Prenatal particulate matter exposure imprints an epigenetic scar on FCER1G in fetal macrophages, reemerging in M2 macrophages to drive atopic dermatitis development

Prenatal environmental exposures may influence the development of atopic dermatitis (AD), yet the underlying mechanisms remain poorly understood. In this study, we conducted an epidemiological analysis of 986 children, revealing that first-trimester PM _2.5 exposure significantly increases AD risk at age three. Integrated epigenomic and transcriptomic profiling of 48 placentae identified PM _2.5 -associated hypomethylation driving FCER1G overexpression, predominantly in fetal macrophages. This "epigenetic scar" persists across developmental stages, as demonstrated through single-cell RNA sequencing of 404,169 cells from placenta, fetal, and adult skin samples. In adult AD skin, FCER1G was progressively overexpressed in M2 macrophages, particularly within AD-specific cell states. Network analysis and in vitro PM exposure experiments identified a mechanistic axis involving FCER1G, CD68, CYBB, MRC1, and MS4A4A, promoting NADPH oxidase–driven reactive oxygen species signaling. Our findings establish a mechanistic link between prenatal PM _2.5 exposure and AD pathogenesis through persistent macrophage FCER1G dysregulation, highlighting placental epigenetic scars as critical mediators of immune pathogenesis and a target for intervention.