• Alain Sewer, Ulrike Kogel, Marja Talikka, Ee Tsin Wong, Florian Martin, Yang Xiang, Emmanuel Guedj, Nikolai V Ivanov, Julia Hoeng, and Manuel C Peitsch.
• 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.
• Regul. Toxicol. Pharmacol. 2016 Nov 30; 81 Suppl 2: S82-S92.

AbstractModified-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.Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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