Unknown,Transcriptomics,Genomics,Proteomics

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Rat-THS2.2-Experiment

ABSTRACT: The objective of the study was to characterize the toxicity due to sub-chronic inhalation of test atmospheres from the heat not burn modified risk tobacco product (MRTP) - Tobacco Heating System version 2.2 (THS2.2) and to compare it to the toxicity inherent to the inhalation of mainstream smoke (MS) from the Reference Cigarette 3R4F (University_of_Kentucky, 2003). The 90-day nose-only inhalation study on Sprague-Dawley rats was performed according to the Organization for Economic Co-operation and Development (OECD) Test Guideline 413 (OECD, 2009), with special emphasis on histopathology of the respiratory tract, lung inflammation and additional systems toxicology-based assessment using transcriptomics. Animals were exposed to mainstream smoke from 3R4F reference cigarettes or THS2.2 mainstream aerosol at 3 target nicotine concentrations. The exposure regimen consisted of 6 hours a day, 5 days per week for 13 weeks, followed by 42 days recovery period. Exposure-related changes such as increased blood neutrophil count, decreased blood lymphocyte count, increased activity of alkaline phosphatase in serum and decreased cholesterol and glucose in serum were observed in 3R4F and THS2.2 exposed animals. Reduction in respiratory minute volume was significantly less pronounced in THS2.2 as compared to 3R4F-exposed groups. Histopathological findings in the respiratory tract including epithelial cell hyperplasia, squamous metaplasia, atrophy and accumulation of pigmented alveolar macrophages were significantly lower in THS2.2 than in 3R4F exposed groups. The degree of lung inflammation as indicated by accumulation of immune cells and pro-inflammatory and chemotactic cytokines in bronchioalveolar lavage fluid were significantly lower in THS2.2 as compared to 3R4F exposed groups. Transcriptomics data obtained from nasal epithelium and lung parenchyma showed concentration-dependent gene expression changes following 3R4F exposure that were much less pronounced in the THS2.2-exposed groups. In summary, the data indicates that the aerosol from THS2.2 did not cause additional toxicity as compared to the smoke from the 3R4F conventional cigarette. The toxicity on respiratory tract organs in THS2.2 exposed animals was much lower than in the rats exposed to 3R4F reference cigarette. Overall, the changes observed following exposure to THS2.2 can be considered mild and are very similar to previously published effects caused by nicotine only exposure at similar test atmosphere concentrations.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Vincenzo Belcastro

PROVIDER: E-MTAB-4492 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In vitro toxicology approaches have evolved, from a focus on the molecular changes within a cell to understanding of toxicity-related mechanisms that simulate the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offer a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the relevancy and application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. The biological impact was assessed following exposure to aerosol generated from a candidate modified risk tobacco product (MRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F using an in vitro human 3-D nasal epithelial cultures. A series of experimental repetitions where multiple doses of the aerosol and smoke were applied, were conducted to obtain reproducible measurements and reliable observations to understand the cellular/molecular changes that occur following exposure. Aligned with the 3Rs Strategy and the Vision-and-Strategy of the Toxicity Testing in the 21st Century, this study implemented a systems toxicology approach and found that for all tested concentrations, the impact of 3R4F smoke was considerably greater than that of THS2.2 aerosol in terms of cytotoxicity levels, alterations in the tissue morphology, secretion of pro-inflammatory mediators, impaired ciliary function, and increased perturbed transcriptomes and miRNA expression profiles. In addition, to evaluate further the possible adverse effects of THS2.2 aerosol, a dose range assessment was conducted. A broader range of THS2.2 concentrations were exposed to the nasal cultures. Various dilutions of THS2.2 were applied to the cultures using the Vitrocellï¾® 24/48 exposure system, corresponding to the concentrations of nicotine between 0.15 mg/L and 1.79 mg/L

Project description:In vitro toxicology approaches have evolved, from a focus on the molecular changes within a cell to understanding of toxicity-related mechanisms that simulate the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offer a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the relevancy and application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. The biological impact was assessed following exposure to aerosol generated from a candidate modified risk tobacco product (MRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F using an in vitro human 3-D nasal epithelial cultures. A series of experimental repetitions where multiple doses of the aerosol and smoke were applied, were conducted to obtain reproducible measurements and reliable observations to understand the cellular/molecular changes that occur following exposure. Aligned with the 3Rs Strategy and the Vision-and-Strategy of the Toxicity Testing in the 21st Century, this study implemented a systems toxicology approach and found that for all tested concentrations, the impact of 3R4F smoke was considerably greater than that of THS2.2 aerosol in terms of cytotoxicity levels, alterations in the tissue morphology, secretion of pro-inflammatory mediators, impaired ciliary function, and increased perturbed transcriptomes and miRNA expression profiles. In addition, to evaluate further the possible adverse effects of THS2.2 aerosol, a dose range assessment was conducted. A broader range of THS2.2 concentrations were exposed to the nasal cultures. Various dilutions of THS2.2 were applied to the cultures using the VitrocellÂ® 24/48 exposure system, corresponding to the concentrations of nicotine between 0.15 mg/L and 1.79 mg/L

Project description:In vitro toxicology approaches have evolved, from a focus on the molecular changes within a cell to understanding of toxicity-related mechanisms that simulate the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offer a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the relevancy and application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. The biological impact was assessed following exposure to aerosol generated from a candidate modified risk tobacco product (MRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F using an in vitro human 3-D nasal epithelial cultures. A series of experimental repetitions where multiple doses of the aerosol and smoke were applied, were conducted to obtain reproducible measurements and reliable observations to understand the cellular/molecular changes that occur following exposure. Aligned with the 3Rs Strategy and the Vision-and-Strategy of the Toxicity Testing in the 21st Century, this study implemented a systems toxicology approach and found that for all tested concentrations, the impact of 3R4F smoke was considerably greater than that of THS2.2 aerosol in terms of cytotoxicity levels, alterations in the tissue morphology, secretion of pro-inflammatory mediators, impaired ciliary function, and increased perturbed transcriptomes and miRNA expression profiles. In addition, to evaluate further the possible adverse effects of THS2.2 aerosol, a dose range assessment was conducted. A broader range of THS2.2 concentrations were exposed to the nasal cultures. Various dilutions of THS2.2 were applied to the cultures using the Vitrocell® 24/48 exposure system, corresponding to the concentrations of nicotine between 0.15 mg/L and 1.79 mg/L.

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.

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Rat-THS2.2-Experiment

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