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Combined biological effects and lung proteomics analysis in mice reveal different toxic impacts of electronic cigarette aerosol and combustible cigarette smoke on the respiratory system

ABSTRACT: Combustible cigarettes produce many toxic substances that have been linked to diseases such as lung cancer and chronic obstructive pulmonary disease (COPD). Electronic cigarettes (e-cigarettes) can be used as an alternative to cigarettes for smokers who are unable or unwilling to quit. However, the effects and mechanisms of e-cigarette aerosol (ECA) on respiratory function have not been fully elucidated, and in vivo studies of its safety are limited compared to cigarette smoke (CS). In this article, we chose nicotine levels as the dose reference and selected C57BL/6 mice for a 10-week subchronic inhalation toxicity study. A comprehensive set of toxicological endpoints was used to study the effects of exposure. Thus, additional evidence is provided for the relative safety of e-cigarettes.

ORGANISM(S): Mus <genus>

SUBMITTER: Jianwen Chen

PROVIDER: PXD035374 | iProX | Thu Jul 14 00:00:00 BST 2022

REPOSITORIES: iProX

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Combined biological effects and lung proteomics analysis in mice reveal different toxic impacts of electronic cigarette aerosol and combustible cigarette smoke on the respiratory system.

Yang Wanchun W Yang Xuemin X Jiang Lujing L Song Hongjia H Huang Guangye G Duan Kun K Jiang Xingtao X Li Min M Liu Peiqing P Chen Jianwen J

Archives of toxicology 20220929 12

Combustible cigarettes produce many toxic substances that have been linked to diseases, such as lung cancer and chronic obstructive pulmonary disease. For those smokers unable or unwilling to quit, electronic cigarettes (e-cigarettes) could be used as an alternative to cigarettes. However, the effects and mechanisms of e-cigarette aerosol (ECA) on respiratory function have not been fully elucidated, and in vivo studies of its safety are limited compared to cigarette smoke (CS). In this article, ...[more]

PMID: 36173423

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Project description:Exposure to cigarette smoke is a leading cause of lung diseases including chronic obstructive pulmonary disease and cancer. Cigarette smoke is a complex aerosol containing over 6000 chemicals, and thus it is difficult to determine individual contributions to overall toxicity, and the molecular mechanisms by which smoke constituents exert their effects. We selected three well-known harmful and potentially harmful constituents (HPHCs) in tobacco smoke: acrolein, formaldehyde and catechol and established a High Content Screening (HCS) method using normal human bronchial epithelial cells, which are the first bronchial cells in contact with cigarette smoke. The impact of each HPHC was investigated using 13 multi-parametric indicators of cellular toxicity and complemented with a microarray-based whole transcriptome analysis followed by a computational approach leveraging mechanistic network models to identify and quantify perturbed molecular pathways. HPHCs were evaluated over a wide range of concentrations and at different exposure time points (4 h, 8 h, and 24 h). By High Content Screening, the toxic effects of the three HPHCs could only be observed at the highest doses. Whole genome transcriptomics unraveled toxicity mechanisms at lower doses and earlier time points. The most prevalent toxicity mechanisms observed were: DNA damage/growth arrest, oxidative stress, mitochondrial stress and apoptosis/necrosis. In summary, combination of multiple toxicological endpoints with a systems-based impact assessment allows for a more robust scientific basis for the toxicological assessment of HPHCs that allows insight into time- and dose-dependent molecular perturbations of specific biological pathways. This approach allowed us to establish an in vitro Systems Toxicology platform that can be applied to a broader selection of HPHCs and their mixtures and can serve more generally as the basis for testing the impact of other environmental toxicants on normal bronchial epithelial cells.

Project description:Pulmonary exposure to high doses of nanoparticles (NP) leads to well characterized lung toxicity in addition to long-term NP retention. However, pulmonary NP accumulation and toxicity following low dose exposures are not well described. In the present study we sought to: (1) investigate particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2) and (2) determine the effects of long-term particle accumulation on pulmonary systems. Female C57BL/6 mice were exposed to rutile nano-TiO2 (primary size of 20.6 nm and surface area of 107.7 m2/g) via single intratracheal instillations of 18, 54 and 162 M-BM-5g/mouse and sampled 1, 3 and 28 days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using Nanoscale Hyperspectral Microscope. DNA microarrays, pathway-specific real-time RT-PCR (qPCR) and gene-specific qPCR arrays, and tissue protein analyses were employed to characterize pulmonary responses. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28 days post-exposure time. Retention did not correlate with the extent of inflammatory neutrophil influx into the lungs. DNA microarray analysis showed altered expression of approximately 3000 genes across all treatment groups (M-BM-11.3 fold; p<0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein levels. Although the low dose exposure failed to induce observable inflammation, significant changes in the expression of genes and proteins associated with inflammation were observed. Moreover, diminished (or absent) neutrophil influx in the low and medium dose groups was correlated with negative regulation of genes associated with ion homeostasis and muscle regulation. Gene expression changes for several inflammatory mediators have previously been noted in mice exposed to the same nano-TiO2 via inhalation. Our results suggest that retention of nano-TiO2 in the absence of inflammation and effective clearance can perturb calcium and ion homeostasis, and affect smooth muscle activities over time. This experiment consists of three different dosages of TiO2, e.g., low (18 ug), medium (54 ug) and high (162 ug), and one control. There are 3 time points for each treatment and control group, e.g., day 1, day 3 and day 28. Each dose or time point has 5-6 biological replicates. There are total 65 samples (arrays)

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Dataset Information

Combined biological effects and lung proteomics analysis in mice reveal different toxic impacts of electronic cigarette aerosol and combustible cigarette smoke on the respiratory system

Publications

Combined biological effects and lung proteomics analysis in mice reveal different toxic impacts of electronic cigarette aerosol and combustible cigarette smoke on the respiratory system.

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