Abstract Body (Do not enter title and authors here): 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.