title: In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures.
abstract: Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis). Alteration of smoking-related gene expression changes in oral epithelial cells is similar to that in bronchial and nasal epithelial cells. Using a systems toxicology approach, we have previously assessed the impact of cigarette smoke (CS) seen as perturbations of biological processes in human nasal and bronchial organotypic epithelial culture models. Here, we report our further assessment using in vitro human oral organotypic epithelium models. We exposed the buccal and gingival organotypic epithelial tissue cultures to CS at the air-liquid interface. CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues. Using microarray technology, gene-set analysis and a novel computational modeling approach leveraging causal biological network models, we identified CS impact on xenobiotic metabolism-related pathways accompanied by a more subtle alteration in inflammatory processes. Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset. These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products.
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Neuchâtel , Switzerland.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.forename: Anita R
authors.initials: AR
authors.lastname: Iskandar
authors.forename: Radina
authors.initials: R
authors.lastname: Kostadinova
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.forename: Alain
authors.initials: A
authors.lastname: Sewer
authors.forename: Shoaib
authors.initials: S
authors.lastname: Majeed
authors.forename: Diana
authors.initials: D
authors.lastname: Kuehn
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.forename: Marcel
authors.initials: M
authors.lastname: Geertz
authors.forename: Carole
authors.initials: C
authors.lastname: Mathis
authors.forename: Nikolai
authors.initials: N
authors.lastname: Ivanov
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
mesh_terms: D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism; D012906:Smoke; D014026:Nicotiana; D059467:Transcriptome
chemical_list: D012906:Smoke
keywords: Air–liquid interface; causal biological network model; oral keratinocytes; organotypic cultures; transcriptomics