Multi-omics systems toxicology study of mouse lung assessing the effects of aerosols from two heat-not-burn tobacco products and cigarette smoke

Titz, Bjoern; Szostak, Justyna; Sewer, Alain; Phillips, Blaine; Nury, Catherine; Schneider, Thomas; Dijon, Sophie; Lavrynenko, Oksana; Elamin, Ashraf; Guedj, Emmanuel; Wong, Ee Tsin; Lebrun, Stefan; Vuillaume, Gregory; Kondylis, Athanasios; Gubian, Sylvain; Cano, Stéphane; Leroy, Patrice; Keppler, Brian; Ivanov, Nikolai V.; Vanscheeuwijck, Patrick; Martin, Florian; Peitsch, Manuel C.; Hoeng, Julia

doi:10.1016/j.csbj.2020.04.011

Cited by 32 publications

(26 citation statements)

References 121 publications

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“…of mice identified dramatic increases in bilirubin production implying a protective role. 10 Population-based cohort studies have also linked moderately raised serum bilirubin levels with lower rates of respiratory diseases and lung cancer with the strongest associations in cigarette smokers. [11][12][13][14] Although these observations are consistent with an endogenous antioxidant function for bilirubin, the relationships with lung cancer could reflect residual confounding or reverse causation.…”

Section: Lung Cancermentioning

confidence: 99%

“… 5–8 For example, the enzymes that generate bilirubin (biliverdin reductase, HMOX1) are found at their highest concentrations in respiratory tissues 9 and a recent network analysis of the effect of cigarette smoke on the lung tissue of mice identified dramatic increases in bilirubin production implying a protective role. 10 Population-based cohort studies have also linked moderately raised serum bilirubin levels with lower rates of respiratory diseases and lung cancer with the strongest associations in cigarette smokers. 11–14 Although these observations are consistent with an endogenous antioxidant function for bilirubin, the relationships with lung cancer could reflect residual confounding or reverse causation.…”

Section: Introductionmentioning

confidence: 99%

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Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

Horsfall¹,

Burgess

Hall

et al. 2020

Thorax

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BackgroundModerately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding.ObjectiveThis study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank.MethodsWe instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated.ResultsWe included 377 294 participants (median bilirubin 8.1 μmol/L (IQR 6.4–10.4)) and 2002 lung cancer events in the MR analysis. Each 5 μmol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 μmol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (≥20/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function.ConclusionGenetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers.

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Section: Lung Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

Horsfall¹,

Burgess

Hall

et al. 2020

Thorax

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“…Micro-RNAs (miRNAs) contribute to the post-transcriptional regulation of various biological processes ( Pritchard et al 2012 ). Changes in miRNA levels upon CS exposure have been reported in vitro , in vivo , and in clinical studies ( Pottelberge et al 2011 ; Titz et al 2020 ; Zanetti et al 2018 ).…”

Section: Resultsmentioning

confidence: 96%

Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice

Titz

Sewer

Luettich

et al. 2020

Toxicological Sciences

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Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases. However, switching to less harmful products (modified risk tobacco products [MRTP]) can be an alternative to help reduce the risk for adult smokers who would otherwise continue to smoke. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed the aerosol of Tobacco Heating System 2.2 (THS 2.2), a candidate MRTP 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. In this part of our publication series, we report on integrative assessment of the apical and molecular exposure effects on the respiratory tract (nose, larynx, and lungs). Across the respiratory tract, we found changes in inflammatory response following 3R4F CS exposure (e.g., antimicrobial peptide response in the nose), with both shared and distinct oxidative and xenobiotic responses. Compared with 3R4F CS, THS 2.2 aerosol exerted far fewer effects on respiratory tract histology, including adaptive tissue changes in nasal and laryngeal epithelium and inflammation and emphysematous changes in the lungs. Integrative analysis of molecular changes confirmed the substantially lower impact of THS 2.2 aerosol than 3R4F CS on toxicologically and disease-relevant molecular processes such as inflammation, oxidative stress responses, and xenobiotic metabolism. In summary, this work exemplifies how apical and molecular endpoints can be combined effectively for toxicology assessment and further supports findings on the reduced respiratory health risks of THS 2.2 aerosol.

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“…It has been described before that the enrichment analysis of combined transcriptomics and proteomics data leads to more significant enrichment compared to the single omics layer, thus showing that the advantages of stronger p-values outweigh the disadvantage of noise that might be provoked by the combination of multiple omics layers [ 60 ]. Likewise, others have described the advantages of integrative multi-omics analyses for toxicological questions before [ 159 , 160 ]. Since tools for an integrated pathway enrichment are emerging [ 161 , 162 ], this should be considered in future multi-omics studies.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages

Karkossa

Raps

Bergen

et al. 2020

IJMS

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Insights into the modes of action (MoAs) of xenobiotics are of utmost importance for the definition of adverse outcome pathways (AOPs), which are essential for a mechanism-based risk assessment. A well-established strategy to reveal MoAs of xenobiotics is the use of omics. However, often an even more comprehensive approach is needed, which can be achieved using multi-omics. Since the immune system plays a central role in the defense against foreign substances and pathogens, with the innate immune system building a first barrier, we systematically reviewed multi-omics studies investigating the effects of xenobiotics on macrophages. Surprisingly, only nine publications were identified, combining proteomics with transcriptomics or metabolomics. We summarized pathways and single proteins, transcripts, or metabolites, which were described to be affected upon treatment with xenobiotics in the reviewed studies, thus revealing a broad range of effects. In summary, we show that macrophages are a relevant model system to investigate the toxicological effects induced by xenobiotics. Furthermore, the multi-omics approaches led to a more comprehensive overview compared to only one omics layer with slight advantages for combinations that complement each other directly, e.g., proteome and metabolome.

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Multi-omics systems toxicology study of mouse lung assessing the effects of aerosols from two heat-not-burn tobacco products and cigarette smoke

Cited by 32 publications

References 121 publications

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice

Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages

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