Dataset Information

"Effects of cigarette smoke, cessation and switching to a modified risk tobacco product on the liver in Apoe-/- mice -- a systems toxicology analysis"

ABSTRACT: "Liver represents one of the most important organs involved in the elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains more than 7000 chemicals, among which compounds that exert biological effects and cause smoking-related diseases. Although CS is not directly hepatotoxic, a growing body of evidence suggests that it may exacerbate (pre-existing) chronic liver diseases. Here we integrated toxicological endpoints with molecular measurements and computational analysis approaches to investigate exposure effects on liver in an Apoe-/- mouse study. The mice were exposed to high concentrations of 3R4F reference CS (600 mg/m3 TPM, 29.9 mg/m3 nicotine), an aerosol from a candidate reduced risk product (RRP) the Tobacco Heating System (THS) 2.2 at matching nicotine concentration, or filtered air (Sham) for up to 8 months. THS2.2 was conceived using the heat-not-burn technology that heats tobacco avoiding pyrogenesis and pyrosynthesis. After 2 months of CS exposure, some groups were either switched to the RRP or underwent exposure cessation. While clear signs of hepatotoxic effects were absent for any exposure group, the integrative analysis of proteomics and transcriptomics data showed a CS-dependent impairment of specific biological networks, including lipid and xenobiotic metabolism, and iron homeostasis, which likely in turn mutually contribute to worsening of the oxidative stress. In contrast, most of these changes were absent in mice exposed to THS2.2, and in the cessation and switching groups. Our findings shed light on the complex biological response of the liver to CS exposure and support the benefits of switching to the tested heat-not-burn product, THS2.2."

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Bjoern Titz

LAB HEAD: Julia Hoeng

PROVIDER: PXD002925 | Pride | 2016-12-22

REPOSITORIES: Pride

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Publications

Effects of cigarette smoke, cessation and switching to a candidate modified risk tobacco product on the liver in Apoe -/- mice--a systems toxicology analysis.

Lo Sasso Giuseppe G Titz Bjoern B Nury Catherine C Boué Stéphanie S Phillips Blaine B Belcastro Vincenzo V Schneider Thomas T Dijon Sophie S Baumer Karine K Peric Daruisz D Dulize Remi R Elamin Ashraf A Guedj Emmanuel E Buettner Ansgar A Leroy Patrice P Kleinhans Samuel S Vuillaume Gregory G Veljkovic Emilija E Ivanov Nikolai V NV Martin Florian F Vanscheeuwijck Patrick P Peitsch Manuel C MC Hoeng Julia J

Inhalation toxicology 20160330 5

The liver is one of the most important organs involved in elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains more than 7000 chemicals, including those that exert biological effects and cause smoking-related diseases. Though CS is not directly hepatotoxic, a growing body of evidence suggests that it may exacerbate pre-existing chronic liver disease. In this study, we integrated toxicological endpoints with molecular measurements and computational analyses to ...[more]

PMID: 27027324

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Project description:The objective of this study was to compare the biological and toxicological response of apolipoprotein E-deficient (Apoe-/-) mice to 3R4F mainstream smoke exposure for 2 months in whole-body exposure chambers (WBEC) and nose-only exposure chambers (NOEC). Female ApoE-/- mice were randomized into four groups: two Sham groups, exposed to filtered air, and two 3R4F groups, exposed to CS from the 3R4F reference cigarette (550 Âµg TPM/L). Half the number of mice in the Sham- and CS-exposed groups were exposed in WBECs and the other half in NOECs. The exposure phase lasted 9 weeks and included 1 week of adaption, during which exposure in both chamber types was escalated in dose and duration to a maximum of 4 h per day. The TPM concentration and exposure duration in WBECs were matched to those in NOECs on the basis of the regimen that the mice tolerated, as determined by in-life findings on acute signs of nicotine toxicity. Fresh air breaks were introduced during the exposure period to maintain carboxyhemoglobin (COHb) concentrations at acceptable levels. More frequent and longer fresh air breaks were required for exposure in the WBEC than in the NOEC because of the greater internal volumeâ€”and, consequently, the longer durationâ€”required to clear smoke from the WBEC than from the NOEC. For animals in NOECs, a 30-min fresh air break was introduced after 2 and 3 h of exposure. For animals in WBECs, a 30-min fresh air break was introduced after 1 and 2 h of exposure and a 60-min fresh air break after the third hour of exposure. The general condition and health of the mice following exposure were monitored throughout the study. Full necropsy was performed 16-20 h after the last exposure without prior fasting, in accordance with previously described methods (Vanscheeuwijck et al., 2002). Differences between WBEC and NOEC expsoure were analyzed with regard to aerosol uptake, disease endpoints (adaptive changes in nasal epithelia, changes in lung function and inflammatory parameters, plasma cholesterol/triglyceride levels in lipoprotein fractions, and atherosclerosis plaque development), and systems biology endpoints (changes in the lung proteome and liver, nasal epithelial, and heart transcriptomes). All procedures involving animals were performed in a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International and licensed by the Agri-Food & Veterinary Authority of Singapore, with approval from an Institutional Animal Care and Use Committee and in compliance with the National Advisory Committee for Laboratory Animal Research Guidelines on the Care and Use of Animals for Scientific Purposes (NACLAR, 2004). Here, the protein expression data for lung tissue assessed by iTRAQ®-based quantitative proteomics will be described.

Dataset Information

"Effects of cigarette smoke, cessation and switching to a modified risk tobacco product on the liver in Apoe-/- mice -- a systems toxicology analysis"

Publications

Effects of cigarette smoke, cessation and switching to a candidate modified risk tobacco product on the liver in Apoe -/- mice--a systems toxicology analysis.

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