title: Comparative systems toxicology analysis of cigarette smoke and aerosol from a candidate modified risk tobacco product in organotypic human gingival epithelial cultures: A 3-day repeated exposure study.
abstract: Smoking is one of the major lifestyle-related risk factors for periodontal diseases. Modified risk tobacco products (MRTP) offer a promising alternative in the harm reduction strategy for adult smokers unable to quit. Using a systems toxicology approach, we investigated and compared the exposure effects of a reference cigarette (3R4F) and a heat-not-burn technology-based candidate MRTP, the Tobacco Heating System (THS) 2.2. Human gingival epithelial organotypic cultures were repeatedly exposed (3 days) for 28 min at two matching concentrations of cigarette smoke (CS) or THS2.2 aerosol. Results showed only minor histopathological alterations and minimal cytotoxicity upon THS2.2 aerosol exposure compared to CS (1% for THS2.2 aerosol vs. 30% for CS, at the high concentration). Among the 14 proinflammatory mediators analyzed, only 5 exhibited significant alterations with THS2.2 exposure compared with 11 upon CS exposure. Transcriptomic and metabolomic analysis indicated a general reduction of the impact in THS2.2 aerosol-exposed samples with respect to CS (∼79% lower biological impact for the high THS2.2 aerosol concentration compared to CS, and 13 metabolites significantly perturbed for THS2.2 vs. 181 for CS). This study indicates that exposure to THS2.2 aerosol had a lower impact on the pathophysiology of human gingival organotypic cultures than CS.
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland. Electronic address: filippo.zanetti@pmi.com.
authors.forename: Filippo
authors.initials: F
authors.lastname: Zanetti
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Titz
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Sewer
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lo Sasso
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Scotti
authors.affiliation: Biology Consultant, Max-Baermann-Str. 21, 51429 Bergisch Gladbach, Germany.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Mathis
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Leroy
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Shoaib
authors.initials: S
authors.lastname: Majeed
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Laura Ortega
authors.initials: LO
authors.lastname: Torres
authors.affiliation: Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Keppler
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Elamin
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Keyur
authors.initials: K
authors.lastname: Trivedi
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
mesh_terms: D000328:Adult; D000336:Aerosols / Q000009:adverse effects*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012906:Smoke / Q000032:analysis*; D062789:Tobacco Products / Q000009:adverse effects* / Q000032:analysis*; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000336:Aerosols; D012906:Smoke
keywords: 21st century toxicology; 3Rs; Air–liquid interface aerosol exposure; Gingiva; Metabolomics; Tobacco heating system 2.2