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Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children
https://orcid.org/0000-0001-9171-4962
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 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. 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.
Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children
https://orcid.org/0000-0001-9171-4962
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 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. 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.
Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children
https://orcid.org/0000-0001-9171-4962
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 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. 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.
Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children
Choi, Hyunok (author) / Song, Won-min (author) / Wang, Minghui (author) / Sram, Radim J. (author) / Zhang, Bin (author)
Environmental International ; 128 ; 218-232
2019-04-22
15 pages
Article (Journal)
Electronic Resource
English
ALAS2 , 5-aminolevulinic acid synthase-2 , B[<italic>a</italic>]P , Benzo[<italic>a</italic>]pyrene , <italic>BTN3A2</italic> , 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 , <italic>NF-κB</italic> , 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 , PM<inf>2.5</inf> , particulate matter <2.5 <italic>μ</italic>m in aerodynamic diameter , <italic>FCRL2</italic> , Fc receptor-like 2 , Asthma , Air pollution , Gene co-expression network analysis , Multiscale clustering analysis , Environmental systems biology
Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children
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