Experimental Acute Exposure to Thirdhand Smoke and Changes in the Human Nasal Epithelial Transcriptome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129959 | GEO | 2019/04/18
REPOSITORIES: GEO
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Project description:Aiming to reduce smoking-related health risks, potential reduced risk products (pRRPs) are being developed. The Tobacco Heating System (THS) 2.2 is a recently developed pRRP, which utilizes the heat-not-burn principle. In this study, systems toxicology approaches were engaged to assess the respiratory effects of a mentholated version of THS2.2 (THS2.2M) in a 90-day rat inhalation study (OECD test guideline 413). This is the quantitative proteomics data set for rat nasal epithelium. As described in the sample processing protocol, two different iTRAQ sets were defined and analyzed separately. See i_Rat-THS2.2M-TG413_protItraq_RNE.xlsx for sample annotations and file mappings.
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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 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: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
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Project description:Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is recognized as a public health concern. The nasal epithelium is particularly susceptible to H2S-induced pathology. Injury to and regeneration of the nasal respiratory mucosa occurred in animals with ongoing H2S exposure suggesting that the regenerated respiratory epithelium undergoes an adaptive response and becomes resistant to further H2S induced toxicity. To better understand this adaptive response, twenty-four naive 10-week old male Sprague-Dawley rats were exposed to air or 200 ppm H2S in a nose-only exposure system for 3h/d for 1 or 5 consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected and gene expression profiles were generated at time 3h, 6h, 24h, and 144h post initial exposure using the Affymetrix Rat Genome 430 2.0 microarray. Gene ontology enrichment analysis identified early gene changes in such functional categories as signal transduction, inflammatory/defense response, cell cycle, and response to oxidative stress. Later gene changes occurred in categories involved in cell cycle, DNA repair, transport, and micro-tubule-based movement. These data contribute to our understanding of the nasal epithelial cells? response to inhaled environmental toxicants. A better understanding of the H2S cytotoxicity mechanism will improve human risk assessment. Experiment Overall Design: Twenty-four naive 10-week old male Sprague-Dawley rats were exposed to air or 200 ppm H2S in a nose-only exposure system for 3h/d for 1 or 5 consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected and gene expression profiles were generated at time 3h, 6h, 24h, and 144h post initial exposure using the Affymetrix Rat Genome 430 2.0 microarray.
2009-10-18 | E-GEOD-5349 | biostudies-arrayexpress
Project description:Toward the reduction of smoking-related health risks potential reduced risk products (pRRPs) are being developed. The Tobacco Heating System (THS) 2.2 is a recently developed pRRP, which relies on the heat-not-burn principle. We present results from the systems-toxicology arm of a 90-day Organization for Economic Co-operation and Development test guideline 413 inhalation study for the assessment of a mentholated version of THS2.2 (THS2.2M). Sprague-Dawley rats were nose-only exposed, 6?h/day, 5 days/week to filtered air, three concentrations of THS2.2M aerosol (15μg/l, 23μg/l, 50μg/l nicotine), cigarette smoke (CS) from the reference cigarette 3R4F (23μg/l nicotine), or CS from reference cigarettes with two different menthol concentrations (23μg/l nicotine; 1.2 and 2.4 mg menthol/cigarette). Reversibility of the exposure effects was assessed in a subset of the groups following 42 days of filtered air exposure. Standard toxicology endpoints were complemented by transcriptomics and quantitative proteomics analyses of nasal epithelium and lung tissue and by lipidomics analysis of lung tissue. The adaptive response of the nasal epithelium to CS exposure included squamous cell metaplasia and an inflammatory response, with high correspondence between the molecular and histopathological results. In contrast to CS exposure, the adaptive tissue and molecular changes to THS2.2M aerosol exposure were much reduced and mostly limited to the highest THS2.2M concentration in female rats. In the lung, CS exposure induced an inflammatory response, triggered cellular stress responses (e.g., oxidative stress and xenobiotic metabolism), and affected sphingolipid metabolism. These responses were not observed or much lower upon THS2.2M aerosol exposure. All in all, this system toxicology analysis complements and reconfirms the classical toxicological endpoints and further suggests a potentially reduced risk of THS2.2M.
2016-10-03 | E-MTAB-4493 | biostudies-arrayexpress
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2018-12-01 | GSE107624 | GEO
Project description:AIM: To investigate the molecular, structural, and functional impact of aerosols from two heat-not-burn-based MRTPs, the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2, compared with that of cigarette mainstream smoke (CS) on the cardiovascular system of ApoE-/- mice. METHOD: Female ApoE-/- mice were exposed to aerosols from THS 2.2 and CHTP 1.2 or to CS from 3R4F for up to 6 months at matching nicotine concentrations. A cessation and a switching group (3 months exposure to 3R4F CS followed by filtered air or CHTP 1.2 for 3 months) were included. Cardiovascular effects were investigated using echocardiography, histopathology, immunohistochemistry, and transcriptomics. RESULTS: Continuous exposure to aerosols from CHTP 1.2 and THS 2.2 did not affect the atherosclerosis progression, heart function, left ventricular structure and cardiovascular transcriptome. Exposure to CS from 3R4F triggered atherosclerosis progression, reduced systolic ejection fraction and fractional shortening, caused heart left ventricle hypertrophy and initiated significant dysregulation in the transcriptomes of the heart ventricle and thoracic aorta. Importantly, smoking cessation and switching to CHTP 1.2 aerosol similarly improved the structural, functional, and molecular changes caused by 3R4F CS. CONCLUSION: Exposure to aerosols from CHTP 1.2 and THS 2.2 lacked most of the CS exposure-related functional, structural and molecular effects. Smoking cessation or switching to CHTP 1.2 aerosol caused a similar recovery from the 3R4F CS effect in the ApoE-/- model with no further acceleration of plaque progression beyond the aging-related rate.
2021-08-16 | E-MTAB-7981 | biostudies-arrayexpress