title: A 28-day rat inhalation study with an integrated molecular toxicology endpoint demonstrates reduced exposure effects for a prototypic modified risk tobacco product compared with conventional cigarettes.
abstract: Towards a systems toxicology-based risk assessment, we investigated molecular perturbations accompanying histopathological changes in a 28-day rat inhalation study combining transcriptomics with classical histopathology. We demonstrated reduced biological activity of a prototypic modified risk tobacco product (pMRTP) compared with the reference research cigarette 3R4F. Rats were exposed to filtered air or to three concentrations of mainstream smoke (MS) from 3R4F, or to a high concentration of MS from a pMRTP. Histopathology revealed concentration-dependent changes in response to 3R4F that were irritative stress-related in nasal and bronchial epithelium, and inflammation-related in the lung parenchyma. For pMRTP, significant changes were seen in the nasal epithelium only. Transcriptomics data were obtained from nasal and bronchial epithelium and lung parenchyma. Concentration-dependent gene expression changes were observed following 3R4F exposure, with much smaller changes for pMRTP. A computational-modeling approach based on causal models of tissue-specific biological networks identified cell stress, inflammation, proliferation, and senescence as the most perturbed molecular mechanisms. These perturbations correlated with histopathological observations. Only weak perturbations were observed for pMRTP. In conclusion, a correlative evaluation of classical histopathology together with gene expression-based computational network models may facilitate a systems toxicology-based risk assessment, as shown for a pMRTP.
authors.affiliation: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany; Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: ulrike.kogel@pmi.com.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kogel
authors.affiliation: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany; Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: walter.schlage@contracted.pmi.com.
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: 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: yang.xiang@pmi.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany; Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: sam.ansari@pmi.com.
authors.forename: Sam
authors.initials: S
authors.lastname: Ansari
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 Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany; Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland; Philip Morris International R&D, Philip Morris Research Laboratories bvba, Grauwmeer 14, Researchpark Haasrode, 3001 Leuven, Belgium. Electronic address: patrick.vanscheeuwijck@pmi.com.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanscheeuwijck
authors.affiliation: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany. Electronic address: stephan.gebel@uni.lu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gebel
authors.affiliation: Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany. Electronic address: a.buettner@histovia.com.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Buettner
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: christoph.wyss@pmi.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wyss
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: marco.esposito@pmi.com.
authors.forename: Marco
authors.initials: M
authors.lastname: Esposito
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
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
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002263:Carboxyhemoglobin / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D003367:Cotinine / Q000031:analogs & derivatives / Q000652:urine; D016207:Cytokines / Q000378:metabolism; D023381:Endpoint Determination / Q000379:methods*; D005260:Female; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects; D008297:Male; D009538:Nicotine / Q000031:analogs & derivatives / Q000652:urine; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000187:drug effects; D018570:Risk Assessment; D012307:Risk Factors; D062789:Tobacco Products / Q000633:toxicity*; D059467:Transcriptome
chemical_list: D018925:Chemokines; D016207:Cytokines; C066333:norcotinine; C001381:hydroxycotinine; D009538:Nicotine; C005311:nornicotine; D002263:Carboxyhemoglobin; D003367:Cotinine
keywords: Computational network model; Histopathology; Systems toxicology; Tobacco-heating; Transcriptomics