Multi-omics systems toxicology study of mouse lung assessing the effects of aerosols from two heat-not-burn tobacco products and cigarette smoke

Bjoern Titz; Justyna Szostak; Alain Sewer; Blaine Phillips; Catherine Nury; Thomas Schneider; Sophie Dijon; Oksana Lavrynenko; Ashraf Elamin; Emmanuel Guedj; Ee Tsin Wong; Stefan Lebrun; Grégory Vuillaume; Athanasios Kondylis; Sylvain Gubian; Stephane Cano; Patrice Leroy; Brian Keppler; Nikolai V Ivanov; Patrick Vanscheeuwijck; Florian Martin; Manuel C Peitsch; Julia Hoeng

doi:10.1016/j.csbj.2020.04.011

Multi-omics systems toxicology study of mouse lung assessing the effects of aerosols from two heat-not-burn tobacco products and cigarette smoke

Comput Struct Biotechnol J. 2020 Apr 25:18:1056-1073. doi: 10.1016/j.csbj.2020.04.011. eCollection 2020.

Authors

Bjoern Titz¹, Justyna Szostak¹, Alain Sewer¹, Blaine Phillips², Catherine Nury¹, Thomas Schneider¹, Sophie Dijon¹, Oksana Lavrynenko¹, Ashraf Elamin¹, Emmanuel Guedj¹, Ee Tsin Wong², Stefan Lebrun¹, Grégory Vuillaume¹, Athanasios Kondylis¹, Sylvain Gubian¹, Stephane Cano¹, Patrice Leroy¹, Brian Keppler³, Nikolai V Ivanov¹, Patrick Vanscheeuwijck¹, Florian Martin¹, Manuel C Peitsch¹, Julia Hoeng¹

Affiliations

¹ PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland.
² Philip Morris International Research Laboratories Pte. Ltd., Science Park II, Singapore.
³ Metabolon Inc., Research Triangle Park, NC, USA.

Abstract

Cigarette smoke (CS) causes adverse health effects and, for smoker who do not quit, modified risk tobacco products (MRTPs) can be an alternative to reduce the risk of developing smoking-related diseases. Standard toxicological endpoints can lack sensitivity, with systems toxicology approaches yielding broader insights into toxicological mechanisms. In a 6-month systems toxicology study on ApoE^-/- mice, we conducted an integrative multi-omics analysis to assess the effects of aerosols from the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2-a potential and a candidate MRTP based on the heat-not-burn (HnB) principle-compared with CS at matched nicotine concentrations. Molecular exposure effects in the lungs were measured by mRNA/microRNA transcriptomics, proteomics, metabolomics, and lipidomics. Integrative data analysis included Multi-Omics Factor Analysis and multi-modality functional network interpretation. Across all five data modalities, CS exposure was associated with an increased inflammatory and oxidative stress response, and lipid/surfactant alterations. Upon HnB aerosol exposure these effects were much more limited or absent, with reversal of CS-induced effects upon cessation and switching to CHTP 1.2. Functional network analysis revealed CS-induced complex immunoregulatory interactions across the investigated molecular layers (e.g., itaconate, quinolinate, and miR-146) and highlighted the engagement of the heme-Hmox-bilirubin oxidative stress axis by CS. This work exemplifies how multi-omics approaches can be leveraged within systems toxicology studies and the generated multi-omics data set can facilitate the development of analysis methods and can yield further insights into the effects of toxicological exposures on the lung of mice.

Keywords: CHTP, Carbon Heated Tobacco Product; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; Cigarette smoking; Inhalation toxicology; LC, liquid chromatography; MOFA, Multi-Omics Factor Analysis; MS, mass spectrometry; Modified risk tobacco product (MRTP); Multi-omics; PCSF, prize-collecting Steiner forest; ROS, reactive oxygen species; Systems toxicology; THS, Tobacco Heating System; cMRTP, candidate modified risk tobacco product; sGCCA, sparse generalized canonical correlation analysis.