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Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children

Choi, Hyunok, Song, Won-min, Wang, Minghui, Sram, Radim J., Zhang, Bin
Environment international 2019 v.128 pp. 218-232
CD8-positive T-lymphocytes, DNA methylation, GATA transcription factors, artificial intelligence, asthma, benzo(a)pyrene, biosynthesis, childhood, children, data analysis, epigenetics, gene expression, glutathione transferase, hematopoiesis, heme, inflammation, regulator genes, stem cells, transcription (genetics), transcription factor NF-kappa B, umbilical cord, urban areas, urban population, Czech Republic
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.