Substantial differences in preterm birth (PTB) persist across populations, with African Americans facing the highest rate. While air pollution contributes to PTB, its role in these uneven health burdens remains poorly understood. Studies of PTB subtypes might uncover racial variation in etiology, yet the impact of air pollution is largely understudied. We assessed the associations of prenatal exposures to ambient fine particulate matters (PM2.5), carbon monoxide (CO), and nitrogen oxides (NOx) with PTB and its subtypes using data from the Atlanta African American Maternal-Child Cohort. We conducted a prospective analysis among 567 African Americans with singleton pregnancies and without chronic medical conditions. Live births were divided into three categories: PTB, early term birth (ETB), and full-term birth, and PTB was further classified into: spontaneous (i.e., sPTB) and medically indicated (i.e., miPTB). Additionally, a composite category combining PTB and ETB was analyzed. We estimated residential air pollution exposures during five critical windows: 1 month prior to conception, entire pregnancy, the 1st, 2nd, and 3rd trimesters. We performed logistic models and discrete-time survival models for individual air pollutants and quantile g-computation models to evaluate the overall effect, with adjustment of selected covariates. We further evaluated whether infant sex modified the associations between gestational air pollution exposure and PTB risk. PM2.5 exposure during the 1st trimester showed a non-significant trend toward increased PTB risk (OR: 1.50, 95

Very preterm infants (<30 weeks gestation) are at elevated risk for neurodevelopmental and social-behavioral challenges. DNA methylation (DNAm) may provide a biological link between preterm birth and later behavioral outcomes. We examined associations between DNAm profiles at neonatal intensive care unit (NICU) discharge and at age 5 with Social Responsiveness Scale (SRS) scores which measure social communication, social interaction, and repetitive behaviors at age 5, including sex-specific effects, in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study. Epigenome-wide buccal DNAm was profiled at NICU discharge (n=218) and at 5 years (n=188). We identified 38 neonatal and 6 age-5 CpG sites associated with SRS scores (all q<0.05) using epigenome-wide association studies (EWAS) at each time point. Several CpGs mapped to genes involved in neurodevelopment including TCF4 , KLC4 , CAP2 , PTDSS1 , ADAM12 , SENP1 , CHN2 , SH3D19 , and ITGA1 , with sex-specific effects observed for CpGs in CAMTA1 and GABBR1 . Enriched pathways included neurodevelopment, cytoskeletal regulation, stress-response, and metabolic processes. DNAm patterns during early life, particularly the neonatal period, were associated with social-behavioral development in very preterm children. Findings in key genes such as TCF4 and CAMTA1 highlight potential epigenetic mechanisms linking early-life biology to later behavioral challenges.

Prenatal exposure to cadmium (Cd) and arsenic (As) can severely impair fetal lung development, leading to lifelong adverse effects. As two of the most common and toxic heavy metals, Cd and As pose risks to many communities through food and water consumption. We have shown that prenatal coexposure to Cd and As at levels relevant to human intake inhibits branching morphogenesis, yet cell type-specific mechanisms remain elusive. Here, we examined early embryonic (Embryonic Day [E]12) lungs from mice exposed prenatally to either 0 (control) or 250 (treated) ppb of both Cd and As. Through single-cell multiome sequencing (single-cell transposase-accessible chromatin with high-throughput sequencing + single-cell RNA sequencing) and high-resolution metabolomics, we present a multifaceted landscape of Cd- and As-induced molecular and cellular disruption. We identified 19 cell states that exhibited state-specific changes in gene expression related to cell proliferation and differentiation. Velocity analysis integrating RNA splicing and chromatin kinetics showed profound disruptions in cell fate, particularly affecting differentiation of Sox2+ proximal progenitors and Wnt2+ mesenchymal progenitors. Gene regulatory network analysis pinpointed the diminished function of Gata6 and Gli2 as central to these disruptions, which was further confirmed by their reduced protein expression in exposed E12, E14.5, and E17 lungs. Additionally, metabolomic alterations in polyamine, tyrosine, and fatty acid biosynthesis correlated with changes in gene expression of catalytic enzymes. These findings demonstrate that Cd and As at levels relevant to human exposure impair early airway formation across multiple regulatory levels, including chromatin accessibility, transcription, and cell metabolism, and they provide insights into the factors central to cell resilience during this vulnerable stage of lung development.

Children born preterm are at higher risk of attention problems compared to children born at term. The purpose of this study was to identify epigenetic predictors of early childhood attention problems among children born very preterm and to examine the joint role of epigenetic and environmental factors in predicting attention problems in this population. We studied 242 participants from a multi-site study of infants born < 30 weeks gestational age. Neonatal buccal swabs were assayed for DNA methylation levels at over 850,000 CpG sites, dimension reduction steps allowed us to focus on 450,000 loci, and age acceleration metrics were calculated using existing epigenetic clocks. Cumulative postnatal environmental adversity was calculated using maternal reported risk factors. Attention problems were assessed in early childhood (mean age 6.58 years) using the Conner’s Kiddie Continuous Performance Test 2nd Edition. After adjustment for multiple testing, DNA methylation at 9 loci were associated with childhood attention problems. Several CpGs were located in genes previously linked to neurodevelopmental traits and inflammation in prior epigenome-wide and genome-wide association studies. Greater environmental adversity was also associated with increased attention problems. When tested together, DNA methylation and environmental adversity independently predicted attention problems. This study is the first to show associations between DNA methylation, environmental adversity, and objectively measured attention problems in school-age children born very preterm. These results could shed light on the etiology of attention problems in this population and may help us identify at birth preterm children at highest risk for later ADHD diagnosis.

BACKGROUND:Epigenetics offers insight into the mechanisms by which early life HIV infection and HIV exposure in utero affects offspring health. However, due to the widespread use of antiretroviral therapy (ART) during pregnancy/infancy, contemporary studies are unable to disentangle effects of HIV from ART exposure on epigenetic profiles. METHODS:Using historical specimens collected before widespread use of ART (1985-1991), we compared DNA methylation (DNAm) profiles among infants with perinatally-acquired HIV (PHIV), HIV-exposed but uninfected (HEU), and HIV-unexposed uninfected (HUU). DNAm in peripheral blood mononuclear cells collected at 3 and 12 months of age (36 PHIV, 33 HEU, and 33 HUU) was profiled using the Illumina Infinium MethylationEPIC BeadChip. We tested for differentially methylated (DM) CpG sites between groups at 3 and 12 months, adjusting for sex, race/ethnicity, and cell type proportions. Biological pathway enrichment analyses were conducted. FINDINGS:Comparing PHIV to HEU, there were 2 DM sites at 3 months and 11 at 12 months. Comparing PHIV to HUU, there was 1 DM CpG site at 3 months and 6 at 12 months. Immune-related pathways, including interferon-mediated signalling pathways were enriched. HIV exposure was not associated with any variation in DNA methylation, as no differences were detected between HEU vs. HUU at 3 or 12 months. INTERPRETATION:HIV infection (in the absence of ART during pregnancy/infancy) was associated with DNA methylation changes at 3 and 12 months of life in infants. Differential methylation in PHIV is related to immune processes and HIV exposure in the absence of infection does not contribute to differential methylation. FUNDING:This study was supported by funding from the National Institutes of Health (R21HD104558 to SS, K01DA053157 to SS, P30ES019776 to CJM, and P30ES005022 to ESB.

Prenatal pesticide exposure may adversely affect child neurodevelopment which may partly arise from impairing the placenta's vital role in fetal development. In a cohort of pregnant farmworkers from Thailand (N = 248), we examined the links between urinary metabolites of pyrethroid pesticides during pregnancy, placental gene expression networks derived from transcriptome sequencing, and newborn neurobehavior assessed using the NICU Network Neurobehavioral Scales (NNNS) at 5 weeks of age. Focusing on the 21 gene network modules in the placenta identified by Weighted Gene Co-expression Network Analysis, our analysis revealed significant associations between metabolites and nine distinct modules, and between thirteen modules and NNNS, with eight modules showing overlap. Notably, stress was negatively associated with the interferon alpha response and Myc target modules, and the interferon alpha response module was correlated positively with attention, and negatively with arousal, and quality of movement. The analysis also highlighted the early and late trimesters as critical periods for the exposures influence on placental function, with pyrethroid metabolites measured early in pregnancy significantly negatively associated with the protein secretion module, and those measured later in pregnancy negatively associated with modules related to oxidative phosphorylation (OXPHOS) and DNA repair. Additionally, the cumulative sum of 3-phenoxybenzoic acid across pregnancy was significantly negatively associated with the OXPHOS module. These findings suggest that prenatal exposure to pyrethroids may influence neonatal neurobehavior through specific placental mechanisms that impact gene expression of metabolic pathways, and these effects may be pregnancy period specific. These results offer valuable insights for future risk assessment and intervention strategies.

We investigated associations between preconception and prenatal heat stress and wildfire (WF) smoke exposures on adverse birth outcomes and whether neighborhood climate vulnerability is an effect modifier in the Maternal And Developmental Risks from Environmental and Social stressors cohort (N = 713). Generalized linear models were fit to test the association between exposures and small-for-gestational-age (SGA), low birthweight (LBW), and Fenton growth z-score outcomes, adjusting for confounders. Living in a high climate vulnerability index neighborhood was tested as an effect modifier. During preconception, increases in heat stress and WF measures were associated with higher odds of SGA. Living in the most climate-vulnerable neighborhoods during preconception significantly modified and nearly doubled the odds of SGA with exposure to heat stress. Similarly, heat stress and WF exposure in trimester-specific time periods were associated with adverse birth outcomes. Conversely, third-trimester exposures were associated with lower odds of LBW. Throughout pregnancy, two measures of infant size (SGA and Fenton z-scores) were lower among those with greater exposure to multiple WF exposures. This study highlights how living in more climate-vulnerable neighborhoods significantly modifies the effect of heat stress on SGA, suggesting that the increasing adaptation capacity of communities may strengthen climate change resilience.

e22576 Background: The biological mechanisms underlying air pollution-induced lung carcinogenesis remained underexplored. We assessed individual and joint effects of six air pollutants on human proteome and their associations with lung cancer risk, aiming to identify key proteins and pathways involved in mediating this process. Methods: We included 95 matched case-control pairs of elderly with pre-diagnosis blood samples from the Cancer Prevention Study-II Nutrition Cohort (1998-2001). Plasma levels of 484 proteins were measured. Annual individual exposures to fine and coarse particulate matter (PM 10 ), nitrogen dioxide, ozone, sulfur dioxide, and carbon monoxide in the year of blood draw were retrieved. We used linear regression for individual pollutant effects and quantile g-computation for joint effects on proteins, and conditional logistic regression for proteins and lung cancer risk, adjusting for confounders and multiple testing. We then conducted pathway analysis to identify overlapping proteins and pathways associated with both exposures and lung cancer risk, followed by an exploratory high-dimensional mediation analysis to investigate the potential mediation roles of proteins. Results: Fifteen proteins were associated with air pollution and six with lung cancer risk (FDR < 0.2). Pathway analysis revealed five pathways related to air pollution and two to lung cancer risk, closely linked to immunity and signaling. Seventeen proteins were associated with both exposures and lung cancer risk ( P < 0.05 or FDR < 0.2), including ADAM15, ATRN, and CX3CL1. The PI3K-Akt signaling pathway was associated with both PM 10 and lung cancer risk. Twenty-two proteins were identified as significant mediators of the association between air pollution and lung cancer risk, including several ILs, CCL20, and IFN-gamma. Conclusions: Various immunity and signaling related proteins and pathways may play significant roles in the association between air pollution exposures and lung cancer. The findings provide novel insights into understanding the underlying etiology and contribute to future biomarker development for preventive and therapeutic strategies.

In the United States, African Americans (AA) are disproportionately exposed to elevated levels of ambient fine particulate matter (PM2.5) while suffering from the highest rates of early births. To elucidate the largely unknown underlying mechanism, we analyzed serum metabolomics from 330 participants in the Atlanta AA Maternal-Child Cohort and performed high-throughput mediation analysis to identify intermediate metabolites and pathways linking PM2.5 to early births. Energy-metabolism-related metabolites (carnitine and adenosine triphosphate), along with lysoPE(20:3) and acetylcysteine, were both associated with PM2.5 exposure and elevated early birth risks. Perturbations in protein digestion and absorption and aromatic amino acid (phenylalanine, tyrosine, and tryptophan) metabolism may potentially mediate the associations between PM2.5 and early births. We identified significant indirect effects of cortexolone (Proportion mediated: -11.8%) and lysoPE(20:3) (9.4%) in mediating the relationship between PM2.5 and early births. Our findings might aid in early birth prevention among AA communities by providing novel insights into the underlying biological mechanism.

BACKGROUND:Children born very preterm (VPT) are at high risk for attention problems. This study's purpose was to describe the Conners Kiddie Continuous Performance Test (K-CPT) assessment in children born VPT, including rates of clinically elevated scores, change over time, and associations between K-CPT scores and parent reported attention problems. METHODS:We studied 305 children from a multi-site study of children born VPT who completed at least one K-CPT assessment at age 5, 6, and/or 7 years. Parent-reported ADHD symptoms and diagnosis were also collected. We calculated K-CPT completion rates, mean scores, and rates of clinically elevated scores at each timepoint. Linear mixed models examined change over time in K-CPT scores. Correlations and generalized linear models investigated associations between K-CPT scores and ADHD symptoms and diagnoses. RESULTS:K-CPT scores showed expected age-related improvements from age 5-7, with significant intra- and inter-individual variability. Up to 1/3 of children had clinically elevated attention problems and another 1/3 had subclinical elevations. K-CPT scores were modestly correlated with parent-rated ADHD symptoms and children with a parent-reported ADHD diagnosis performed worse on nearly all K-CPT metrics. CONCLUSION:Performance-based measures like the K-CPT can be useful for research and clinical practice in VPT populations. IMPACT:Attention problems are a specific area of weakness for children born very preterm. Performance-based tests of attention have benefits and drawbacks compared to parent report measures yet are understudied in this population. We examined one performance-based measure (the Conners Kiddie Continuous Performance Test [K-CPT]) in 305 children born very preterm. We observed improving task scores from age 5-7 years with significant intra- and inter-individual variability, a sizable proportion of children with clinically and subclinically elevated scores, and modest associations between K-CPT scores and parent reported attention problems. The K-CPT could be a useful clinical and research tool in this population.

OBJECTIVES:Several studies suggest that the first immunogenic insult in celiac disease (CeD) could occur during fetal development. The placenta is a key organ that could link the environment with the genome and future outcomes, including CeD. Our objective is to determine the involvement of placental DNA methylation (DNAm) as potential mediator of the genetic susceptibility to CeD. METHODS:We used Summary-data-based Mendelian Randomization to infer what part of the susceptibility to CeD acts through DNAm in placenta or peripheral blood. We interrogated whether DNAm of the CpGs identified correlated with the expression of adjacent genes in the same tissues, and repeated the procedure only in cases and controls carrying the HLA-DQ2 risk haplotype. RESULTS:We identified 248 and 215 CpGs associated with CeD in placenta and blood, respectively. Among the former, the DNAm of seven CpGs correlated with the placental expression of ZFP57. In contrast, in the latter group, the most represented gene was RNF5, with DNAm of 11 CpGs correlating with its expression in blood. In HLA-DQ2 positive individuals, we observed a decrease of placental CpGs associated with CeD, with a remarkable exception in chromosome 2, close to AHSA2. In blood, we identified 44 CpGs associated with CeD in the HLA region, with HLA-DPA1 showing the largest number of DNAm-expression associations. CONCLUSIONS:Our results suggest that placenta does not seem to be a crucial effector in CeD, and show potentially causal relationships between blood DNAm and CeD, with independent signals in the HLA, and particularly in the HLA-DPA1 gene.

The impact of air pollution exposure on circulating proteins remains underexplored, particularly in vulnerable elderly populations. This study investigated the individual and joint effects of air pollutants on circulating proteins in 208 elderly participants from the Cancer Prevention Study-II Nutrition Cohort. Prediagnostic plasma samples were collected (1998-2001), and 484 proteins were measured using the Olink platform. Annual average exposures to six air pollutants in the calendar year of blood draw were estimated. We used linear regression for individual pollutants and quantile g-computation for mixture effects, adjusting for confounders, considering multiple comparison correction, and testing interactions with smoking status. Pathway enrichment and protein-protein interaction analyses were conducted for the associated proteins. We identified 167 distinct proteins associated with individual pollutants or mixtures (p < 0.05), including 15 meeting a false discovery rate <0.2. IL32, ADAM15, and IL8 demonstrated consistent negative associations with ≥4 exposure metrics. Twenty proteins were associated with both mixtures and individual air pollutants with consistent effect directions. These proteins were enriched in pathways linked to immunity and signaling. Stratified analyses revealed differing associations with 99 proteins between current and former smokers. The findings offer valuable insight into the chronic biological response in plasma protein levels to air pollution exposure.

Increasing evidence supports the role of the placenta in neurodevelopment and in the onset of neuropsychiatric disorders. Recently, mQTL and iQTL maps have proven useful in understanding relationships between SNPs and GWAS that are not captured by eQTL. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation. We construct a public placental cis-mQTL database including 214,830 CpG sites calculated in 368 fetal placenta DNA samples from the INMA project, and run cell type-, gestational age- and sex-imQTL models. We combine these data with summary statistics of GWAS on ten neuropsychiatric disorders using summary-based Mendelian randomization and colocalization. We also evaluate the influence of identified DNA methylation sites on placental gene expression in the RICHS cohort. We find that placental cis-mQTLs are enriched in placenta-specific active chromatin regions, and establish that part of the genetic burden for schizophrenia, bipolar disorder, and major depressive disorder confers risk through placental DNA methylation. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, the involvement of cell type-imQTLs, and the correlation of identified DNA methylation sites with the expression levels of relevant genes in the placenta.

Inflammation, a hallmark of cancer and chronic disease, is an established risk factor for lung cancer and is also associated with worse survival in lung cancer cases. C-reactive protein (CRP) is one circulating biomarker of inflammation that has been shown to be associated with DNA methylation (DNAm) in epigenome-wide association studies (EWAS). Several epigenetic CRP scores have been proposed using results from these studies, offering the unique opportunity to approximate CRP in studies without directly measured CRP. A validated DNAm CRP score was recently published by Hillary et al., which explains 18% of CRP variation beyond age, sex, and CRP-based genotype. This score, mCRP, includes 1,468 CpGs obtained from elastic net regression on EWAS results for measured CRP in a training set of nearly 18k individuals. Using an additive linear combination of the published CpGs and EWAS regression weights, we estimated pre-diagnosis mCRP in individuals with a heavy smoking history from the β-Carotene and Retinol Efficacy Trial (CARET) and assessed associations with both lung cancer risk and mortality for all cases and by histotype. Analytic samples included: 316 lung cancer case-control pairs through 2005, matched on age (±5 years), sex, race and ethnicity, enrollment year (±2 years), smoking status (ever/never), asbestos exposure, and follow-up time, (mean 57 pack years, range 11-185) for risk; and 372 lung cancer cases diagnosed through 2013 (mean 59 pack years, range 20-162) for mortality. DNAm data was assayed on the Illumina EPIC array in blood collected on average 4.3 years before diagnosis in cases for risk and 4.9 years for mortality. Conditional logistic regression models adjusted for age and pack years revealed no strong evidence of increased lung cancer risk with increasing mCRP. Cox proportional hazards models adjusted for age, sex, smoking status (current/former), pack years, and time from blood draw to diagnosis with stage as a stratification variable (early I/II, advanced III/IV, unknown) showed a greater hazard of death per standard deviation increase in mCRP among all lung cancer cases (Hazard Ratio (HR) 1.13, CI: 1.02-1.25), adenocarcinoma (HR 1.21, CI: 1.02-1.43), and small cell carcinoma (SCLC; HR 1.33, CI: 1.06-1.68). No associations were observed for squamous cell carcinoma, and results were similar for lung cancer-specific mortality among each case group. While these results do not provide support that pre-diagnosis mCRP is associated with lung cancer risk in individuals with a heavy smoking history, we observed that greater pre-diagnosis mCRP may be an indicator of mortality in members of this population. This work highlights the possible importance of pre-diagnosis inflammation via mCRP and mortality in heavy smokers who later develop lung cancer, particularly adenocarcinoma and SCLC. Laurie Grieshober, Stefan Graw, Matt J. Barnett, Gary E. Goodman, Chu Chen, Devin C. Koestler, Carmen J. Marsit, Jennifer A. Doherty. DNA methylation-estimated C-reactive protein levels and lung cancer risk and mortality in individuals with a heavy smoking history [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2263.

BACKGROUND:Environmental exposures and social determinants likely influence specific childhood asthma phenotypes. OBJECTIVE:We hypothesized that the Child Opportunity Index (COI) at birth, measuring multiple neighborhood opportunities, influences incidence rates (IRs) for asthma with recurrent exacerbations (ARE). METHODS:We tested for COI associations with ARE IRs in 15,877 children born between 1990 and 2018 in the ECHO (Environmental Influences on Child Health Outcomes) program. Parent-reported race and ethnicity and other demographics were assessed as effect modifiers. RESULTS:The IRs of ARE for children born in very low COI neighborhoods was higher (IR = 10.98; 95% CI: 9.71, 12.25) than for other COI categories. Rates for non-Hispanic Black (NHB) children were significantly higher than non-Hispanic White children in every COI category. The ARE IRs for children born in very low COI neighborhoods were several-fold higher for NHB and Hispanic Black children (IR = 15.30; 95% CI: 13.10, 17.49; and IR = 18.48; 95% CI: 8.80, 28.15, respectively) when compared to White children. Adjusting for individual-level characteristics, children born in very low COI neighborhoods demonstrated an ARE IR ratio of 1.26 (95% CI: 0.99, 1.59) with a higher incidence of cases among children ages 2 to 4 years and with a parental history of asthma. CONCLUSIONS:Rates of ARE were higher among children born in under-resourced communities, and this relationship is strongest for young minoritized children with a parental history of asthma. Higher rates for NHB even in the highest COI categories suggest that risk associated with race persists regardless of social disadvantage.

Background Circulating extracellular and vesicle particle (EVP) miRNAs have been associated with cardiovascular risk and adverse birth outcomes. Hypertensive disorders of pregnancy (HDP) increase risk for adverse birth outcomes and future cardiovascular outcomes in mothers and children and have been associated with altered maternal circulating EVP miRNA levels during pregnancy. Whether these relationships exist for elevated blood pressure (BP) in the subclinical range is unknown. We investigated associations between (1) hypertensive disorders of pregnancy and (2) maternal BP trajectories, including in the subclinical range, and circulating EVP miRNA levels during pregnancy in the MADRES (Maternal and Developmental Risks From Environmental and Social Stressors) Study (n=372). Methods Latent class trajectory modeling was used to identify trajectories from BP measures abstracted from medical records. The NanoString nCounter platform was used to quantify 798 miRNAs extracted from maternal blood (median gestational age: 31.6 weeks). Covariate‐adjusted regression models assessed associations between each hypertensive disorders of pregnancy subtype or BP trajectory and levels of each miRNA. Results Three BP trajectories were identified: Low, Moderate, and High. Chronic hypertension was associated with higher levels of miR‐1185‐2‐3p (Pfalse discovery rate<0.05), a placenta‐specific miRNA linked to arterial stiffness and preterm delivery. Many placenta‐expressed miRNAs previously associated with a longer gestational duration in the same cohort were lower among participants with elevated BP (P<0.05). Target genes of BP‐associated EVP miRNAs were overrepresented in pathways involved in vascular inflammation, oxidative stress, endothelial dysfunction, and placental function. Conclusions Circulating levels of placenta‐expressed EVP miRNAs previously implicated in adverse birth and cardiovascular outcomes are sensitive to elevated maternal BP during pregnancy, including in the subclinical range.

Prenatal exposure to pesticides has been linked to disrupted fetal growth, which contributes to cardiometabolic disease risk. The placenta, as the maternal–fetal interface, undergoes extensive DNA methylation remodeling that may record environmental exposures and mediate downstream metabolic effects, including those related to cardiometabolic risk in offspring. We hypothesized that placental DNA methylation patterns vary with maternal pesticide exposure, that exposure-associated CpG sites overlap with those predictive of neonatal anthropometry, and that genes with altered methylation may represent pathways relevant to cardiometabolic health. We analyzed 254 term placentas from the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) cohort using the Illumina EPIC v2.0 array. Robust linear regression models assessed associations between placental DNA methylation and infant head circumference, birth length, and birth weight z-scores. Each outcome was analyzed separately, adjusting for estimated proportions of eight placental cell types, infant sex, maternal age, BMI, and gestational age. Parallel analyses examined urinary organophosphate metabolites (OP), pyrethroid metabolites (PYR), and a composite exposure index (MIX). CpGs with Benjamini–Hochberg FDR < 0.05 were considered significant. Significant CpGs were intersected across exposures and outcomes and mapped to genes for Gene Ontology and KEGG pathway enrichment (FDR < 0.05). EWAS of growth traits identified 26, 1,626, and 1,729 CpGs associated with head circumference, birth length, and birthweight, respectively. CpGs associated with weight and length were enriched for pathways including insulin resistance and MAPK signaling. Exposure-related EWAS identified 46,519 significant CpGs for OP and 46,564 for MIX; none for PYR. MAPK signaling was the top enriched pathway for both OP and MIX. Intersection of OP and MIX signatures yielded 46,417 shared CpGs, with 102 and 135 overlapping length- and weight-associated sites, respectively. Nine genes were common to both exposure and growth signatures, with IRS1 identified as a central node linking insulin and MAPK pathways. Placental methylation patterns associated with prenatal pesticide exposure overlap with epigenetic signals linked to neonatal growth, particularly involving insulin resistance and MAPK signaling, highlighting mechanisms of fetal programming relevant to long-term cardiometabolic health.