Evaluation of a non-animal toolbox informed by adverse outcome pathways (AOPs) for human inhalation safety
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 4000
ORGANISM(S): Homo sapiens
SUBMITTER: Renato de-Avila
PROVIDER: E-MTAB-14272 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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.
2018-03-01 | E-MTAB-6545 | biostudies-arrayexpress
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.
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Project description:Modified risk tobacco products (MRTPs) have the potential to reduce smoking-related health risks. The Carbon Heated Tobacco Product 1.2 (CHTP1.2) is a potential MRTP that uses a pressed carbon heat source to generate an aerosol by heating tobacco. This study reports the results from the systems toxicology arm of a 90-day rat inhalation study (OECD test guideline 413) to assess the effects of CHTP1.2 aerosol compared with cigarette smoke (CS). Rats were exposed to filtered air (sham), to CHTP1.2 aerosol (at 15, 23 and 50 µg nicotine / L), or to the 3R4F reference cigarette smoke (at 23 µg nicotine / L).
2018-03-19 | PXD008422 | Pride
Project description:Modified risk tobacco products (MRTPs) have the potential to reduce smoking-related health risks. The Carbon Heated Tobacco Product 1.2 (CHTP1.2) is a potential MRTP that uses a pressed carbon heat source to generate an aerosol by heating tobacco. This study reports the results from the systems toxicology arm of a 90-day rat inhalation study (OECD test guideline 413) to assess the effects of CHTP1.2 aerosol compared with cigarette smoke (CS). Rats were exposed to filtered air (sham), to CHTP1.2 aerosol (at 15, 23 and 50 µg nicotine / L), or to the 3R4F reference cigarette smoke (at 23 µg nicotine / L).
2018-03-19 | PXD008424 | Pride
Project description:The current study was performed for analysis of the biological effects of vapor from novel tobacco vapor product in comparison with 3R4F cigarette smoke. This study was performed using a three-dimensional culture system composed of an air-liquid interface culture of primary normal human bronchial epithelial cells (MucilAir). The MucilAir tissues were subjected to 17 days of exposure to the aqueous extract of novel tobacco product vapor or 3R4F cigarette smoke. The number of differentially expressed genes increased in MucilAir tissues exposed to aqueous extract of each test product dependent on exposure duration. The number of differentially expressed genes was lower in the tissues exposed to aqueous extract of novel tobacco product vapor compared to the tissues exposed to aqueous extract of 3R4F cigarette smoke.
2020-04-15 | E-MTAB-8920 | biostudies-arrayexpress
Project description:We previously put forward a multi-layer systems toxicology framework for in vitro assessment of e-liquids that is meant to complement the battery of classical assays for genotoxicity testing. The framework started with the first layer to screen e-liquids for their potential toxicity, followed by the second layer to investigate the toxicity-related mechanism of a selected e-liquid(s), and finally the third layer to evaluate the toxicity-related mechanism of the corresponding aerosol(s). In this work, we leveraged this framework to assess the biological impact of an e-liquid MESH™ “Classic Tobacco” and its aerosol in comparison with the impact of 3R4F reference cigarettes. In the first layer, we evaluated the cytotoxicity profile of the MESH Classic Tobacco liquid (containing humectants, nicotine, and flavors) and its Base liquid (containing humectant and nicotine only) in comparison with total particulate matter (TPM) of 3R4F cigarette smoke (CS). In the second layer, we explored changes in specific markers using high content screening assays to identify potential toxicity-related mechanisms of the MESH Classic Tobacco and Base liquids beyond cell viability compared with the 3R4F TPM-induced effects. In the third layer, we compared the biological impact of exposure to the MESH Classic Tobacco aerosol with CS using human organotypic buccal and small airway epithelial cultures. The results showed that the cytotoxicity profile of the MESH Classic Tobacco liquid was similar to the Base liquid but lower than the toxicity of 3R4F TPM at comparable nicotine concentrations. When compared with CS exposure, MESH Classic Tobacco aerosol exposure did not cause tissue damage and elicited lower changes in the global mRNA, global microRNA, and protein markers. The global mRNA changes following Classic Tobacco aerosol exposure indicated perturbations in processes related to cell fate, cell stress, and inflammatory response that were less than 20% of the perturbations following CS exposure. In the context of tobacco-harm reduction strategy, the framework is suitable to assess the potential reduced impact of EC aerosol relative to CS.
2019-11-01 | E-MTAB-7912 | biostudies-arrayexpress
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
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Project description:Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with occupational exposure to crystalline silica. Rats were exposed to crystalline silica by inhalation (15 mg/m3, 6 h/day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8, and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5 fold change and <0.01 FDR p value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The various biological functions, canonical pathways, and molecular networks affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved lung inflammation was the single most significant biological response to pulmonary exposure to crystalline silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat and these findings may be useful in future to develop strategies to prevent occupational silicosis. A total of 60 rat lung samples were analyzed in this gene expression experiment. Rats were exposed to crystalline silica at a concentration of 15 mg/m³, 6-hours/day for 5 consecutive days. Rats exposed simultaneously to filtered air served as the controls. The control (n=4) and silica exposed (n=8) rats were sacrificed at post-exposure time intervals of 1, 2, 4, 8, and 16 weeks following termination of silica exposure and lung gene expression profile was determined.
2012-06-29 | E-GEOD-32147 | biostudies-arrayexpress