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

Abstract

Background: The extent to which ambient benzo[a]pyrene (B[a]P) contributes to mechanistically distinct de novo asthma remains unknown.

Objectives: To identify molecular signatures and regulatory networks underlying childhood exposure to ambient B[a]P and asthma, using robust and unbiased systems biology approaches.

Methods: 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).

Results: 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 CD71^low 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.

Conclusions: 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.

Keywords: Air pollution; Asthma; Environmental systems biology; Gene co-expression network analysis; Multiscale clustering analysis; Polycyclic aromatic hydrocarbon.