Dataset Information

Comprehensive systems biology analysis of a seven-month cigarette smoke inhalation study in C57BL/6 mice.

ABSTRACT: Combustible cigarette smoking has major impact on human health. In order to reduce smoking-related health risk, the tobacco industry is developing modified risk tobacco products (MRTP). To assess the potential of such a prototype (pMRTP) to reduce health risk, we used C57BL/6 mice, model of chronic obstructive pulmonary disease (COPD), in a systems toxicology approach to investigate in a large, controlled study, classical toxicology end points in parallel to transcriptomics, lipidomics, and proteomics profiles in mice exposed to conventional cigarette smoke (3R4F) or a pMRTP aerosol for up to 7 months. We also included a cessation group and a switching-to-pMRTP group (after 2 months of 3R4F exposure), in addition to the control (fresh air exposed) group, to understand the potential benefit of switching to pMRTP for smokers who cannot or do not want to quit smoking. For quantitative proteomics analysis with the iTRAQ method, lung tissue samples from six mice (ie, six biological replicates) were analyzed for each exposure condition and time point (months 1, 3, 5, and 7 for 3R4F and pMRTP exposure and months 3, 5, and 7 for cessation and switch).

OTHER RELATED OMICS DATASETS IN: MTBLS143

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

SUBMITTER: Bjoern Titz

LAB HEAD: Julia Hoeng

PROVIDER: PXD001369 | Pride | 2016-01-04

REPOSITORIES: Pride

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Comprehensive systems biology analysis of a 7-month cigarette smoke inhalation study in C57BL/6 mice.

Ansari Sam S Baumer Karine K Boué Stéphanie S Dijon Sophie S Dulize Remi R Ekroos Kim K Elamin Ashraf A Foong Clement C Guedj Emmanuel E Hoeng Julia J Ivanov Nikolai V NV Krishnan Subash S Leroy Patrice P Martin Florian F Merg Celine C Peck Michael J MJ Peitsch Manuel C MC Phillips Blaine B Schlage Walter K WK Schneider Thomas T Talikka Marja M Titz Bjoern B Vanscheeuwijck Patrick P Veljkovic Emilija E Vihervaara Terhi T Vuillaume Gregory G Woon Ching Qing CQ

Scientific data 20160105

Smoking of combustible cigarettes has a major impact on human health. Using a systems toxicology approach in a model of chronic obstructive pulmonary disease (C57BL/6 mice), we assessed the health consequences in mice of an aerosol derived from a prototype modified risk tobacco product (pMRTP) as compared to conventional cigarettes. We investigated physiological and histological endpoints in parallel with transcriptomics, lipidomics, and proteomics profiles in mice exposed to a reference cigaret ...[more]

PMID: 26731301

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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 lung tissue assessed by iTRAQ®-based quantitative proteomics.

Project description:The objective of this study was to compare the biological and toxicological response of apolipoprotein E-deficient (Apoe-/-) mice to 3R4F mainstream smoke exposure for 2 months in whole-body exposure chambers (WBEC) and nose-only exposure chambers (NOEC). Female ApoE-/- mice were randomized into four groups: two Sham groups, exposed to filtered air, and two 3R4F groups, exposed to CS from the 3R4F reference cigarette (550 Âµg TPM/L). Half the number of mice in the Sham- and CS-exposed groups were exposed in WBECs and the other half in NOECs. The exposure phase lasted 9 weeks and included 1 week of adaption, during which exposure in both chamber types was escalated in dose and duration to a maximum of 4 h per day. The TPM concentration and exposure duration in WBECs were matched to those in NOECs on the basis of the regimen that the mice tolerated, as determined by in-life findings on acute signs of nicotine toxicity. Fresh air breaks were introduced during the exposure period to maintain carboxyhemoglobin (COHb) concentrations at acceptable levels. More frequent and longer fresh air breaks were required for exposure in the WBEC than in the NOEC because of the greater internal volumeâ€”and, consequently, the longer durationâ€”required to clear smoke from the WBEC than from the NOEC. For animals in NOECs, a 30-min fresh air break was introduced after 2 and 3 h of exposure. For animals in WBECs, a 30-min fresh air break was introduced after 1 and 2 h of exposure and a 60-min fresh air break after the third hour of exposure. The general condition and health of the mice following exposure were monitored throughout the study. Full necropsy was performed 16-20 h after the last exposure without prior fasting, in accordance with previously described methods (Vanscheeuwijck et al., 2002). Differences between WBEC and NOEC expsoure were analyzed with regard to aerosol uptake, disease endpoints (adaptive changes in nasal epithelia, changes in lung function and inflammatory parameters, plasma cholesterol/triglyceride levels in lipoprotein fractions, and atherosclerosis plaque development), and systems biology endpoints (changes in the lung proteome and liver, nasal epithelial, and heart transcriptomes). All procedures involving animals were performed in a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International and licensed by the Agri-Food & Veterinary Authority of Singapore, with approval from an Institutional Animal Care and Use Committee and in compliance with the National Advisory Committee for Laboratory Animal Research Guidelines on the Care and Use of Animals for Scientific Purposes (NACLAR, 2004). Here, the protein expression data for lung tissue assessed by iTRAQ®-based quantitative proteomics will be described.

Project description:A 7-month inhalation study in C57BL/6 mice was conducted to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation or switching to an e-vapor product after 3 months of exposure to 3R4F cigarette smoke (CS). In this study, we performed a chronic inhalation (4 h/day, 5 d/week, up to 7 months) study in C57BL/6 mice using a commercial (MarkTen®) e-vapor product and a combustible reference cigarette (3R4F) using a Switching and Cessation study design. A commercial e-vapor product (MarkTen® device [version 2.6.8]; “Test Red”) was supplied by Altria Client Services LLC (Richmond, VA, USA). The Test Red formulation was composed of aerosol formers (propylene glycol [PG] and vegetable glycerol [VG]), ~4% nicotine by weight, and flavors (non-menthol). The 3R4F commercial reference cigarettes were purchased from the University of Kentucky (Lexington, KY). HEPA filtered air at the testing facility (Battelle, West Jefferson, OH) was used as Sham Control. General procedures for animal care and housing met the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) recommendations and requirements stated in the “Guide for Care and Use of Laboratory Animals” [National Research Council (NRC)] and approved by the Institutional Animal Care and Use Committee (IACUC). Female C57BL/6 mice were received from Charles River Kingston (Stone Ridge, NY). Test atmosphere was generated from smoking machines and delivered to the mice through a nose-only exposure system. The modified Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Reference Method 81 regimen (55/30/5: a 55 ± 0.3 mL puff volume, a puff every 30 seconds, a 5-second puff duration) was used to generate e-vapor aerosol for 130 puffs/cartridge. Mainstream smoke from 3R4F cigarette was generated using a modified Health Canada Intense regimen (55/30/2: a 55 ± 0.3 mL puff volume, a puff every 30 seconds, a 2-second puff duration, and a near-square puff profile) for 8 puffs/cigarette. Female C57BL/6 mice (~10 weeks old) were randomly assigned based on body weight to one of five exposure groups: Sham Control, 3R4F CS, Test Red, Switching, and Cessation. Mice were exposed to 3R4F CS (550 µg/L TPM) or e-vapor aerosols (Test Red; 1100 µg/L TPM) via nose-only inhalation up to 4 h/day, 5 d/week for up to 7 months. After the first 3 months of exposure, groups of 3R4F CS mice were subjected to exposures of: (1) Test Red aerosol (“Switching”) or (2) filtered air (“Cessation”), while a group of mice continued to be exposed to 3R4F CS. Here, the protein expression data for lung tissue assessed by iTRAQ®-based quantitative proteomics is reported.

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.

Dataset Information

Comprehensive systems biology analysis of a seven-month cigarette smoke inhalation study in C57BL/6 mice.

Publications

Comprehensive systems biology analysis of a 7-month cigarette smoke inhalation study in C57BL/6 mice.

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