Aorta transcriptome of ApoE-/- mice exposed to mainstream cigarette smoke for 30 days.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Affymetrix GeneChip(R) HT Scanner
ORGANISM(S): Mus musculus
SUBMITTER: Sam Ansari
PROVIDER: E-MTAB-1696 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Objective: Although relationships between smoking and cardiovascular diseases (CVD), and CVD and lipids are established, direct impact of cigarette smoke (CS) on lipidomes remains elusive. We investigated the effect of 6 month smoke exposure on a well-established mouse model for human atherogenesis, Apoe mouse plasma, liver, and aorta molecular lipid profiles and liver transcriptome. // Methods: Plasma, liver, and aorta samples from Apoe mice exposed to CS or fresh air for 6 months were extracted for lipids using robotic-assisted method and analyzed by mass spectrometry. Gene expression of samples from the same livers was obtained on microarrays. Development of atherosclerosis in aorta was further assessed by plaque size measurement in the aortic arch and lipoprotein measurements in plasma and in the plaque. // Results: CS increased most lipid classes and molecular lipid species in tissues evaluated. In plasma, free cholesterol, ceramides, cerebrosides, and majority of phospholipids were increased in CS-exposed mice. In liver, CS elevated several lipid species including free and esterified cholesterol, triacylglycerols, phospholipids, sphingomyelins, and ceramides. In aorta, more than 2-fold higher cholesteryl ester (CE), lysophosphatidylcholine, and glucosyl/galactosylceramide levels were recorded in mice exposed to CS compared to mice exposed to fresh air. Moreover, CS exposure induced a significant decrease in several plasma CE and phosphatidylcholine species that contained polyunsaturated fatty acids. Genes involved in amino acid and lipid metabolism showed perturbed transcription profiles in liver. // Conclusion: These data reveal molecular details accompanying the increase in plaque size, sign of atherogenesis in Apoe mice, which is accelerated by CS exposure.
2013-10-03 | E-MTAB-1195 | biostudies-arrayexpress
Project description:Modern 'omic' technologies, where changes in the expression of thousands of molecular species can be investigated in even a simple experiment, provide contemporary biomedical researchers with an unprecedented level of molecular granularity. An outstanding challenge is transformation of this experimental detail and complexity into meaningful biological insight. This is especially true for drug development and toxicological risk assessment, where molecular profiling data is increasingly being used to investigate the biological effects of a variety of exposures, from drugs to environmental factors, on human systems. Recently, we proposed a systems-based strategy for objectively predicting the mechanistic impact of biologically active substances from transcriptomic data, and report here on an initial implementation of this strategy. We applied a set of biological network models and novel scoring algorithms to investigate transcriptomic data from a range of experimental systems. Importantly, this approach enabled continuity between investigation at the molecular, pathway, and systems levels. For both in vitro systems with simple exposures and in vivo systems with complex exposures, the method was able to identify and provide relative quantitation for the precise mechanisms that were impacted. For example, when applied to data from mice exposed to cigarette smoke, the methodology correctly identified known mechanistic effects of the exposure, including increased pulmonary inflammation, necrosis, and proliferation. Importantly, many of the effects indicated by the methodology were supported by experimental endpoint data, providing further objective validation of the general approach. We propose that various fields of human disease research, from drug development to consumer product testing, could benefit from using this or similar approaches to evaluate the biological impact of exposures.
2013-02-15 | E-MTAB-1313 | biostudies-arrayexpress
Project description:Although smoking cessation shows clear cardiovascular risk benefits, lung-related disease risk remains higher in former smokers than in never smokers. To better understand the factors involved in this phenomenon, ApoE-/- mice were exposed to mainstream cigarette smoke (CS) or a smoking cessation-mimicking protocol for up to six months. Analysis of bronchoalveolar lavage fluid (BALF) from CS-exposed ApoE-/- mice revealed the presence of high concentrations of mediators involved in functions ranging from inflammation to cell proliferation and tissue remodeling. Gene expression levels for many analytes found elevated in BALF were also increased in lung tissue, indicating that the inflammatory response was the result of local tissue activation and the contribution of recruited inflammatory cells. Gene set enrichment analysis (GSEA) of expression data from lungs of CS-exposed mice showed activation of pathways involved in cell proliferation and tissue remodeling and a progressive deactivation upon smoke exposure cessation. Distinct activation patterns of inflammation, complement, and xenobiotic metabolism pathways were found in nasal epithelium and lung parenchyma during CS exposure and smoking cessation. Exposure of ApoE-/- mice to CS for up to 6 months induced adaptive and inflammatory responses in the respiratory tract that were partially deactivated upon cessation. We were able to reveal molecular perturbations accompanying these changes during CS exposure and cessation. Differential CS-mediated responses of pulmonary and nasal tissues reflect common mechanisms but also the varying degrees of epithelial functional specialization along the respiratory tract. These findings provide novel clues for the identification of markers of COPD progression.
2013-10-19 | E-MTAB-1390 | biostudies-arrayexpress
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 µg 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 volume—and, consequently, the longer duration—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.
2021-02-26 | PXD018185 | Pride
Project description:"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."
2016-12-22 | PXD002925 | Pride
Project description:The aim of this study was to develop human bronchial and nasal epithelium culture models that are relevant to investigate the impact of cigarette smoke (CS) observed in vivo in respiratory tract tissues in contact with inhaled CS. We used two organotypic cultures generated from primary cells derived from non-smoking donors that contain fibroblasts and epithelial cells in order to reproduce as closely as possible the in vivo situation. To mimic the smoking behavior of a moderate smoker during one day, human tissue cultures (bronchial and nasal epithelium) were exposed repeatedly and directly at the air/liquid interface (using the Vitrocell(R) System) to two doses (high 4.2 ug TPM/cm2 and low 2.2 ug TPM/cm2 per cigarette) of the whole smoke generated by one cigarette or to humidified air (sham). CS exposure was repeated four times with one hour intervals between each cigarette. Various endpoints (e.g., gene and microRNA expression, CYP activity, pro-inflammatory markers release, differential cell counts, cytotoxicity measurement) were then captured to assess the baseline (time 0) and early responses of the tissues after exposure (4 hours) as well as the recovery phase (24 and 48 hours).
2013-12-11 | E-MTAB-1721 | biostudies-arrayexpress
Project description:Liver represents one of the most important organs involved in the elimination of xenobiotic and potentially toxic substances. Cigarette smoke (CS) contains several compounds that exert biological effects and cause smoking related diseases. Although cigarette smoke is not directly hepatotoxic, a growing body of evidence suggests that CS may exacerbate chronic liver diseases. Here we integrated classical toxicological endpoints with molecular measurement 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), aerosol from a candidate modified risk tobacco product (MRTP), the Tobacco Heating System (THS) 2.2, or filtered air (Sham) for up to 8 months. After 2 months of CS exposure, some groups were either switched to the MRTP or underwent cessation. While clear signs of hepatotoxic effects were absent for any exposure group, the integrative analysis of proteomic and transcriptomic data showed a CS-dependent impairment of specific biological networks, such as lipid, xenobiotic, 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 in the 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.
2016-10-31 | E-MTAB-3876 | biostudies-arrayexpress
Project description:Aortic arch profiling of Apoe-/- mice fed a high fat diet (HFD, Harlan Teklad 88137, 21% fat, 0.15% cholesterol) starting at 8 weeks of age for 8, 16, and 24 weeks. B6 mice fed HFD for 16 weeks starting at 8 weeks of age were used as controls. Apoe-/- mice were fed a high fat diet (HFD, Harlan Teklad 88137, 21% fat, 0.15% cholesterol) starting at 8 weeks of age for 8, 16, and 24 weeks. B6 mice fed HFD for 16 weeks starting at 8 weeks of age were used as controls. At each time point, 9 mice were studied. Mice were euthanized at each time point and whole aorta (from aortic root to renal bifurcation) of each mouse was immediately collected and flash-frozen in liquid N2. Mice were fasted overnight prior to euthanasia. the aortic arches of three mice in the same study group were pooled, resulting in three pools per study group.
2010-06-22 | E-GEOD-18443 | biostudies-arrayexpress
Project description:Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disorder that is the result of extended exposure of the airways to noxious stimuli, principally cigarette smoke (CS). The mechanisms through which COPD evolves are not fully understood though it is believed that the disease process includes a genetic component since not all smokers develop COPD. To investigate the mechanism leading to the development of COPD/emphysema, we performed an experiment in which whole genome gene expression and several COPD-relevant biological endpoints (MMP-9, MMP activity, TIMP-1 and lung weight) were measured in lung tissue after exposure to two doses of CS for various periods of time. A novel and powerful method, known as reverse engineering and forward simulation (REFS(TM)), was employed to identify key molecular drivers by integrating gene expression data and 4 measured COPD-relevant endpoints. An ensemble of molecular networks was generated using REFS(TM). Simulations showed that this ensemble could successfully recover the measured experimental data for gene expression and measured COPD-relevant endpoints. This ensemble of networks was then further employed to simulate thousands of in silico gene knockdown experiments. Based on the in silico gene knockdown, thirty-three molecular key drivers for the above four COPD-relevant endpoints were identified, with the majority of them being enriched in inflammation, emphysema and COPD.
2014-05-14 | E-MTAB-1426 | biostudies-arrayexpress
Project description: Not available
| S-EPMC2626665 | biostudies-literature