A systemic approach to identify signaling pathways activated during short-term exposure to traffic-related urban air pollution from human blood

Abstract

The molecular mechanisms that promote pathologic alterations in human physiology mediated by short-term exposure to traffic pollutants remains not well understood. This work was to develop mechanistic networks to determine which specific pathways are activated by real-world exposures of traffic-related air pollution (TRAP) during rest and moderate physical activity (PA). A controlled crossover study to compare whole blood gene expression pre and post short-term exposure to high and low of TRAP was performed together with systems biology analysis. Twenty-eight healthy volunteers aged between 21 and 53 years were recruited. These subjects were exposed during 2 h to different pollution levels (high and low TRAP levels), while either cycling or resting. Global transcriptome profile of each condition was performed from human whole blood samples. Microarrays analysis was performed to obtain differential expressed genes (DEG) to be used as initial input for GeneMANIA software to obtain protein-protein (PPI) networks. Two networks were found reflecting high or low TRAP levels, which shared only 5.6 and 15.5% of its nodes, suggesting specific cell signaling pathways being activated in each environmental condition. However, gene ontology analysis of each PPI network suggests that each level of TRAP regulate common members of NF-κB signaling pathway. Our work provides the first approach describing mechanistic networks to understand TRAP effects on a system level.

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References

  1. Aad G (2014) Observation of an excited Bc(+/−) meson state with the ATLAS detector. Phys Rev Lett 113:212004

    Article  Google Scholar 

  2. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29

    CAS  Article  Google Scholar 

  3. Bauer RN, Diaz-Sanchez D, Jaspers I (2012) Effects of air pollutants on innate immunity: the role of Toll-like receptors and nucleotide-binding oligomerization domain-like receptors. J Allergy Clin Immunol 129:14–24 quiz 25-6

    CAS  Article  Google Scholar 

  4. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093

    CAS  Article  Google Scholar 

  5. Cai Y, Schikowski T, Adam M, Buschka A, Carsin AE, Jacquemin B, Marcon A, Sanchez M, Vierkötter A, al-Kanaani Z, Beelen R, Birk M, Brunekreef B, Cirach M, Clavel-Chapelon F, Declercq C, de Hoogh K, de Nazelle A, Ducret-Stich RE, Valeria Ferretti V, Forsberg B, Gerbase MW, Hardy R, Heinrich J, Hoek G, Jarvis D, Keidel D, Kuh D, Nieuwenhuijsen MJ, Ragettli MS, Ranzi A, Rochat T, Schindler C, Sugiri D, Temam S, Tsai MY, Varraso R, Kauffmann F, Krämer U, Sunyer J, Künzli N, Probst-Hensch N, Hansell AL (2014) Cross-sectional associations between air pollution and chronic bronchitis: an ESCAPE meta-analysis across five cohorts. Thorax 69:1005–1014

    Article  Google Scholar 

  6. Cantorna MT et al (1994) In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J Immunol 152:1515–1522

    CAS  Google Scholar 

  7. Carlisle AJ, Sharp NC (2001) Exercise and outdoor ambient air pollution. Br J Sports Med 35:214–222

    CAS  Article  Google Scholar 

  8. Carmona JJ, Sofer T, Hutchinson J, Cantone L, Coull B, Maity A, Vokonas P, Lin X, Schwartz J, Baccarelli AA (2014) Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study. Environ Health 13:94

    Article  Google Scholar 

  9. Cassandro E, Chiarella G, Cavaliere M, Sequino G, Cassandro C, Prasad SC, Scarpa A, Iemma M (2015) Hyaluronan in the treatment of chronic rhinosinusitis with nasal polyposis. Indian J Otolaryngol Head Neck Surg 67:299–307

    Article  Google Scholar 

  10. Chiarella E, Carrà G, Scicchitano S, Codispoti B, Mega T, Lupia M, Pelaggi D, Marafioti MG, Aloisio A, Giordano M, Nappo G, Spoleti CB, Grillone T, Giovannone ED, Spina R, Bernaudo F, Moore MAS, Bond HM, Mesuraca M, Morrone G (2014) UMG Lenti: novel lentiviral vectors for efficient transgene- and reporter gene expression in human early hematopoietic progenitors. PLoS One 9:e114795

    Article  Google Scholar 

  11. Chiarella SE, Soberanes S, Urich D, Morales-Nebreda L, Nigdelioglu R, Green D, Young JB, Gonzalez A, Rosario C, Misharin AV, Ghio AJ, Wunderink RG, Donnelly HK, Radigan KA, Perlman H, Chandel NS, Budinger GRS, Mutlu GM (2014) β2-Adrenergic agonists augment air pollution-induced IL-6 release and thrombosis. J Clin Invest 124:2935–2946

    CAS  Article  Google Scholar 

  12. Chinenov Y, Kerppola TK (2001) Close encounters of many kinds: Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene 20:2438–2452

    CAS  Article  Google Scholar 

  13. Choi P, Reiser H (1998) IL-4: role in disease and regulation of production. Clin Exp Immunol 113:317–319

    CAS  Article  Google Scholar 

  14. De Luca L et al (2014) A decade of changes in clinical characteristics and management of elderly patients with non-ST elevation myocardial infarction admitted in Italian cardiac care units. Open Heart 1:e000148

    Article  Google Scholar 

  15. Edwards TM, Myers JP (2007) Environmental exposures and gene regulation in disease etiology. Environ Health Perspect 115:1264–1270

    CAS  Article  Google Scholar 

  16. Flynn MG, McFarlin BK, Markofski MM (2007) The anti-inflammatory actions of exercise training. Am J Lifestyle Med 1:220–235

    Article  Google Scholar 

  17. Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315

    CAS  Article  Google Scholar 

  18. Gerlo S, Kooijman R, Beck IM, Kolmus K, Spooren A, Haegeman G (2011) Cyclic AMP: a selective modulator of NF-kappaB action. Cell Mol Life Sci 68:3823–3841

    CAS  Article  Google Scholar 

  19. Gowdy KM, Krantz QT, King C, Boykin E, Jaspers I, Linak WP, Gilmour MI (2010) Role of oxidative stress on diesel-enhanced influenza infection in mice. Part Fibre Toxicol 7:34

    CAS  Article  Google Scholar 

  20. Gringhuis SI, Kaptein TM, Wevers BA, Mesman AW, Geijtenbeek TBH (2014) Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKepsilon- and CYLD-dependent Bcl3 activation. Nat Commun 5:3898

    CAS  Article  Google Scholar 

  21. Grunig G, Marsh LM, Esmaeil N, Jackson K, Gordon T, Reibman J, Kwapiszewska G, Park SH (2014) Perspective: ambient air pollution: inflammatory response and effects on the lung's vasculature. Pulm Circ 4:25–35

    Article  Google Scholar 

  22. Gulati M, Shaw LJ, Thisted RA, Black HR, Bairey Merz CN, Arnsdorf MF (2010) Heart rate response to exercise stress testing in asymptomatic women: the St. James women take heart project. Circulation 122:130–137

    Article  Google Scholar 

  23. Hao M, Comier S, Wang M, Lee JJ, Nel A (2003) Diesel exhaust particles exert acute effects on airway inflammation and function in murine allergen provocation models. J Allergy Clin Immunol 112:905–914

    CAS  Article  Google Scholar 

  24. Harriss DJ, Atkinson G, Batterham A, George K, Tim Cable N, Reilly T, Haboubi N, Renehan AG, The Colorectal Cancer, Lifestyle, Exercise And Research Group (2009) Lifestyle factors and colorectal cancer risk (2): a systematic review and meta-analysis of associations with leisure-time physical activity. Color Dis 11:689–701

    CAS  Article  Google Scholar 

  25. Hostager BS, Bishop GA (2013) CD40-mediated activation of the NF-kappaB2 pathway. Front Immunol 4:376

    Article  Google Scholar 

  26. Huang J, Deng F, Wu S, Lu H, Hao Y, Guo X (2013) The impacts of short-term exposure to noise and traffic-related air pollution on heart rate variability in young healthy adults. J Expo Sci Environ Epidemiol 23:559–564

    CAS  Article  Google Scholar 

  27. Jacobs JL, Coyne CB (2013) Mechanisms of MAVS regulation at the mitochondrial membrane. J Mol Biol 425:5009–5019

    CAS  Article  Google Scholar 

  28. Jin C, Shelburne CP, Li G, Potts EN, Riebe KJ, Sempowski GD, Foster WM, Abraham SN (2011) Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation. J Clin Invest 121:941–955

    CAS  Article  Google Scholar 

  29. Kubesch N, de Nazelle A, Guerra S, Westerdahl D, Martinez D, Bouso L, Carrasco-Turigas G, Hoffmann B, Nieuwenhuijsen MJ (2015) Arterial blood pressure responses to short-term exposure to low and high traffic-related air pollution with and without moderate physical activity. Eur J Prev Cardiol 22:548–557

    CAS  Article  Google Scholar 

  30. Kubesch NJ, de Nazelle A, Westerdahl D, Martinez D, Carrasco-Turigas G, Bouso L, Guerra S, Nieuwenhuijsen MJ (2015) Respiratory and inflammatory responses to short-term exposure to traffic-related air pollution with and without moderate physical activity. Occup Environ Med 72:284–293

    Article  Google Scholar 

  31. Lai YJ, Lin VTG, Zheng Y, Benveniste EN, Lin FT (2010) The adaptor protein TRIP6 antagonizes Fas-induced apoptosis but promotes its effect on cell migration. Mol Cell Biol 30:5582–5596

    CAS  Article  Google Scholar 

  32. Li L, Bin LH, Li F, Liu Y, Chen D, Zhai Z, Shu HB (2005) TRIP6 is a RIP2-associated common signaling component of multiple NF-kappaB activation pathways. J Cell Sci 118:555–563

    CAS  Article  Google Scholar 

  33. Li N, Harkema JR, Lewandowski RP, Wang M, Bramble LA, Gookin GR, Ning Z, Kleinman MT, Sioutas C, Nel AE (2010) Ambient ultrafine particles provide a strong adjuvant effect in the secondary immune response: implication for traffic-related asthma flares. Am J Phys Lung Cell Mol Phys 299:L374–L383

    CAS  Google Scholar 

  34. Libermann TA, Baltimore D (1990) Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 10:2327–2334

    CAS  Article  Google Scholar 

  35. Lindgren A et al (2009) Traffic-related air pollution associated with prevalence of asthma and COPD/chronic bronchitis. A cross-sectional study in Southern Sweden. Int J Health Geogr 8:2

    Article  Google Scholar 

  36. Liu S, Chen ZJ (2011) Expanding role of ubiquitination in NF-kappaB signaling. Cell Res 21:6–21

    Article  Google Scholar 

  37. Liu H, Deng X, Shyu YJ, Li JJ, Taparowsky EJ, Hu CD (2006) Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. EMBO J 25:1058–1069

    CAS  Article  Google Scholar 

  38. Lopez-Bergami P, Lau E, Ronai Z (2010) Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10:65–76

    CAS  Article  Google Scholar 

  39. Madsen C, Rosland P, Hoff DA, Nystad W, Nafstad P, Næss ØE (2012) The short-term effect of 24-h average and peak air pollution on mortality in Oslo, Norway. Eur J Epidemiol 27:717–727

    CAS  Article  Google Scholar 

  40. Moore AR, Willoughby DA (1995) The role of cAMP regulation in controlling inflammation. Clin Exp Immunol 101:387–389

    CAS  Article  Google Scholar 

  41. Mustafic H et al (2012) Main air pollutants and myocardial infarction: a systematic review and meta-analysis. JAMA 307:713–721

    CAS  Article  Google Scholar 

  42. Nepusz T, Yu H, Paccanaro A (2012) Detecting overlapping protein complexes in protein-protein interaction networks. Nat Methods 9:471–472

    CAS  Article  Google Scholar 

  43. Newman MEJ (2005) A measure of betweenness centrality based on random walks. Soc Networks 27:39–54

    Article  Google Scholar 

  44. Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1:a000034

    Article  Google Scholar 

  45. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, Buchner D, Ettinger W, Heath GW, King AC (1995) Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 273:402–407

    CAS  Article  Google Scholar 

  46. Peters A, von Klot S, Heier M, Trentinaglia I, Hörmann A, Wichmann HE, Löwel H, Cooperative Health Research in the Region of Augsburg Study Group (2004) Exposure to traffic and the onset of myocardial infarction. N Engl J Med 351:1721–1730

    CAS  Article  Google Scholar 

  47. Pourazar J, Blomberg A, Kelly FJ, Davies DE, Wilson SJ, Holgate ST, Sandström T (2008) Diesel exhaust increases EGFR and phosphorylated C-terminal Tyr 1173 in the bronchial epithelium. Part Fibre Toxicol 5:8

    Article  Google Scholar 

  48. Ritchie ME et al (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47

    Article  Google Scholar 

  49. Samoli E, Atkinson RW, Analitis A, Fuller GW, Green DC, Mudway I, Anderson HR, Kelly FJ (2016) Associations of short-term exposure to traffic-related air pollution with cardiovascular and respiratory hospital admissions in London, UK. J Occup Environ Med 73:300–307

    Article  Google Scholar 

  50. Scardoni G, Petterlini M, Laudanna C (2009) Analyzing biological network parameters with CentiScaPe. Bioinformatics 25:2857–2859

    CAS  Article  Google Scholar 

  51. Schifano P, Asta F, Dadvand P, Davoli M, Basagana X, Michelozzi P (2016) Heat and air pollution exposure as triggers of delivery: a survival analysis of population-based pregnancy cohorts in Rome and Barcelona. Environ Int 88:153–159

    CAS  Article  Google Scholar 

  52. Sun Q, Hong X, Wold LE (2010) Cardiovascular effects of ambient particulate air pollution exposure. Circulation 121:2755–2765

    Article  Google Scholar 

  53. Weichenthal S, Hatzopoulou M, Goldberg MS (2014) Exposure to traffic-related air pollution during physical activity and acute changes in blood pressure, autonomic and micro-vascular function in women: a cross-over study. Part Fibre Toxicol 11:70

    Article  Google Scholar 

  54. Yu RY, Wang X, Pixley FJ, Yu JJ, Dent AL, Broxmeyer HE, Stanley ER, Ye BH (2005) BCL-6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production. Blood 105:1777–1784

    CAS  Article  Google Scholar 

  55. Zhang S, Li G, Tian L, Guo Q, Pan X (2016) Short-term exposure to air pollution and morbidity of COPD and asthma in East Asian area: a systematic review and meta-analysis. Environ Res 148:15–23

    CAS  Article  Google Scholar 

  56. Zuberi K, Franz M, Rodriguez H, Montojo J, Lopes CT, Bader GD, Morris Q (2013) GeneMANIA prediction server 2013 update. Nucleic Acids Res 41:W115–W122

    Article  Google Scholar 

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Correspondence to José Eduardo Vargas or Juan R. González.

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The Institut Municipal d’Investigació Mèdica (IMIM) Ethics Review Committee approved the model of this study. All the volunteers signed a consent form before participating in this research.

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The authors declare that they have no conflict of interest.

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Responsible editor: Philippe Garrigues

Electronic supplementary material

Supplementary figure 1
figure7

All PPI networks obtained after meta-analysis of microarrays data. These networks were obtained from peripheral blood samples of adults exposed to low and high traffic-related air pollution exposures during moderate physical activity. (PNG 457 kb)

Supplementary figure 2
figure8

ClueGO results of LE and HE PPI networks. These networks are created with Cohen’s kappa statistics, reflecting similarity between biological terms based on the similarity of their associated genes. A- Result derived from clustered LE PPI network. Networks derived from ClueGO analysis of unclustered LE and HE PPI networks, B and C respectively. (PNG 1231 kb)

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Vargas, J.E., Kubesch, N., Hernandéz-Ferrer, C. et al. A systemic approach to identify signaling pathways activated during short-term exposure to traffic-related urban air pollution from human blood. Environ Sci Pollut Res 25, 29572–29583 (2018). https://doi.org/10.1007/s11356-018-3009-8

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Keywords

  • Traffic-related air pollution
  • Human interactome
  • Systems biology
  • Moderate physical activity