Transcriptomic response of primary human airway epithelial cells to flavoring chemicals in electronic cigarettes

Scientific Reports

Volumn 9, Issue 1, 2019, Pages

  Park, Hae Ryung ^a   O’Sullivan, Michael ^a   Vallarino, Jose ^a   Shumyatcher, Maya ^b   Himes, Blanca E ^b   Park, Jin Ah ^a   Christiani, David C ^a   Allen, Joseph ^a   Lu, Quan ^a  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,3 BUTANEDIONE; FLAVORING AGENT; TRANSCRIPTOME;

ADVERSE EVENT; BRONCHUS; CELL CULTURE; CILIUM; CYTOLOGY; CYTOSKELETON; ELECTRONIC CIGARETTE; EPITHELIUM CELL; EXPOSURE; HUMAN; LUNG; METABOLISM; PATHOLOGY; PHYSIOLOGY;

BRONCHI; CELLS, CULTURED; CILIA; CYTOSKELETON; DIACETYL; ELECTRONIC NICOTINE DELIVERY SYSTEMS; EPITHELIAL CELLS; FLAVORING AGENTS; HUMANS; INHALATION EXPOSURE; LUNG; TRANSCRIPTOME;

EID: 85060944682     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/s41598-018-37913-9     Document Type: Article

References (83)

1. CDC. E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General. (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and HealthAtlanta, GA, 2016)
2. WHO. Electronic Nicotine Delivery Systems and Electronic Non-Nicotine Delivery Systems (ENDS/ENNDS). (World Health Organizatioon, Conference of the Parties to the WHO Framework Conventionon Tobacco Control, Delhi, India, 2016)
3. Goniewicz, M. L., Hajek, P. & McRobbie, H. Nicotine content of electronic cigarettes, its release in vapour and its consistency across batches: regulatory implications. Addiction 109, 500–507, 10.1111/add.12410 (2014)
4. Long, G. A. Comparison of select analytes in exhaled aerosol from e-cigarettes with exhaled smoke from a conventional cigarette and exhaled breaths. Int J Environ Res Public Health 11, 11177–11191, 10.3390/ijerph111111177 (2014)
5. McMillen, R. C., Gottlieb, M. A., Shaefer, R. M., Winickoff, J. P. & Klein, J. D. Trends in Electronic Cigarette Use Among USAdults: Use is Increasing in Both Smokers and Nonsmokers. Nicotine Tob Res 17, 1195–1202, 10.1093/ntr/ntu213 (2015)
6. ML, T. et al. Analysis of electronic cigarette cartridges, refill solutions, and smoke for nicotine and nicotine related impurities. J Liq Chromatogr Relat Technol 34, 1442–1458 (2011)
7. Bekki, K. et al. Carbonyl compounds generated from electronic cigarettes. Int J Environ Res Public Health 11, 11192–11200, 10.3390/ijerph111111192 (2014)
8. Callahan-Lyon, P. Electronic cigarettes: human health effects. Tob Control 23(Suppl 2), ii36–40, 10.1136/tobaccocontrol-2013-051470 (2014)
9. Cheng, T. Chemical evaluation of electronic cigarettes. Tob Control 23(Suppl 2), ii11–17, 10.1136/tobaccocontrol-2013-051482 (2014)
10. Goniewicz, M. L. et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control 23, 133–139, 10.1136/tobaccocontrol-2012-050859 (2014)
11. Hutzler, C. et al. Chemical hazards present in liquids and vapors of electronic cigarettes. Arch Toxicol 88, 1295–1308, 10.1007/s00204-014-1294-7 (2014)
12. Jensen, R. P., Luo, W., Pankow, J. F., Strongin, R. M. & Peyton, D. H. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med 372, 392–394, 10.1056/NEJMc1413069 (2015)
13. Orr, M. S. Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future. Tob Control 23(Suppl 2), ii18–22, 10.1136/tobaccocontrol-2013-051474 (2014)
14. Pellegrino, R. M. et al. Electronic cigarettes: an evaluation of exposure to chemicals and fine particulate matter (PM). Ann Ig 24, 279–288 (2012)
15. Uchiyama, S., Ohta, K., Inaba, Y. & Kunugita, N. Determination of carbonyl compounds generated from the E-cigarette using coupled silica cartridges impregnated with hydroquinone and 2,4-dinitrophenylhydrazine, followed by high-performance liquid chromatography. Anal Sci 29, 1219–1222 (2013)
16. Williams, M., To, A., Bozhilov, K. & Talbot, P. Strategies to Reduce Tin and Other Metals in Electronic Cigarette Aerosol. PLoS One 10, e0138933, 10.1371/journal.pone.0138933 (2015)
17. Allen, J. G. et al. Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3-Pentanedione, and Acetoin in a Sample of 51 Products, Including Fruit-, Candy-, and Cocktail-Flavored E-Cigarettes. Environ Health Perspect 124, 733–739, 10.1289/ehp.1510185 (2016)
18. Clark, S. & Winter, C. K. Diacetyl in Foods: A Review of Safety and Sensory Characteristics. Comprehensive Reviews in Food Science and Food Safety 14, 634–643 (2015)
19. Hilts, P. In New York Times (New York, NY, 2011)
20. OSHA. (Occupational Safety and Health Administration, 2007)
21. CDC. Vol. 56(16), 389–393 (Centers for Disease Control, MMWR Morb Mortal Wkly, 2007)
22. NIOSH. Draft—Criteria for a recommended standard. Occupational Exposure to Diacetyl and 2,3-Pentanedione. National Institute for Occupational Safety and Health (2011)
23. Kreiss, K. et al. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 347, 330–338, 10.1056/NEJMoa020300 (2002)
24. NIOSH. Criteria for a recommended standard: occupational exposure to diacetyl and 2,3-pentanedione. By McKernan, L. T., et al. (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH, 2016)
25. Hubbs, A. F. et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol 185, 128–135 (2002)
26. Hubbs, A. F. et al. Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in Sprague-Dawley rats. Am J Pathol 181, 829–844, 10.1016/j.ajpath.2012.05.021 (2012)
27. Hubbs, A. F. et al. Respiratory toxicologic pathology of inhaled diacetyl in sprague-dawley rats. Toxicol Pathol 36, 330–344, 10.1177/0192623307312694 (2008)
28. Morgan, D. L., Flake, G. P., Kirby, P. J. & Palmer, S. M. Respiratory toxicity of diacetyl in C57BL/6 mice. Toxicol Sci 103, 169–180, 10.1093/toxsci/kfn016 (2008)
29. Morgan, D. L. et al. Chemical Reactivity and Respiratory Toxicity of the alpha-Diketone Flavoring Agents: 2,3-Butanedione, 2,3-Pentanedione, and 2,3-Hexanedione. Toxicol Pathol 44, 763–783, 10.1177/0192623316638962 (2016)
30. Pezzulo, A. A. et al. The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia. Am J Physiol Lung Cell Mol Physiol 300, L25–31, 10.1152/ajplung.00256.2010 (2011)
31. Larsen, S. T., Alarie, Y., Hammer, M. & Nielsen, G. D. Acute airway effects of diacetyl in mice. Inhal Toxicol 21, 1123–1128, 10.3109/08958370902795311 (2009)
32. Zaccone, E. J. et al. Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents. Toxicol Appl Pharmacol 289, 542–549, 10.1016/j.taap.2015.10.004 (2015)
33. Zaccone, E. J. et al. Popcorn flavoring effects on reactivity of rat airways in vivo and in vitro. J Toxicol Environ Health A 76, 669–689, 10.1080/15287394.2013.796302 (2013)
34. Yaghi, A. & Dolovich, M. B. Airway Epithelial Cell Cilia and Obstructive Lung Disease. Cells 5, https://doi.org/10.3390/cells5040040 (2016)
35. Harvey, B. G. et al. Modification of gene expression of the small airway epithelium in response to cigarette smoking. J Mol Med (Berl) 85, 39–53, 10.1007/s00109-006-0103-z (2007)
36. Patton, J. S. & Byron, P. R. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov 6, 67–74, 10.1038/nrd2153 (2007)
37. Yaghi, A., Zaman, A. & Dolovich, M. B. The direct effect of hyperosmolar agents on ciliary beating of human bronchial epithelial cells. J Aerosol Med Pulm Drug Deliv 25, 88–95, 10.1089/jamp.2011.0914 (2012)
38. Yaghi, A., Zaman, A., Cox, G. & Dolovich, M. B. Ciliary beating is depressed in nasal cilia from chronic obstructive pulmonary disease subjects. Respir Med 106, 1139–1147, 10.1016/j.rmed.2012.04.001 (2012)
39. Chilvers, M. A. & O’Callaghan, C. Local mucociliary defence mechanisms. Paediatr Respir Rev 1, 27–34, 10.1053/prrv.2000.0009 (2000)
40. Iida, H., Matsuura, S., Shirakami, G., Tanimoto, K. & Fukuda, K. Differential effects of intravenous anesthetics on ciliary motility in cultured rat tracheal epithelial cells. Can J Anaesth 53, 242–249, 10.1007/BF03022209 (2006)
41. Yaghi, A., Dolovich, M. Investigating the Function of Epithelial Cell Cilia Using High Speed Digital Imaging. Am. J. Respir. Crit. Care Med 177 (2008)
42. Leopold, P. L. et al. Smoking is associated with shortened airway cilia. PLoS One 4, e8157, 10.1371/journal.pone.0008157 (2009)
43. Satir, P. & Christensen, S. T. Overview of structure and function of mammalian cilia. Annu Rev Physiol 69, 377–400, 10.1146/annurev.physiol.69.040705.141236 (2007)
44. Stannard, W. & O’Callaghan, C. Ciliary function and the role of cilia in clearance. J Aerosol Med 19, 110–115, 10.1089/jam.2006.19.110 (2006)
45. Workman, A. D. & Cohen, N. A. The effect of drugs and other compounds on the ciliary beat frequency of human respiratory epithelium. Am J Rhinol Allergy 28, 454–464, 10.2500/ajra.2014.28.4092 (2014)
46. Dowling, R. B. & Wilson, R. Bacterial toxins which perturb ciliary function and respiratory epithelium. Symp Ser Soc Appl Microbiol 27, 138S–148S (1998)
47. Salathe, M. Regulation of mammalian ciliary beating. Annu Rev Physiol 69, 401–422, 10.1146/annurev.physiol.69.040705.141253 (2007)
48. Braiman, A. & Priel, Z. Efficient mucociliary transport relies on efficient regulation of ciliary beating. Respir Physiol Neurobiol 163, 202–207, 10.1016/j.resp.2008.05.010 (2008)
49. Puchelle, E., Zahm, J. M., Tournier, J. M. & Coraux, C. Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc Am Thorac Soc 3, 726–733, 10.1513/pats.200605-126SF (2006)
50. Thomas, B. et al. Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma. J Allergy Clin Immunol 126, 722–729 e722, 10.1016/j.jaci.2010.05.046 (2010)
51. de Iongh, R. U. & Rutland, J. Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia. Am J Respir Crit Care Med 151, 1559–1567, 10.1164/ajrccm.151.5.7735615 (1995)
52. Rutland, J. & de Iongh, R. U. Random ciliary orientation. A cause of respiratory tract disease. N Engl J Med 323, 1681–1684, 10.1056/NEJM199012133232406 (1990)
53. Karp, P. H. et al. An in vitro model of differentiated human airway epithelia. Methods for establishing primary cultures. Methods Mol Biol 188, 115–137, 10.1385/1-59259-185-X:115 (2002)
54. Hubbs, A. F. et al. Airway epithelial toxicity of the flavoring agent, 2,3-pentanedione (abstract). Toxicologists 114, 239 (2010)
55. Karantza, V. Keratins in health and cancer: more than mere epithelial cell markers. Oncogene 30, 127–138, 10.1038/onc.2010.456 (2011)
56. Moll, R., Divo, M. & Langbein, L. The human keratins: biology and pathology. Histochem Cell Biol 129, 705–733, 10.1007/s00418-008-0435-6 (2008)
57. Jorissen, M. Correlations among mucociliary transport, ciliary function, and ciliary structure. Am J Rhinol 12, 53–58 (1998)
58. Willems, T. & Jorissen, M. Correlations between ciliary structure and ciliary function. Acta Otorhinolaryngol Belg 54, 299–308 (2000)
59. Chilvers, M. A., Rutman, A. & O’Callaghan, C. Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia. J Allergy Clin Immunol 112, 518–524 (2003)
60. Rossman, C. M., Lee, R. M., Forrest, J. B. & Newhouse, M. T. Nasal cilia in normal man, primary ciliary dyskinesia and other respiratory diseases: analysis of motility and ultrastructure. Eur J Respir Dis Suppl 127, 64–70 (1983)
61. Rossman, C. M., Forrest, J. B., Lee, R. M., Newhouse, A. F. & Newhouse, M. T. The dyskinetic cilia syndrome; abnormal ciliary motility in association with abnormal ciliary ultrastructure. Chest 80, 860–865 (1981)
62. Satir, P., Dirksen, E. R. In The Respiratory System Volume 1: Circulation and Nonrespiratory Functions (ed. E. R. Weibel) 473–494 (The American Physiological Society, 1985)
63. Castell, J. V., Donato, M. T. & Gomez-Lechon, M. J. Metabolism and bioactivation of toxicants in the lung. The in vitro cellular approach. Exp Toxicol Pathol 57(Suppl 1), 189–204 (2005)
64. Schwartz, N. B. et al. Sulfate activation and transport in mammals: system components and mechanisms. Chem Biol Interact 109, 143–151 (1998)
65. Shi, I., Hashemi Sadraei, N., Duan, Z. H. & Shi, T. Aberrant signaling pathways in squamous cell lung carcinoma. Cancer Inform 10, 273–285, 10.4137/CIN.S8283 (2011)
66. Larzabal, L. et al. TMPRSS4 regulates levels of integrin alpha5 in NSCLC through miR-205 activity to promote metastasis. Br J Cancer 110, 764–774, 10.1038/bjc.2013.761 (2014)
67. Tellez, C. S. et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res 71, 3087–3097, 10.1158/0008-5472.CAN-10-3035 (2011)
68. Song, H. & Bu, G. MicroRNA-205 inhibits tumor cell migration through down-regulating the expression of the LDL receptor-related protein 1. Biochem Biophys Res Commun 388, 400–405, 10.1016/j.bbrc.2009.08.020 (2009)
69. Wu, X. et al. Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy. J Natl Cancer Inst 103, 817–825, 10.1093/jnci/djr075 (2011)
70. Miller, A. G. & Gerrard, J. A. Assessment of Protein Function following Cross-Linking by alph-Dicarbonyls. Annals of the New York Academy of Sciences 1043, 195–200 (2005)
71. Didon, L. et al. RFX Modulation of FOXJ1 regulation of cilia genes in the human airway epithelium. Respiratory Research 14, 1–13 (2013)
72. Kanwal, R. et al. Evaluation of flavorings-related lung disease risk at six microwave popcorn plants. J Occup Environ Med 48, 149–157, 10.1097/01.jom.0000194152.48728.fb (2006)
73. Anderson, S. E., Jackson, L. G., Franko, J. & Wells, J. R. Evaluation of dicarbonyls generated in a simulated indoor air environment using an in vitro exposure system. Toxicol Sci 115, 453–461, 10.1093/toxsci/kfq067 (2010)
74. FEMA. Respiratory Health and Safety in the Flavor Manufacturing Workplace. Update. (Flavor and Extract Manufacturers, Washington, 2012)
75. Park, J. A. & Tschumperlin, D. J. Chronic intermittent mechanical stress increases MUC5AC protein expression. American journal of respiratory cell and molecular biology 41, 459–466, 10.1165/rcmb.2008-0195OC (2009)
76. Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120, 10.1093/bioinformatics/btu170 (2014)
77. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21, 10.1093/bioinformatics/bts635 (2013)
78. Barnett, D. W., Garrison, E. K., Quinlan, A. R., Stromberg, M. P. & Marth, G. T. BamTools: a C++ API and toolkit for analyzing and managing BAM files. Bioinformatics 27, 1691–1692, 10.1093/bioinformatics/btr174 (2011)
79. Anders, S., Pyl, P. T. & Huber, W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169, 10.1093/bioinformatics/btu638 (2015)
80. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15, 550, 10.1186/s13059-014-0550-8 (2014)
81. Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4, 44–57, 10.1038/nprot.2008.211 (2009)
82. Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3, 1101–1108 (2008)
83. Cao, X. et al. Tight junction disruption by cadmium in an in vitro human airway tissue model. Respir Res 16, 30, 10.1186/s12931-015-0191-9 (2015)