title: Evaluation of the Tobacco Heating System 2.2 (THS2.2). Part 5: microRNA expression from a 90-day rat inhalation study indicates that exposure to THS2.2 aerosol causes reduced effects on lung tissue compared with cigarette smoke.
abstract: Modified-risk tobacco products (MRTP) are designed to reduce the individual risk of tobacco-related disease as well as population harm compared to smoking cigarettes. Experimental proof of their benefit needs to be provided at multiple levels in research fields. Here, we examined microRNA (miRNA) levels in the lungs of rats exposed to a candidate modified-risk tobacco product, the Tobacco Heating System 2.2 (THS2.2) in a 90-day OECD TG-413 inhalation study. Our aim was to assess the miRNA response to THS2.2 aerosol compared with the response to combustible cigarettes (CC) smoke from the reference cigarette 3R4F. CC smoke exposure, but not THS2.2 aerosol exposure, caused global miRNA downregulation, which may be explained by the interference of CC smoke constituents with the miRNA processing machinery. Upregulation of specific miRNA species, such as miR-146a/b and miR-182, indicated that they are causal elements in the inflammatory response in CC-exposed lungs, but they were reduced after THS2.2 aerosol exposure. Transforming transcriptomic data into protein activity based on corresponding downstream gene expression, we identified potential mechanisms for miR-146a/b and miR-182 that were activated by CC smoke but not by THS2.2 aerosol and possibly involved in the regulation of those miRNAs. The inclusion of miRNA profiling in systems toxicology approaches increases the mechanistic understanding of the complex exposure responses.
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, 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, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kogel
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.affiliation: Philip Morris International Research Laboratories Pte Ltd, Part of Philip Morris International Group of Companies, 50 Science Park Road, The Kendall #02-07, Science Park II, 117406, Singapore.
authors.forename: Ee Tsin
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
authors.affiliation: Philip Morris International R&D, Part of Philip Morris International Group of Companies, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
mesh_terms: D000336:Aerosols; D000818:Animals; D019295:Computational Biology; D003257:Consumer Product Safety; D066300:Electronic Nicotine Delivery Systems / Q000009:adverse effects*; D004867:Equipment Design; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005819:Genetic Markers; D023281:Genomics; D040261:Harm Reduction; D006358:Hot Temperature; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics; D013997:Time Factors; D019460:Tobacco Industry; D062789:Tobacco Products / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000336:Aerosols; D005819:Genetic Markers; D035683:MicroRNAs; D012906:Smoke
keywords: Heat-not-burn; Inflammation-related microRNAs; Inhalation toxicology study; Modified risk tobacco product; microRNA expression