Dataset Information

Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice.

ABSTRACT: Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases. However, switching to less harmful products (modified-risk tobacco products [MRTP]) can be an alternative to help reduce the risk for adult smokers who would otherwise continue to smoke. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed the aerosol of Tobacco Heating System 2.2 (THS 2.2), a candidate MRTP based on the heat-not-burn principle, compared with 3R4F cigarette smoke (CS). To capture toxicity- and disease-relevant mechanisms, we complemented standard toxicology endpoints with in-depth systems toxicology analyses. In this part of our publication series, we report on integrative assessment of the apical and molecular exposure effects on the respiratory tract (nose, larynx, and lungs). Across the respiratory tract, we found changes in inflammatory response following 3R4F CS exposure (eg, antimicrobial peptide response in the nose), with both shared and distinct oxidative and xenobiotic responses. Compared with 3R4F CS, THS 2.2 aerosol exerted far fewer effects on respiratory tract histology, including adaptive tissue changes in nasal and laryngeal epithelium and inflammation and emphysematous changes in the lungs. Integrative analysis of molecular changes confirmed the substantially lower impact of THS 2.2 aerosol than 3R4F CS on toxicologically and disease-relevant molecular processes such as inflammation, oxidative stress responses, and xenobiotic metabolism. In summary, this work exemplifies how apical and molecular endpoints can be combined effectively for toxicology assessment and further supports findings on the reduced respiratory health risks of THS 2.2 aerosol.

SUBMITTER: Titz B

PROVIDER: S-EPMC7657339 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice.

Titz Bjoern B Sewer Alain A Luettich Karsta K Wong Ee Tsin ET Guedj Emmanuel E Nury Catherine C Schneider Thomas T Xiang Yang Y Trivedi Keyur K Vuillaume Grégory G Leroy Patrice P Büttner Ansgar A Martin Florian F Ivanov Nikolai V NV Vanscheeuwijck Patrick P Hoeng Julia J Peitsch Manuel C MC

Toxicological sciences : an official journal of the Society of Toxicology 20201101 1

Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases. However, switching to less harmful products (modified-risk tobacco products [MRTP]) can be an alternative to help reduce the risk for adult smokers who would otherwise continue to smoke. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed the aerosol of Tobacco Heating System 2.2 (THS 2.2), a candidate MRTP based on the heat-not-burn principle, c ...[more]

PMID: 32780831

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Project description:Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases but switching to less harmful products (modified-risk tobacco products) can be an alternative for smokers who would otherwise not quit. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed aerosol from the Tobacco Heating System 2.2 (THS 2.2), a candidate modified-risk tobacco product based on the heat-not-burn principle, compared with 3R4F cigarette smoke (CS). To capture toxicity- and disease-relevant mechanisms, we complemented standard toxicology endpoints with in-depth systems toxicology analyses. Briefly, female A/J mice were exposed to fresh air (Sham), three concentrations of THS 2.2 aerosol corresponding to nicotine concentrations of 6.7 (Low; L), 13.4 (Medium; M), and 26.8 (High; H) µg nicotine\L test atmosphere, or to one concentration of 3R4F CS (13.4 µg nicotine\L test atmosphere) in whole-body exposure chambers for 6 h per day, 5 days per week, and up to 18 months. Interim dissections were scheduled for months 1, 5, and 10. Male mice were exposed to either fresh air (Sham) or to the high THS 2.2 aerosol concentration for 15 months. Chronic toxicity and carcinogenicity endpoints outlined in the OECD protocol were assessed; detailed findings will be reported separately (Wong et al.). For evaluation of non-OECD endpoints following a systems toxicology approach (proteomics, transcriptomics, and genomics), several tissues were collected for further analysis. Housing and all procedures involving animals were performed in accordance with the approved Institutional Animal Care and Use Committee protocol in an Agri-Food & Veterinary Authority of Singapore-licensed and Association for Assessment and Accreditation of Laboratory Animal Care International-accredited facility, where the care and use of the animals for scientific purposes were in accordance with the National Advisory Committee for Laboratory Animal Research (NACLAR) Guideline (NACLAR, 2004). Animals allocated to the omics endpoints (N=8-20) were dissected within 16-24 h of the last exposure and following randomization of all planned necropsies for the dissection time point in question. All efforts to minimize potential nucleic acid and protein degradation were made, and samples were frozen as rapidly as possible once ex vivo. Lungs collected after month 1 were snap-frozen and the right caudal lobe was used for proteomics analysis. These are the protein expression data for the respiratory nasal epithelium assessed by iTRAQÂ®-based quantitative proteomics.

Project description:Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases but switching to less harmful products (modified-risk tobacco products) can be an alternative for smokers who would otherwise not quit. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed aerosol from the Tobacco Heating System 2.2 (THS 2.2), a candidate modified-risk tobacco product based on the heat-not-burn principle, compared with 3R4F cigarette smoke (CS). To capture toxicity- and disease-relevant mechanisms, we complemented standard toxicology endpoints with in-depth systems toxicology analyses. Briefly, female A/J mice were exposed to fresh air (Sham), three concentrations of THS 2.2 aerosol corresponding to nicotine concentrations of 6.7 (Low; L), 13.4 (Medium; M), and 26.8 (High; H) µg nicotine\L test atmosphere, or to one concentration of 3R4F CS (13.4 µg nicotine\L test atmosphere) in whole-body exposure chambers for 6 h per day, 5 days per week, and up to 18 months. Interim dissections were scheduled for months 1, 5, and 10. Male mice were exposed to either fresh air (Sham) or to the high THS 2.2 aerosol concentration for 15 months. Chronic toxicity and carcinogenicity endpoints outlined in the OECD protocol were assessed; detailed findings will be reported separately (Wong et al.). For evaluation of non-OECD endpoints following a systems toxicology approach (proteomics, transcriptomics, and genomics), several tissues were collected for further analysis. Housing and all procedures involving animals were performed in accordance with the approved Institutional Animal Care and Use Committee protocol in an Agri-Food & Veterinary Authority of Singapore-licensed and Association for Assessment and Accreditation of Laboratory Animal Care International-accredited facility, where the care and use of the animals for scientific purposes were in accordance with the National Advisory Committee for Laboratory Animal Research (NACLAR) Guideline (NACLAR, 2004). Animals allocated to the omics endpoints (N=8-20) were dissected within 16-24 h of the last exposure and following randomization of all planned necropsies for the dissection time point in question. All efforts to minimize potential nucleic acid and protein degradation were made, and samples were frozen as rapidly as possible once ex vivo. Lungs collected after month 1 were snap-frozen and the right caudal lobe was used for proteomics analysis. These are the protein expression data for lung tissue assessed by iTRAQ®-based quantitative proteomics.

Dataset Information

Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice.

Publications

Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice.

Similar Datasets

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