Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: Liver represents one of the most important organs involved in the elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains several compounds that exert biological effects and cause smoking related diseases. Although cigarette smoke is not directly hepatotoxic, a growing body of evidence suggests that CS may exacerbate chronic liver diseases. Here we integrated classical toxicological endpoints with molecular measurement and computational analysis approaches to investigate exposure effects on liver in an Apoe-/- mouse study. The mice were exposed to high concentrations of 3R4F reference CS (600 mg/m3 TPM, 29.9 mg/m3 nicotine), aerosol from a candidate modified risk tobacco product (MRTP), the Tobacco Heating System (THS) 2.2, or filtered air (Sham) for up to 8 months. After 2 months of CS exposure, some groups were either switched to the MRTP or underwent cessation. While clear signs of hepatotoxic effects were absent for any exposure group, the integrative analysis of proteomic and transcriptomic data showed a CS-dependent impairment of specific biological networks, such as lipid, xenobiotic, and iron homeostasis, which likely in turn mutually contribute to worsening of the oxidative stress. In contrast, most of these changes were absent in mice exposed to THS2.2, and in the cessation and in the switching groups. Our findings shed light on the complex biological response of the liver to CS exposure and support the benefits of switching to the tested heat-not-burn product, THS2.2.

ORGANISM(S): Mus musculus

SUBMITTER: Blaine Phillips

PROVIDER: E-MTAB-3876 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Besides its well-known effects increasing predisposition to oral cancer, cigarette smoke (CS) exposure is an important risk factor for many conditions including periodontal diseases, gingivitis and other benign mucosal disorders. Smoking cessation remains the most effective approach for minimizing risk of smoking-related diseases. However, reduction of harmful constituents by heating rather than combusting tobacco, without modifying the amount of nicotine, is a promising new paradigm in harm reduction. In this study we compared effects of exposure to aerosol derived from a candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, with those of conventional smoke generated from the 3R4F reference cigarette. Human organotypic oral epithelial tissue cultures (EpiOralï¾, MatTek Corporation) were exposed for 28 min to 3R4F CS or THS2.2 aerosol, both diluted with air to comparable nicotine concentrations (0.32 or 0.51 mg nicotine/L aerosol/smoke for 3R4F and 0.31 or 0.46 mg/L for THS2.2). We also tested one higher concentration (1.09 mg/L) of THS2.2. A systems toxicology approach was employed combining cellular assays (i.e. cytotoxicity and cytochrome P450 activity assays), comprehensive molecular investigations of the buccal epithelial transcriptome (mRNA and miRNA) by means of computational network biology, measurements of secreted proinflammatory markers, histopathological analysis. We observed that the impact of 3R4F CS was greater than THS2.2 aerosol in terms of cytotoxicity, morphological tissue alterations and secretion of inflammatory mediators. Analysis of the transcriptomic changes in the exposed oral cultures revealed significant perturbations in various network models such as apoptosis, necroptosis, senescence, xenobiotic metabolism, oxidative stress and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) signaling. The stress responses following THS2.2 aerosol exposure were markedly decreased and the exposed cultures recovered better as compared with those exposed to 3R4F CS.

Project description:Cigarette smoke (CS) has been reported to increase predisposition to oral cancer and is also recognized as a risk factor for many conditions including periodontal diseases, gingivitis, and other benign mucosal disorders. Smoking cessation remains the most effective approach for minimizing the risk of smoking-related diseases. However, reduction of harmful constituents by heating rather than combusting tobacco, without modifying the amount of nicotine, is a promising new paradigm in harm reduction. In this study, we compared effects of exposure to aerosol derived from a candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, with those of CS generated from the 3R4F reference cigarette. Human organotypic oral epithelial tissue cultures (EpiOral, MatTek Corporation) were exposed for 28 min to 3R4F CS or THS2.2 aerosol, both diluted with air to comparable nicotine concentrations (0.32 or 0.51 mg nicotine/L aerosol/CS for 3R4F and 0.31 or 0.46 mg/L for THS2.2). We also tested one higher concentration (1.09 mg/L) of THS2.2. A systems toxicology approach was employed combining cellular assays (i.e., cytotoxicity and cytochrome P450 activity assays), comprehensive molecular investigations of the buccal epithelial transcriptome (mRNA and miRNA) by means of computational network biology, measurements of secreted proinflammatory markers, and histopathological analysis. We observed that the impact of 3R4F CS was greater than THS2.2 aerosol in terms of cytotoxicity, morphological tissue alterations, and secretion of inflammatory mediators. Analysis of the transcriptomic changes in the exposed oral cultures revealed significant perturbations in various network models such as apoptosis, necroptosis, senescence, xenobiotic metabolism, oxidative stress, and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) signaling. The stress responses following THS2.2 aerosol exposure were markedly decreased, and the exposed cultures recovered more completely compared with those exposed to 3R4F CS.

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

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