Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children. (July 2019)

• Record Type: Journal Article
• Authors: Choi, Hyunok; Song, Won-min; Wang, Minghui; Sram, Radim J.; Zhang, Bin
• Is Part Of: Environment international. Volume 128(2019)
• Page Start: 218
• Page End: 232
• Publication Date: 2019-07
• Subjects: ALAS2 5-aminolevulinic acid synthase-2 -- B[a]P Benzo[a]pyrene -- BTN3A2 Butyrophilin Subfamily 3 Member A2 -- CAP Czech Asthma Pathway -- CREED CRowd Extracted Expression of Differential Signatures -- CYP450s cytochromes P450 -- DEG Differentially expressed genes -- FET Fisher's Exact Test -- ICAC inner city children asthma/healthy cohort -- ICD International Classification of Diseases -- IPAH idiopathic pulmonary arterial hypertension -- JT Jonkheere-Terpestra -- KS Komologorov-Smirnov -- meSCG correlation analysis of methylation profiles and gene expression -- NF-κB Nuclear factor kappa-B -- NK Nature Killer -- AMOD Atopic March Onset & Diversity -- ONOO- Peroxynitrite -- PAH Polycyclic aromatic hydrocarbon -- ROS reactive oxygen species -- SCG Significantly correlated genes -- PM2.5 particulate matter <2.5 μm in aerodynamic diameter -- FCRL2 Fc receptor-like 2; Polycyclic aromatic hydrocarbon -- Asthma -- Air pollution -- Gene co-expression network analysis -- Multiscale clustering analysis -- Environmental systems biology; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2019.04.052
• Languages: English
• ISSNs: 0160-4120

Abstract

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 &#39;moderate&#39; or &#39;severe&#39; 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. Highlights: 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.