Effects of cigarette smoke, cessation and switching to a candidate modified risk tobacco product on the liver in Apoe^−/− mice – a systems toxicology analysis

Abstract

The liver is one of the most important organs involved in elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains more than 7000 chemicals, including those that exert biological effects and cause smoking-related diseases. Though CS is not directly hepatotoxic, a growing body of evidence suggests that it may exacerbate pre-existing chronic liver disease. In this study, we integrated toxicological endpoints with molecular measurements and computational analyses to investigate effects of exposures on the livers of Apoe^−/−mice. Mice were exposed to 3R4F reference CS, to an aerosol from the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product (MRTP) or to filtered air (Sham) for up to 8 months. THS2.2 takes advantage of a “heat-not-burn” technology that, by heating tobacco, avoids pyrogenesis and pyrosynthesis. After CS exposure for 2 months, some groups were either switched to the MRTP or filtered air. While no group showed clear signs of hepatotoxicity, integrative analysis of proteomics and transcriptomics data showed a CS-dependent impairment of specific biological networks. These networks included lipid and xenobiotic metabolism and iron homeostasis that likely contributed synergistically to exacerbating oxidative stress. In contrast, most proteomic and transcriptomic changes were lower in mice exposed to THS2.2 and in the cessation and switching groups compared to the CS group. Our findings elucidate the complex biological responses of the liver to CS exposure. Furthermore, they provide evidence that THS2.2 aerosol has reduced biological effects, as compared with CS, on the livers of Apoe^−/−mice.

• Data integration
• inhalation toxicology
• lipidomics
• modified risk tobacco product
• quantitative proteomics
• reduced risk product
• systems toxicology
• transcriptomics

Acknowledgements

We thank the members of the bioresearch and aerosol generation teams at PMIRL-S for their technical contributions. We thank Marja Talikka for manuscript revision and scientific discussion.

Declaration of interest

All (except for A.B.) authors are employees of Philip Morris International. Philip Morris International is the sole source of funding and sponsor of this project. GLS and VB are contracted paid by Philip Morris International. A.B. is an employee of Histovia GmbH which was contracted and paid by Philip Morris International to perform the histopathological analysis.

Supplementary material available online

Supplementary Figures S1–S8, and Tables S1 and S2