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Integration of toxicological end points with molecular measurements in a 28-day rat repeated dose inhalation study with cigarette smoke provides mechanistic understanding of smoke impact

ABSTRACT: Demonstration of reduced biological effects with a prototypic modified risk tobacco product. Towards a systems toxicology-based risk assessment, we investigated molecular perturbations accompanying histopathological changes in a 28-day rat inhalation study combining transcriptomics with classical histopathology, and demonstrated reduced biological activity of a prototypic modified risk tobacco product (pMRTP) in comparison to the reference research cigarette 3R4F. Rats were exposed to filtered air or to three concentrations of mainstream smoke (MS) from 3R4F, or to a high concentration of MS from a pMRTP. Histopathology revealed dose-dependent changes for 3R4F: irritative stress-related in nasal and bronchial epithelium and inflammation-related in the lung parenchyma. For pMRTP, significant changes were seen in the nasal epithelium only. Transcriptomics data were obtained from nasal and bronchial epithelium and lung parenchyma. Dose-dependent gene expression changes were seen for 3R4F with much smaller changes for pMRTP. A computational-modeling approach that is based on causal models of tissue-specific biological networks identified cell stress, inflammation, cell proliferation, and senescence as the most perturbed molecular mechanisms. These perturbations correlated with the histopathological observations. Only weak perturbations were observed for the pMRTP. In conclusion, a correlative evaluation of classical histopathology together with gene expression?based computational network models may facilitate a systems toxicology-based risk assessment as shown for a pMRTP.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE50254 | GEO | 2014/05/15

SECONDARY ACCESSION(S): PRJNA217343

REPOSITORIES: GEO

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Project description: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.

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Integration of toxicological end points with molecular measurements in a 28-day rat repeated dose inhalation study with cigarette smoke provides mechanistic understanding of smoke impact

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