Advanced in vitro exposure systems.

Integration of Targeted Proteomics into Systems Toxicology Approach: Candidate Modified-Risk Tobacco Product Assessment using Nasal Cultures

17. Sep. 2017

HUPO 2017, Dublin

T. Schneider, A. Elamin, A.R. Iskandar, F. Zanetti, C. Merg, A. Sewer, B. Titz, P. Leroy, E. Guedj, S. Majeed, L. Ortega-Torres, W. Schlage, C. Mathis, F. Martin, S. Frentzel, N. V. Ivanov, M.C. Peitsch, J. Hoeng

Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland (Part of Philip Morris International group of companies)

The objectives of this study included to demonstrate robustness and reproducibility of systems biology data obtained from an organotypic in vitro nasal culture model for cigarette smoke and aerosol exposure assessment. Cellular stress and pro-inflammatory responses were investigated on the primary nasal epithelial cells of a non-smoker.

Introduction and Objectives
Systems biology combines comprehensive molecular analyses and quantitative modeling to understand the characteristics of a biological system as a whole. Leveraging a similar approach, Systems Toxicology aims to decipher complex biological responses following exposures. This work reports parts of a Systems Toxicology analysis in the context of the in vitro assessment of a candidate modified-risk tobacco product (cMRTP) using a human nasal organotypic culture model1,2. The term "modified risk tobacco product"means any tobacco product that is sold or distributed for use to reduce harm or risk of tobacco-related diseases associated with commercially marketed tobacco products"3. The objectives of this study included to demonstrate (1) robustness and reproducibility of systems biology data obtained from an organotypic in vitro nasal culture model for cigarette smoke (CS) and aerosol exposure assessment; (2) relevancy of this approach in a comparative risk assessment of aerosols from a cMRTP compared with CS; and (3) the benefit of including complementary data modalities such as targeted proteomics in this assessment approach. Complementing a series of functional measures, a causal network enrichment analysis of transcriptomic data was used to compare quantitatively the biological impact of aerosol from the Tobacco Heating System (THS) 2.2, a candidate MRTP, with 3R4F CS at similar nicotine concentrations. In addition, the tissue response was measured by a mass-spectrometry based targeted proteomics approach, parallel reaction monitoring (PRM), and antibody-based multi-analyte profiling (MAP).

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