Peer-Reviewed Publications

    Systems toxicology assessment of the biological impact of a candidate Modified Risk Tobacco Product on human organotypic oral epithelial cultures

    Zanetti, F.; Sewer, A.; Mathis, C.; Iskandar, A. R.; Kostadinova, R.; Schlage, W. K.; Leroy, P.; Majeed, S.; Guedj, E.; Trivedi, K.; Martin, F.; Elamin, A.; Merg, C.; Ivanov, N. V.; Frentzel, S.; Peitsch, M. C.; Hoeng, J.

    Published
    Jul 12, 2016
    DOI
    10.1021/acs.chemrestox.6b00174
    PMID
    27404394
    Link to publication
    Topic
    Summary

    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.

    Related Publications

    Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Toxicity of aerosols of nicotine and pyruvic acid (separate and combined) in Sprague–Dawley rats in a 28-day OECD 412 inhalation study and assessment of systems toxicology

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Cigarette smoke induces molecular responses in respiratory tissues of ApoE−/− mice that are progressively deactivated upon cessation

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    The biological effects of long-term exposure of human bronchial epithelial cells to total particulate matter from a candidate modified-risk tobacco product

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Toxicity of aerosols of nicotine and pyruvic acid (separate and combined) in Sprague–Dawley rats in a 28-day OECD 412 inhalation study and assessment of systems toxicology

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Cigarette smoke induces molecular responses in respiratory tissues of ApoE−/− mice that are progressively deactivated upon cessation

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    The biological effects of long-term exposure of human bronchial epithelial cells to total particulate matter from a candidate modified-risk tobacco product

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    Toxicity of aerosols of nicotine and pyruvic acid (separate and combined) in Sprague–Dawley rats in a 28-day OECD 412 inhalation study and assessment of systems toxicology

    Aerosol Chemistry Pre-clinical Toxicology Systems Toxicology

    PMIScience.com is operated by Philip Morris International for the purpose of publishing and disseminating scientific information about Philip Morris International’s efforts in support of its smoke-free product portfolio. This site is a global site for use by scientists, the public health and regulatory communities, and other stakeholders with an interest in tobacco policy. The purpose of this site is not advertising or marketing, nor is it directed at any specific market. It is not intended for use by consumers. New tobacco products sold in the United States are subject to FDA regulation; therefore the content of this site is not intended to make, and nor should it be construed as making, any product related claims in the United States without proper FDA authorization. ​
    ​
    Reduced Risk Products ("RRPs”) is the term we use to refer to products that present, are likely to present, or have the potential to present less risk of harm to smokers who switch to these products versus continuing smoking. PMI has a range of RRPs in various stages of development, scientific assessment and commercialization. All of our RRPs are smoke-free products that deliver nicotine with far lower quantities of harmful and potentially harmful constituents than found in cigarette smoke.