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The extent to which ambient benzo[ a ]pyrene (B[ a ]P) contributes to mechanistically distinct de novo asthma remains unknown. To identify molecular signatures and regulatory networks underlying childhood exposure to ambient B[ a ]P and asthma, using robust and unbiased systems biology approaches. Clinically confirmed asthmatic (n = 191) vs. control (n = 194) children (aged, 7–15) were enrolled from a polluted urban center and semi-rural region in Czech Republic. Contemporaneous B[ a ]P concentration, gene expressions, DNA methylation data were analyzed against asthma diagnosis, as well as a modified prognostic index of asthma, using integrative multiscale co-expression network analysis. Sample-wise cell type compositions were inferred by a machine learning approach (i.e. CIBERSORT) with reference gene expressions of purified 38 distinct hematopoietic cell states from umbilical cord (i.e. stem cell/progenitors) or peripheral blood (i.e. lymphocytes). The median outdoor B[ a ]P was increased near the homes of the urban children with 'moderate' or 'severe' prognostic markers of asthma, but not in the urban controls. An elevated B[ a ]P induced epigenetic suppression of NF-κB inflammation, decreased Natural Killer T (NKT) cells and activated anti-inflammatory IL10-secreting CD8+ T effective memory cells. B[ a ]P was positively correlated with an increased expression of a heme biosynthesis gene, ALAS2 , which in turn, appears to promote concurrent increase of neutrophilic metamyelocyte and mature CD71low erythroid cells. Furthermore, erythroid-specific master transcription regulator gene (GATA1), glutathione transferase genes (GSTM1 and GSTM3) and Eosinophil marker (IL5RA) were simultaneously activated in the urban asthma cases. B[ a ]P might contribute to concurrent suppression of pro-inflammatory (e.g. NF-κB mediated NKT cells), and activation of anti-inflammatory pathways (e.g. IL10-secreting CD8+ T cells) in the urban asthmatic children. In addition, B[ a ]P appears to elevate heme biosynthesis, which in turn, promotes neutrophilic metamyelocyte expansion and reduction of CD71+ erythroids. • B[ a ]P suppresses NF-κB mediated inflammation by inducing the IL10-secreting CD8+ T cells (TEMRA: M7/M11). • B[ a ]P mis associated with maturation of erythoid cells and expansion of neutrophilic metamyelocyte population. • B[ a ]P regulates eosinophil (M30) through epigenetic modification of transcription in its cis-CpG sites. [ABSTRACT FROM AUTHOR]