title: A systems toxicology approach for comparative assessment: Biological impact of an aerosol from a candidate modified-risk tobacco product and cigarette smoke on human organotypic bronchial epithelial cultures.
abstract: This study reports a comparative assessment of the biological impact of a heated tobacco aerosol from the tobacco heating system (THS) 2.2 and smoke from a combustible 3R4F cigarette. Human organotypic bronchial epithelial cultures were exposed to an aerosol from THS2.2 (a candidate modified-risk tobacco product) or 3R4F smoke at similar nicotine concentrations. A systems toxicology approach was applied to enable a comprehensive exposure impact assessment. Culture histology, cytotoxicity, secreted pro-inflammatory mediators, ciliary beating, and genome-wide mRNA/miRNA profiles were assessed at various time points post-exposure. Series of experimental repetitions were conducted to increase the robustness of the assessment. At similar nicotine concentrations, THS2.2 aerosol elicited lower cytotoxicity compared with 3R4F smoke. No morphological change was observed following exposure to THS2.2 aerosol, even at nicotine concentration three times that of 3R4F smoke. Lower levels of secreted mediators and fewer miRNA alterations were observed following exposure to THS2.2 aerosol than following 3R4F smoke. Based on the computational analysis of the gene expression changes, 3R4F (0.13 mg nicotine/L) elicited the highest biological impact (100%) in the context of Cell Fate, Cell Proliferation, Cell Stress, and Inflammatory Network Models at 4 h post-exposure. Whereas, the corresponding impact of THS2.2 (0.14 mg nicotine/L) was 7.6%.
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Anita.Iskandar@pmi.com.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Iskandar
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Carole.Mathis@pmi.com.
authors.forename: Carole
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Biology Consultant, Max-Baermann-Str. 21, 51429, Bergisch Gladbach, Germany. Electronic address: WK.Schlage@t-online.de.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Stefan.Frentzel@pmi.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Patrice.Leroy@pmi.com.
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Yang.Xiang@pmi.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Alain.Sewer@pmi.com.
authors.forename: Alain
authors.initials: A
authors.lastname: Sewer
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Shoaib.Majeed@pmi.com.
authors.forename: Shoaib
authors.initials: S
authors.lastname: Majeed
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Laura.OrtegaTorres@pmi.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Ortega-Torres
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Stephanie.Johne@pmi.com.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Johne
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Emmanuel.Guedj@pmi.com.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Keyur.Trivedi@pmi.com.
authors.forename: Keyur
authors.initials: K
authors.lastname: Trivedi
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Gilles.Kratzer@gmail.com.
authors.forename: Gilles
authors.initials: G
authors.lastname: Kratzer
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Celine.Merg@pmi.com.
authors.forename: Celine
authors.initials: C
authors.lastname: Merg
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Ashraf.Elamin@pmi.com.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Elamin
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Florian.Martin@pmi.com.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Nikolai.Ivanov@pmi.com.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Manuel.Peitsch@pmi.com.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland. Electronic address: Julia.Hoeng@pmi.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000328:Adult; D000336:Aerosols; D001980:Bronchi / Q000166:cytology*; D002923:Cilia / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D012306:Risk; D012906:Smoke / Q000009:adverse effects*; D049490:Systems Biology; D062789:Tobacco Products; D055815:Young Adult
chemical_list: D000336:Aerosols; D035683:MicroRNAs; D012333:RNA, Messenger; D012906:Smoke
keywords: Reconstituted epithelium; air-liquid interface; causal biological network modelling; product testing; transcriptomics