in North Carolina during 2003-2015, using data on live births obtained from the North Carolina Birth Defects Monitoring Program. By employing a Bayesian space-time Poisson model, we estimated spatial and temporal trends of non-chromosomal and chromosomal birth defects. During 2003-2015, 52,524 (3.3 %) of 1598,807 live births had at least one recorded birth defect. The prevalence of non-chromosomal birth defects decreased from 3.8 % in 2003-2.9 % in 2015. Spatial modeling suggested a large geographic variation in non-chromosomal birth defects at census-tract level, with the highest prevalence in southeastern North Carolina. The strong spatial heterogeneity revealed in this work allowed us to identify geographic areas with higher prevalence of non-chromosomal birth defects in North Carolina. This variation will help inform future research focused on epidemiologic studies of birth defects to identify etiologic factors.

Exposure to adverse environments early in life can shape health trajectories across the lifespan. A key mechanism by which this life-long reprogramming occurs is via epigenetic modifications, including altered DNA methylation (DNAm), histone modifications, and microRNA (miRNA) regulation. This invited perspective highlights key human population studies and selected animal studies from our group and collaborators that have examined toxicant exposure occurring during or prior to pregnancy including metals, pharmaceuticals, microorganisms, air pollution, and socioeconomic stressors and their impact on the epigenome. Exposure to these substances is associated with altered epigenetic patterning in fetal blood and placenta, often in a gene- and sex-specific manner. This gene specificity may be tied to the transcription factor occupancy, where environmental exposures alter transcription factor binding at regulatory regions, influencing downstream epigenetic patterns. In relation to adverse health outcomes, these epigenetic modifications have been associated with adverse pregnancy outcomes such as preeclampsia as well as neonatal health (i.e. preterm birth, retinopathy of prematurity, chronic lung disease, and congenital heart defects). Additionally, these epigenetic alterations have been associated with outcomes later in childhood, including cognition, neurodevelopmental disorders [e.g. autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD)], obesity, metabolic dysregulation, asthma, and immune dysfunction. Collectively, these studies highlight the relationships among early-life environmental factors, epigenetic biomarkers, and maternal and child health outcomes.

Background Silicone bands offer a non-invasive method for measuring environmental chemicals; however, their feasibility with young children is uncertain. This mixed-methods study examines toddler compliance with silicone bands, identifies predictors of compliance, and offers recommendations for research. Methods Children wore silicone wrist and ankle bands for 1 week; parents completed daily diaries capturing wear time of each band (hours) to indicate compliance (focal outcome). Mothers completed questionnaires capturing family characteristics and child cognitive and behavioral characteristics. Compliance and its associations with family and child characteristics were examined using descriptive, comparative, and associative statistics, and predictive modeling. Comments provided by parents in diaries and research assistants’ feedback were summarized to inform recommendations for future studies. Results Children ( n = 115, 28–39 months) tended to be highly compliant with wearing both bands (56%) or the ankle band only (23%), as reflected by a median of 11–12 hours/day of wear time over the week. Compliance was higher for ankle than wrist bands ( p -value <0.001). Wear time was not associated with child age, sex, associated clothing when wearing the band, or socioeconomic status ( p -values >0.05). Child language and anxiety were positively associated with wristband compliance ( p -values ≤0.038), whereas higher behavioral inhibition and lower effortful control were associated with higher ankle band compliance ( p -values ≤0.016). Qualitative data suggest improving band appeal and resolving sizing issues could improve compliance. Conclusions Results support the feasibility of deploying silicone bands with toddler-aged children. Studies using child-worn bands should account for hourly wear time, as compliance may predict both chemical exposure levels and child characteristics.

More than 60 million people in the United States and Canada rely on private drinking water systems (mostly private wells), which fall outside of national regulations for water quality and management. This decentralized infrastructure creates unique challenges. First, fragmented policy oversight leads to inconsistent data availability. Second, population heterogeneity in well users requires accounting for the social determinants of health and behavioral differences. Additionally, the individualized nature of well management creates persistent gaps between knowledge generation and the protective action. A broad goal of private well research is to (1) understand, predict, and prevent potential health problems related to well water consumption and (2) enable individual and collective action to reduce exposures to contaminants in well water. Here, we propose a conceptual model to advance private well research through a transdisciplinary approach that links water sources to health and prioritizes engagement among researchers, communities, and decision makers. We also identify challenges and opportunities aimed at improving data systems, refining hazard and risk assessments, linking interdisciplinary research and practical knowledge, and sustaining long-term partnerships. While our geographic focus is on North America, the principles and strategies outlined are globally relevant to addressing health risks associated with unregulated private drinking water sources.

The increased understanding of epigenetics has significantly advanced our understanding of cancer development, especially regarding environmental, occupational, and lifestyle exposures. Unlike genetic mutations, epigenetic changes may be reversible, making them critical mediators and promising targets for cancer prevention and control. This review synthesizes two decades of transformative research by the International Agency for Research on Cancer (IARC), which positioned the epigenome as a central focus in cancer epidemiology and mechanistic research among the 10 Key Characteristics (KCs) of carcinogens by the IARC Monographs program. From foundational in vitro and animal studies to large-scale population-based research, IARC researchers contributed to unraveling epigenetic mechanisms of carcinogenesis and identifying epigenetic biomarkers of exposures and cancer risk. We highlight progress in epigenetic biomarker development, mechanistic epigenomics, toxico-epigenomics, and the interplay between diet, microbiome, and epigenome. As IARC marks its 60th anniversary, this review underscores the growing role of epigenetics in guiding global cancer prevention efforts and public health strategies.

AIM:To predict trajectories of cognitive abilities from ages 2 years to 15 years in children born extremely preterm. METHOD:This longitudinal cohort study examined 659 (330 males) children born at 23 weeks to 27 weeks' gestation with cognitive assessments at ages 2 years, 10 years, and 15 years. Early factors analysed included maternal and neonatal characteristics, comorbidities, and neonatal inflammatory proteins. RESULTS:For verbal, non-verbal, and combined cognitive abilities, greater social disadvantage at birth, male sex, 23 weeks to 24 weeks gestational age, bronchopulmonary dysplasia (BPD), ultrasound-detected cerebral white matter injury (WMI), and elevated inflammatory proteins in neonatal blood were associated with lower scores over the 15-year time frame for all outcomes. Analyses of joint association between socially disadvantaged groups and WMI suggested that the effect of no social disadvantage was evident only among children without WMI, whereas the effect of WMI was evident irrespective of social disadvantage. INTERPRETATION:In this cohort of children born extremely preterm, social disadvantage at birth, male sex, BPD, WMI, and neonatal systemic inflammation were associated with slower gains in cognitive scores from age 2 years to 15 years. Early WMI moderated the associations between social disadvantage and cognitive functioning. Efforts to address both neonatal morbidities and social factors could improve cognitive functioning in children born extremely preterm.

Acetaminophen is among the most common over-the-counter medications used during pregnancy. Given inconsistent findings from both experimental and epidemiological studies on associations between use and adverse health outcomes, further research is warranted. To address this, our objective was to assess the relationship between prenatal acetaminophen use and birth outcomes. We studied 8957 mother-infant pairs from 36 pediatric study sites participating in the Environmental influences on Child Health Outcomes (ECHO) program. After imputation and inverse probability weighting, we used regression models to examine the relationship between acetaminophen during pregnancy and the following outcomes: (1) preterm birth, (2) birthweight, (3) small-for-gestational age (SGA), and (4) large-for-gestational-age (LGA). Approximately 59% of mothers reported using acetaminophen at any point during their pregnancy (n = 5257). After adjustment for relevant covariates, prenatal acetaminophen use was associated with lower odds of LGA (adjusted odds ratio [aOR]: 0.87; 95% CI: 0.79, 0.96). Prenatal acetaminophen use was not associated with preterm birth (aOR: 0.99; 95% CI: 0.86, 1.14), birthweight (aβ: -7.52 g; 95% CI: -27.80, 12.77) or SGA (aOR: 1.02; 95% CI: 0.88, 1.18). Based on these findings, future research should test for dose-response, trimester-specific exposures, and factors affecting individual responses.

Prior studies suggest fluoride exposure in drinking water above 1500 μg/L is associated with lower child cognition, but evidence is limited at lower exposure levels and in U.S. populations. We evaluated whether prenatal exposure to fluoride in regulated public drinking water was associated with cognition in a pooled U.S. cohort. We analyzed observational data from the Environmental influences on Child Health Outcomes (ECHO) Cohort, including 2514 children born 2006-2019 across 17 sites in 23 states. Individual prenatal time-weighted average public water fluoride concentrations were estimated by linking census tract-level concentrations to residential addresses across pregnancy. Fluid and crystallized cognition were assessed using NIH Toolbox scores. Generalized estimating equation models estimated adjusted mean differences using restricted cubic spline and linear change-point models. Individual prenatal time-weighted average water fluoride concentrations ranged from < 1.0-1940.0 μg/L (mean = 396.9 μg/L). Cubic spline models showed significant inverse associations for fluid cognition above 1107.0 μg/L. Linear change-point models identified 675 μg/L as the best-fitting change-point for fluid cognition; above this value, fluid scores were 0.67 points lower (95% CI, -0.92, -0.42) per 100 μg/L higher fluoride. These findings indicate that prenatal fluoride exposure in regulated public water is nonlinearly associated with lower fluid cognition scores in U.S. children at concentrations below current WHO and U.S. EPA thresholds.

Importance:Although fluoride exposure at high levels during the perinatal period has been associated with socioemotional problems among children, there is limited evidence regarding potential associations at lower levels of fluoride exposure, particularly in the US. Objective:To examine the association between prenatal exposure to public drinking water fluoride levels and children's socioemotional problems in a pooled US pediatric consortium. Design, Setting, and Participants:This cohort study used observational pregnancy cohort data from January 1, 2005, to December 31, 2019, on children aged 1.5 to 17 years from the Environmental Influences on Child Health Outcomes (ECHO) Cohort, which took place at 20 prenatal pediatric cohort sites across 34 US states. Statistical analysis was conducted from December 2024 to December 2025. Exposure:Area-level, time-weighted, mean fluoride concentrations in public water were estimated based on residential addresses during pregnancy. Main Outcomes and Measures:Children's socioemotional problems were assessed using caregiver reports of internalizing and externalizing problems via the Child Behavior Checklist. Generalized estimating equation models evaluated the adjusted mean difference in T scores (1) across the range of exposure values in cubic spline models, (2) per 500.0-µg/L higher fluoride level in linear models, (3) across quartiles of exposure, and (4) at the US Public Health Services recommended cutoff (≤700.0 µg/L; 3998 less than the cutoff). Results:The cohort comprised 5520 children (mean [SD] age, 5.8 [3.0] years; 2849 boys [51.6%]). The mean (SD) prenatal time-weighted water fluoride level was 407.9 (361.0) µg/L (range, <1.4-3272.5 µg/L). The adjusted mean difference in emotional and behavioral problem T scores per 500.0-μg/L higher exposure to prenatal public water fluoride was -0.15 (95% CI, -0.85 to 0.56) for internalizing problems and 0.06 (95% CI, -0.44 to 0.55) for externalizing problems, consistently showing no associations at the continuous level. However, some positive associations were observed only when using change point models for externalizing problems (adjusted mean difference, 1.59 [95% CI, 0.72-2.47] per 500.0-µg/L increase above the inflection point), and for some subgroups. Conclusions and Relevance:In this cohort study, prenatal exposure to fluoride levels in regulated public water was not associated with internalizing and externalizing problems among offspring. In change point models, positive associations were found for externalizing problems. The results contribute to growing evidence that could inform future policy decisions regarding fluoride in the US public water systems. Additional studies are needed to further investigate this association, especially examining other sources of fluoride that may have an association with children's emotional and behavioral problems.

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetes, but the role of iAs exposure prior to conception and its transgenerational effects are understudied. Our recent study using C57BL/6 J mice found that exposure of both parents to 2 ppm iAs in drinking water prior to mating resulted in diabetic phenotypes in two consecutive generations of offspring, suggesting epigenetic inheritance. The goal of the present study was to determine if iAs exposure prior to conception was associated with heritable dysregulation of DNA methylation in parental (G0) germ cells and/or differential expression of diabetes-associated genes in G1 and G2 offspring. The Infinium Mouse Methylation BeadChip was employed to assess CpG methylation in G0 sperm and in G1 and G2 sperm, liver, and adipose tissue. DNA methylation in oocytes was assessed by whole-genome bisulfite sequencing. RNA sequencing was used to identify differentially expressed genes (DEGs). We found that the preconception iAs exposure significantly altered expression of genes in tissues of G1 and G2 offspring. Notably, 55

BackgroundThe prevalence of tetralogy of Fallot (TOF), a common congenital heart defect, has increased over the last two decades.MethodsGenome-wide CpG methylation patterns were assessed and analyzed in relation to gestational air pollution exposure among 24 infants with TOF and 24 sex-matched control infants without a birth defect from a North Carolina population-based, case-control study of major structural birth defects (2006-2011). Air pollution exposure during obstetric weeks 3-8 was assigned based on self-reported residence. DNA was extracted from residual newborn blood spots, and DNA methylation levels were measured using the Illumina EPIC Array.ResultsCases had higher exposure to both PM2.5 and O3 compared to controls. No specific CpG loci were statistically significantly associated with TOF status or air pollution exposure; however, we observed associations between TOF case status and DNA methylation at specific genomic regions with genes enriched for functions in metabolism. Additionally, there were significant regions that displayed differential DNA methylation in relation to air pollution exposure within genes involved in apoptosis, necrosis, inflammation, and immune response pathways.ConclusionsGenerally, air pollution exposure and TOF were associated with differential DNA methylation in distinct genes. These results highlight suggestive links between the environment, epigenome, and TOF to be further investigated in larger studies.

The natural, built, and social environments shape drinking water quality supplied by private wells. However, the combined effects of these factors are not well understood. Using North Carolina as a case study, we (i) estimate the demographic characteristics of the private well population; (ii) evaluate representation in well testing records; and (iii) demonstrate how spatial scale influences knowledge of well-using household demographics and representation in testing. We leverage a statewide database of 117,960 well testing records collected over 20 years and a national model predicting well locations. An estimated 25% well-using households identify as Black, Indigenous, and Persons of Color (BIPOC) and 15% have incomes below the poverty threshold. While there is robust well sampling (an average of 4,269 wells tested annually), we observed that most testing records were from predominately White block groups (BGs). Well-using households that did not participate in state testing were 2.4 times more likely to be from predominately BIPOC BGs compared predominately White BGs. Due to the spatial heterogeneity of the well population, demographic differences in well populations were more evident using higher resolution data. Multifaceted testing approaches that couple government-driven efforts with localized studies that engage underrepresented communities are needed to facilitate evidence-based management.

BACKGROUND:DNA methylation (DNAm) at birth has been linked to childhood asthma in epigenome-wide association studies (EWASs). However, existing EWASs have limited representation of non-European and extremely preterm participants and have not explored sex-specific DNAm differences. This study examined the association between DNAm in newborn blood and subsequent childhood asthma risk in a diverse population. METHODS:Data from the Environmental influences on Child Health Outcomes (ECHO) Program were used for EWAS meta-analyses in United States (US) cohorts of children born before and after 28 weeks of gestation. DNAm was measured in newborn blood using Illumina arrays. Childhood asthma was defined as provider-diagnosed asthma with persistent symptoms beyond age 5. Linear regression was used to identify differentially methylated positions (DMPs), and "comb-p" was used to identify differentially methylated regions (DMRs). Sex-stratified analyses were performed. RESULTS:The meta-analysis included 942 children (369 asthma cases) born after 28 weeks of gestation. We identified a novel DMP (cg24749470 in CADM1, P = 9.31 × 10-8) and 18 DMRs (Šidák P-value <.001) associated with asthma, with four DMRs in the human leukocyte antigen region. At these four DMRs, the association between DNAm and asthma differed by sex. In the extremely preterm cohort (n = 271, 106 asthma cases), we identified 20 DMRs, with two novel asthma-associated DMPs (cg03237868 in SPATA18, P = 2.71 × 10-8; cg20681219 in IRF2, P = 5.18 × 10-8) identified in males. CONCLUSION:In US children born before and after 28 weeks of gestation, we discovered novel genomic loci linking newborn blood DNAm to childhood asthma, suggesting DNAm involvement in early asthma development.

PURPOSE:The Environmental influences on Child Health Outcomes (ECHO) Cohort has enrolled over 60,000 children to examine how early environmental factors (broadly defined) are associated with key child health outcomes. The ECHO Cohort may be well-positioned to contribute to our understanding of rural environments and contexts, which has implications for rural health disparities research. The present study examined the outcome of child obesity to not only illustrate the suitability of ECHO Cohort data for these purposes but also determine how various definitions of rural and urban populations impact the presentation of findings and their interpretation. METHODS:This analysis uses data from children in the ECHO Cohort study who had residential address information between January 2010 and October 2023, including a subset who also had height and weight data. Several rural-urban classification schemes were examined with and without collapsing into binary rural/urban groupings (ie, the Rural-Urban Continuum Codes, 2010 Rural-Urban Commuting Area [RUCA] Codes, and Urban Influence Codes). FINDINGS:Various rural/urban definitions and classification schemes produce similar obesity prevalence (17%) when collapsed into binary categories (rural vs urban) and for urban participants in general. When all categories within a classification scheme are examined, however, the rural child obesity prevalence ranges from 5.8% to 24%. CONCLUSIONS:Collapsing rural-urban classification schemes into binary groupings erases nuance and context needed for interpreting findings, ultimately impacting health disparities research. Future work should leverage both individual- and community-level datasets to provide context, and all categories of classification schemes should be used when examining rural populations.

Preterm birth (PTB) is a common pregnancy complication associated with significant neonatal morbidity. Prenatal exposure to environmental chemicals, including toxic and/or essential metal(loid)s, may contribute to PTB risk. We aimed to summarize the epidemiologic evidence of the associations among levels of arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), manganese (Mn), lead (Pb), and zinc (Zn) assessed during the prenatal period and PTB or gestational age at delivery; to assess the quality of the literature and strength of evidence for an effect for each metal; and to provide recommendations for future research. We adapted the Navigation Guide methodology and followed PRISMA guidelines. We searched the MEDLINE/PubMed database for epidemiologic studies from 1995 to 2023. We used a customized risk of bias protocol and evaluated the sufficiency of evidence for an effect of each metal(loid) on PTB risk. A total of 1206 studies were identified and screened. Of these, 139 were assessed for eligibility by reading the full-text, and 92 studies were ultimately included (arsenic: 40, cadmium: 30, chromium: 11, copper: 21, mercury: 27, manganese: 17, lead: 41, zinc: 18, metal(loid) mixtures: 12). We found sufficient evidence that lead increases the risk of PTB and, while the evidence was limited, suggestive evidence that cadmium and chromium increase the risk of PTB. The evidence was deemed inadequate to determine an effect for the other metal(loid)s. Future research would benefit from more precise PTB clinical phenotyping, measuring exposure early and longitudinally throughout pregnancy, using an appropriate media for metal(loid)s under study, and evaluating metal mixtures. Given the strength of evidence linking lead exposure and PTB, active and comprehensive prenatal screening for lead exposure among pregnant individuals is warranted.