Placental DNA methylation gene networks correlate with wildfire-informed particulate matter exposure and child neurodevelopment outcomes.

Methods

We performed whole-genome bisulfite sequencing (WGBS) on 221 placentae from the MARBLES and B-SAFE, then performed comethylation network analysis to identify modules of correlated DNA methylation associated with wilfire-informed particulate exposures and neurodevelopmental outcomes. Results: We identified 85 placental comethylation modules, 22 of which were significantly associated with prenatal air pollution exposures.

Preconception and pregnancy exposures associated with distinct module sets. Pregnancy air pollution preferentially correlated with modules annotated to semaphorin signaling and cytoskeletal remodeling pathways, including SEMA3A and RND3. In contrast, preconception exposures were enriched for modules proximal to transcriptional regulators.

Ten exposure-associated modules also correlated with child neurodevelopmental measures, including ASD diagnosis. These modules contained neurodevelopmentally relevant genes, including NHIP, AUTS2, EBF3, PLCB1, and SLIT2, and were enriched for synaptic and cell-cell signaling pathways. Conclusions: Prenatal air pollution exposure associates with temporally and source-specific placental methylation networks enriched for signaling pathways relevant to placental function and neurodevelopment.

These findings support the placenta as an epigenetic interface linking air pollution exposure to altered developmental trajectories.