Unknown,Transcriptomics,Genomics,Proteomics

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Rat-THS2.2M-Experiment

ABSTRACT: 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 (15Î¼g/l, 23Î¼g/l, 50Î¼g/l nicotine), cigarette smoke (CS) from the reference cigarette 3R4F (23Î¼g/l nicotine), or CS from reference cigarettes with two different menthol concentrations (23Î¼g/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.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Vincenzo Belcastro

PROVIDER: E-MTAB-4493 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Rat-THS2.2M-Experiment

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