The Experts below are selected from a list of 1839 Experts worldwide ranked by ideXlab platform

Florian Martin - One of the best experts on this subject based on the ideXlab platform.

  • Systems Toxicology approach for testing chemical cardiotoxicity in larval zebrafish
    Chemical Research in Toxicology, 2020
    Co-Authors: Roman Li, Florian Martin, Vincenzo Belcastro, Marja Talikka, Justyna Szostak, Anze Zupanic, Sumit Madan, Jens Dorpinghaus, Colette Vom Berg, Manuel C Peitsch
    Abstract:

    Transcriptomic approaches can give insight into molecular mechanisms underlying chemical toxicity and are increasingly being used as part of toxicological assessments. To aid the interpretation of transcriptomic data we have developed a Systems Toxicology method that relies on a computable biological network model. We created the first network model describing cardiotoxicity in zebrafish larvae - a valuable emerging model species in testing cardiotoxicity associated with drugs and chemicals. The network is based on scientific literature and represents hierarchical molecular pathways that lead from receptor activation to cardiac pathologies. To test the ability of our approach to detect cardiotoxic outcomes from transcriptomic data, we have selected three publicly available datasets that reported chemically induced heart pathologies in zebrafish larvae for five different chemicals. Network based analysis detected cardiac perturbations for four out of five chemicals tested, for two of them using transcriptomic data collected up to three days before the onset of a visible phenotype. Additionally, we identified distinct molecular pathways that were activated by the different chemicals. The results demonstrate that the proposed integrational method can be used for evaluating the effects of chemicals on the zebrafish cardiac function and, together with observed cardiac apical endpoints, can provide a comprehensive method for connecting molecular events to organ toxicity. The computable network model is freely available and may be used to generate mechanistic hypotheses and quantifiable perturbation values from any zebrafish transcriptomic data.

  • Systems Toxicology meta-analysis—From aerosol exposure to nanoToxicology
    Current Opinion in Toxicology, 2019
    Co-Authors: Marja Talikka, Florian Martin, Manuel C Peitsch, Vincenzo Belcastro, Sylvain Gubian, Julia Hoeng
    Abstract:

    Abstract Systems Toxicology marks an important stage in the evolution of Toxicology. It combines the insights from traditional Toxicology end points, high-throughput data, and quantitative analysis of large cause-and-effect molecular network models that provide the most mechanistic information in the interpretation of high-throughput data. Here, we show an example on how pulmonary causal biological network models can be used in a meta-analysis of independent studies on engineered nanomaterials to gain mechanistic insight into the similarities and differences of the ways the engineered nanomaterials impact biological processes in the mouse lung. Meta-analyses using the lung network models could be used in various toxicological applications to find underlying trends in response to exposures, derive compound-specific mechanistic signatures, and translate between species.

  • a lower impact of an acute exposure to electronic cigarette aerosols than to cigarette smoke in human organotypic buccal and small airway cultures was demonstrated using Systems Toxicology assessment
    Internal and Emergency Medicine, 2019
    Co-Authors: Anita R Iskandar, Florian Martin, Yang Xiang, Shoaib Majeed, Patrice Leroy, Filippo Zanetti, Laura Ortega Torres, Athanasios Kondylis, Sandro Steiner, Keyur Trivedi
    Abstract:

    In the context of tobacco harm-reduction strategy, the potential reduced impact of electronic cigarette (EC) exposure should be evaluated relative to the impact of cigarette smoke exposure. We conducted a series of in vitro studies to compare the biological impact of an acute exposure to aerosols of “test mix” (flavors, nicotine, and humectants), “base” (nicotine and humectants), and “carrier” (humectants) formulations using MarkTen® EC devices with the impact of exposure to smoke of 3R4F reference cigarettes, at a matching puff number, using human organotypic air–liquid interface buccal and small airway cultures. We measured the concentrations of nicotine and carbonyls deposited in the exposure chamber after each exposure experiment. The deposited carbonyl concentrations were used as representative measures to assess the reduced exposure to potentially toxic volatile substances. We followed a Systems Toxicology approach whereby functional biological endpoints, such as histopathology and ciliary beating frequency, were complemented by multiplex and omics assays to measure secreted inflammatory proteins and whole-genome transcriptomes, respectively. Among the endpoints analyzed, the only parameters that showed a significant response to EC exposure were secretion of proteins and whole-genome transcriptomes. Based on the multiplex and omics analyzes, the cellular responses to EC aerosol exposure were tissue type-specific; however, those alterations were much smaller than those following cigarette smoke exposure, even when the EC aerosol exposure under the testing conditions resulted in a deposited nicotine concentration approximately 200 times that in saliva of EC users. Electronic supplementary material The online version of this article (10.1007/s11739-019-02055-x) contains supplementary material, which is available to authorized users.

  • A six-month Systems Toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products, CHTP 1.2 and THS 2.2, compared with conventional cigarettes.
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • a six month Systems Toxicology inhalation cessation study in apoe mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products chtp 1 2 and ths 2 2 compared with conventional cigarettes
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

Patrice Leroy - One of the best experts on this subject based on the ideXlab platform.

  • application of a multi layer Systems Toxicology framework for in vitro assessment of the biological effects of classic tobacco e liquid and its corresponding aerosol using an e cigarette device with mesh technology
    Archives of Toxicology, 2019
    Co-Authors: Anita Iskandar, Vincenzo Belcastro, Diego Marescotti, Alain Sewer, Patrice Leroy, Filippo Zanetti, Laura Ortega Torres, Bjorn Titz, Athanasios Kondylis, Stefano Acali
    Abstract:

    We previously proposed a Systems Toxicology framework for in vitro assessment of e-liquids. The framework starts with the first layer aimed at screening the potential toxicity of e-liquids, followed by the second layer aimed at investigating the toxicity-related mechanism of e-liquids, and finally, the third layer aimed at evaluating the toxicity-related mechanism of the corresponding aerosols. In this work, we applied this framework to assess the impact of the e-liquid MESH Classic Tobacco and its aerosol compared with that of cigarette smoke (CS) from the 3R4F reference cigarette. In the first layer, we evaluated the cytotoxicity profile of the MESH Classic Tobacco e-liquid (containing humectants, nicotine, and flavors) and its Base e-liquid (containing humectant and nicotine only) in comparison with total particulate matter (TPM) of 3R4F CS using primary bronchial epithelial cell cultures. In the second layer, the same culture model was used to explore changes in specific markers using high-content screening assays to identify potential toxicity-related mechanisms induced by the MESH Classic Tobacco and Base e-liquids beyond cell viability in comparison with the 3R4F CS TPM-induced effects. Finally, in the third layer, we compared the impact of exposure to the MESH Classic Tobacco or Base aerosols with 3R4F CS using human organotypic air–liquid interface buccal and small airway epithelial cultures. The results showed that the cytotoxicity of the MESH Classic Tobacco liquid was similar to the Base liquid but lower than 3R4F CS TPM at comparable nicotine concentrations. Relative to 3R4F CS exposure, MESH Classic Tobacco aerosol exposure did not cause tissue damage and elicited lower changes in the mRNA, microRNA, and protein markers. In the context of tobacco harm reduction strategy, the framework is suitable to assess the potential-reduced impact of electronic cigarette aerosol relative to CS.

  • a lower impact of an acute exposure to electronic cigarette aerosols than to cigarette smoke in human organotypic buccal and small airway cultures was demonstrated using Systems Toxicology assessment
    Internal and Emergency Medicine, 2019
    Co-Authors: Anita R Iskandar, Florian Martin, Yang Xiang, Shoaib Majeed, Patrice Leroy, Filippo Zanetti, Laura Ortega Torres, Athanasios Kondylis, Sandro Steiner, Keyur Trivedi
    Abstract:

    In the context of tobacco harm-reduction strategy, the potential reduced impact of electronic cigarette (EC) exposure should be evaluated relative to the impact of cigarette smoke exposure. We conducted a series of in vitro studies to compare the biological impact of an acute exposure to aerosols of “test mix” (flavors, nicotine, and humectants), “base” (nicotine and humectants), and “carrier” (humectants) formulations using MarkTen® EC devices with the impact of exposure to smoke of 3R4F reference cigarettes, at a matching puff number, using human organotypic air–liquid interface buccal and small airway cultures. We measured the concentrations of nicotine and carbonyls deposited in the exposure chamber after each exposure experiment. The deposited carbonyl concentrations were used as representative measures to assess the reduced exposure to potentially toxic volatile substances. We followed a Systems Toxicology approach whereby functional biological endpoints, such as histopathology and ciliary beating frequency, were complemented by multiplex and omics assays to measure secreted inflammatory proteins and whole-genome transcriptomes, respectively. Among the endpoints analyzed, the only parameters that showed a significant response to EC exposure were secretion of proteins and whole-genome transcriptomes. Based on the multiplex and omics analyzes, the cellular responses to EC aerosol exposure were tissue type-specific; however, those alterations were much smaller than those following cigarette smoke exposure, even when the EC aerosol exposure under the testing conditions resulted in a deposited nicotine concentration approximately 200 times that in saliva of EC users. Electronic supplementary material The online version of this article (10.1007/s11739-019-02055-x) contains supplementary material, which is available to authorized users.

  • A six-month Systems Toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products, CHTP 1.2 and THS 2.2, compared with conventional cigarettes.
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • a six month Systems Toxicology inhalation cessation study in apoe mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products chtp 1 2 and ths 2 2 compared with conventional cigarettes
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • comparative biological impacts of an aerosol from carbon heated tobacco and smoke from cigarettes on human respiratory epithelial cultures a Systems Toxicology assessment
    Food and Chemical Toxicology, 2018
    Co-Authors: Anita R Iskandar, Florian Martin, Thomas Schneider, Walter K Schlage, Patrice Leroy, Carole Mathis, Bjorn Titz, Athanasios Kondylis, Gregory Vuillaume, Alain Sewer
    Abstract:

    Abstract The biological impact of an aerosol of a potential modified-risk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a Systems Toxicology approach. The potentially reduced effects of CHTP1.2 aerosol exposure were benchmarked against those of 3R4F cigarette smoke at similar nicotine concentrations. Experimental repetitions were conducted for which new batches of small airway and nasal cultures were exposed to CHTP1.2 aerosol or 3R4F smoke for 28 minutes. The biological impacts were determined based on a collection of endpoints including morphology, cytotoxicity, proinflammatory mediator profiles, cytochrome P450 1A1/1B1 activity, global mRNA and microRNA changes and proteome profiles. Alterations in mRNA expression were detected in cultures exposed to CHTP1.2 aerosol, without noticeable morphological changes and cytotoxicity, and minimal impact on proinflammatory mediator and proteome profiles. The changes linked to CHTP1.2 aerosol exposure, when observed, were transient. However, the impact of 3R4F smoke exposure persisted long post-exposure and greater than CHTP1.2 aerosol. Morphological changes were observed only in cultures exposed to 3R4F smoke. The lower biological effects of CHTP1.2 aerosol than 3R4F smoke exposure were observed similarly in both small airway and nasal epithelial cultures.

Walter K Schlage - One of the best experts on this subject based on the ideXlab platform.

  • A six-month Systems Toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products, CHTP 1.2 and THS 2.2, compared with conventional cigarettes.
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • a six month Systems Toxicology inhalation cessation study in apoe mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products chtp 1 2 and ths 2 2 compared with conventional cigarettes
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • a 90 day oecd tg 413 rat inhalation study with Systems Toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1 2 chtp1 2 compared with cigarette smoke ii Systems Toxicology assessment
    Food and Chemical Toxicology, 2018
    Co-Authors: Bjoern Titz, Florian Martin, Sophie Dijon, Walter K Schlage, Ulrike Kogel, Yang Xiang, Catherine Nury, Karine Baumer, Dariusz Peric, David Bornand
    Abstract:

    Abstract Modified risk tobacco products (MRTPs) have the potential to reduce smoking-related health risks. The Carbon Heated Tobacco Product 1.2 (CHTP1.2) is a potential MRTP that uses a pressed carbon heat source to generate an aerosol by heating tobacco. Here, we report the results from the Systems Toxicology arm of a 90-day rat inhalation study (OECD test guideline 413) to assess the effects of CHTP1.2 aerosol compared with cigarette smoke (CS). Transcriptomics, proteomics, and lipidomics analyses complemented the standard endpoints. In the respiratory nasal epithelium, CS induced an adaptive tissue and inflammatory response, which was much weaker after CHTP1.2 aerosol exposure, mostly limited to the highest CHTP1.2 concentration (at twice the 3R4F CS concentration: 50 vs. 23 μg nicotine/L), in female rats. In the lungs, the effects of CS exposure included inflammatory and cellular stress responses, which were absent or much lower after CHTP1.2 aerosol exposure. Outside of the respiratory tract, CS and CHTP1.2 aerosol induced effects that were previously associated with exposure to any nicotine-containing aerosol, e.g., lower lipid concentrations in serum. Overall, this Systems Toxicology analysis complements and confirms the results from classical toxicological endpoints and further suggests potentially reduced respiratory health risks of CHTP1.2.

  • comparative biological impacts of an aerosol from carbon heated tobacco and smoke from cigarettes on human respiratory epithelial cultures a Systems Toxicology assessment
    Food and Chemical Toxicology, 2018
    Co-Authors: Anita R Iskandar, Florian Martin, Thomas Schneider, Walter K Schlage, Patrice Leroy, Carole Mathis, Bjorn Titz, Athanasios Kondylis, Gregory Vuillaume, Alain Sewer
    Abstract:

    Abstract The biological impact of an aerosol of a potential modified-risk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a Systems Toxicology approach. The potentially reduced effects of CHTP1.2 aerosol exposure were benchmarked against those of 3R4F cigarette smoke at similar nicotine concentrations. Experimental repetitions were conducted for which new batches of small airway and nasal cultures were exposed to CHTP1.2 aerosol or 3R4F smoke for 28 minutes. The biological impacts were determined based on a collection of endpoints including morphology, cytotoxicity, proinflammatory mediator profiles, cytochrome P450 1A1/1B1 activity, global mRNA and microRNA changes and proteome profiles. Alterations in mRNA expression were detected in cultures exposed to CHTP1.2 aerosol, without noticeable morphological changes and cytotoxicity, and minimal impact on proinflammatory mediator and proteome profiles. The changes linked to CHTP1.2 aerosol exposure, when observed, were transient. However, the impact of 3R4F smoke exposure persisted long post-exposure and greater than CHTP1.2 aerosol. Morphological changes were observed only in cultures exposed to 3R4F smoke. The lower biological effects of CHTP1.2 aerosol than 3R4F smoke exposure were observed similarly in both small airway and nasal epithelial cultures.

  • a 90 day oecd tg 413 rat inhalation study with Systems Toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1 2 chtp1 2 compared with cigarette smoke i inhalation exposure clinical p
    Food and Chemical Toxicology, 2018
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Ulrike Kogel, Patrice Leroy, Gregory Vuillaume, Davide Sciuscio, Subash Krishnan, Emilija Veljkovic
    Abstract:

    Abstract Within the framework of a Systems Toxicology approach, the inhalation toxicity of aerosol from a novel tobacco-heating potentially modified risk tobacco product (MRTP), the carbon-heated tobacco product (CHTP) 1.2, was characterized and compared with that of mainstream smoke (CS) from the 3R4F reference cigarette in a 90-day nose-only rat inhalation study in general accordance with OECD TG 413. CHTP1.2 is a heat-not-burn product using a carbon heat source to produce an aerosol that contains nicotine and tobacco flavor. At equal or twice the nicotine concentration in the test atmospheres, inhalation of CHTP1.2 aerosol led to a significantly lower exposure to harmful constituents and induced less respiratory tract irritation, systemic, and pathological effects compared with CS. Nasal epithelial changes were less pronounced in the CHTP1.2- than in the CS-exposed groups and reverted in the nicotine concentration-matched group after a recovery period. Lung inflammation was minimal in the CHTP1.2-treated groups compared with the moderate extent seen in the 3R4F groups. Many other toxicological endpoints evaluated did not show CHTP1.2 aerosol exposure-related effects, and no effects not seen for 3R4F were observed. These observations were consistent with findings from previous studies in which rats were exposed to MRTP aerosols containing similar nicotine concentrations.

Bjoern Titz - One of the best experts on this subject based on the ideXlab platform.

  • multi omics Systems Toxicology study of mouse lung assessing the effects of aerosols from two heat not burn tobacco products and cigarette smoke
    Computational and structural biotechnology journal, 2020
    Co-Authors: Bjoern Titz, Ashraf Elamin, Thomas Schneider, Sophie Dijon, Alain Sewer, Catherine Nury, Justyna Szostak, Blaine Phillips, Oksana Lavrynenko, Emmanuel Guedj
    Abstract:

    Abstract Cigarette smoke (CS) causes adverse health effects and, for smoker who do not quit, modified risk tobacco products (MRTPs) can be an alternative to reduce the risk of developing smoking-related diseases. Standard toxicological endpoints can lack sensitivity, with Systems Toxicology approaches yielding broader insights into toxicological mechanisms. In a 6-month Systems Toxicology study on ApoE−/− mice, we conducted an integrative multi-omics analysis to assess the effects of aerosols from the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2—a potential and a candidate MRTP based on the heat-not-burn (HnB) principle—compared with CS at matched nicotine concentrations. Molecular exposure effects in the lungs were measured by mRNA/microRNA transcriptomics, proteomics, metabolomics, and lipidomics. Integrative data analysis included Multi-Omics Factor Analysis and multi-modality functional network interpretation. Across all five data modalities, CS exposure was associated with an increased inflammatory and oxidative stress response, and lipid/surfactant alterations. Upon HnB aerosol exposure these effects were much more limited or absent, with reversal of CS-induced effects upon cessation and switching to CHTP 1.2. Functional network analysis revealed CS-induced complex immunoregulatory interactions across the investigated molecular layers (e.g., itaconate, quinolinate, and miR-146) and highlighted the engagement of the heme–Hmox–bilirubin oxidative stress axis by CS. This work exemplifies how multi-omics approaches can be leveraged within Systems Toxicology studies and the generated multi-omics data set can facilitate the development of analysis methods and can yield further insights into the effects of toxicological exposures on the lung of mice.

  • A six-month Systems Toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products, CHTP 1.2 and THS 2.2, compared with conventional cigarettes.
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • a six month Systems Toxicology inhalation cessation study in apoe mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products chtp 1 2 and ths 2 2 compared with conventional cigarettes
    Food and Chemical Toxicology, 2019
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Patrice Leroy, Emmanuel Guedj, Justyna Szostak, Gregory Vuillaume, Ansgar Buettner, Ashraf Elamin
    Abstract:

    Abstract Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A Systems Toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.

  • a 90 day oecd tg 413 rat inhalation study with Systems Toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1 2 chtp1 2 compared with cigarette smoke ii Systems Toxicology assessment
    Food and Chemical Toxicology, 2018
    Co-Authors: Bjoern Titz, Florian Martin, Sophie Dijon, Walter K Schlage, Ulrike Kogel, Yang Xiang, Catherine Nury, Karine Baumer, Dariusz Peric, David Bornand
    Abstract:

    Abstract Modified risk tobacco products (MRTPs) have the potential to reduce smoking-related health risks. The Carbon Heated Tobacco Product 1.2 (CHTP1.2) is a potential MRTP that uses a pressed carbon heat source to generate an aerosol by heating tobacco. Here, we report the results from the Systems Toxicology arm of a 90-day rat inhalation study (OECD test guideline 413) to assess the effects of CHTP1.2 aerosol compared with cigarette smoke (CS). Transcriptomics, proteomics, and lipidomics analyses complemented the standard endpoints. In the respiratory nasal epithelium, CS induced an adaptive tissue and inflammatory response, which was much weaker after CHTP1.2 aerosol exposure, mostly limited to the highest CHTP1.2 concentration (at twice the 3R4F CS concentration: 50 vs. 23 μg nicotine/L), in female rats. In the lungs, the effects of CS exposure included inflammatory and cellular stress responses, which were absent or much lower after CHTP1.2 aerosol exposure. Outside of the respiratory tract, CS and CHTP1.2 aerosol induced effects that were previously associated with exposure to any nicotine-containing aerosol, e.g., lower lipid concentrations in serum. Overall, this Systems Toxicology analysis complements and confirms the results from classical toxicological endpoints and further suggests potentially reduced respiratory health risks of CHTP1.2.

  • a 90 day oecd tg 413 rat inhalation study with Systems Toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1 2 chtp1 2 compared with cigarette smoke i inhalation exposure clinical p
    Food and Chemical Toxicology, 2018
    Co-Authors: Blaine Phillips, Bjoern Titz, Florian Martin, Walter K Schlage, Ulrike Kogel, Patrice Leroy, Gregory Vuillaume, Davide Sciuscio, Subash Krishnan, Emilija Veljkovic
    Abstract:

    Abstract Within the framework of a Systems Toxicology approach, the inhalation toxicity of aerosol from a novel tobacco-heating potentially modified risk tobacco product (MRTP), the carbon-heated tobacco product (CHTP) 1.2, was characterized and compared with that of mainstream smoke (CS) from the 3R4F reference cigarette in a 90-day nose-only rat inhalation study in general accordance with OECD TG 413. CHTP1.2 is a heat-not-burn product using a carbon heat source to produce an aerosol that contains nicotine and tobacco flavor. At equal or twice the nicotine concentration in the test atmospheres, inhalation of CHTP1.2 aerosol led to a significantly lower exposure to harmful constituents and induced less respiratory tract irritation, systemic, and pathological effects compared with CS. Nasal epithelial changes were less pronounced in the CHTP1.2- than in the CS-exposed groups and reverted in the nicotine concentration-matched group after a recovery period. Lung inflammation was minimal in the CHTP1.2-treated groups compared with the moderate extent seen in the 3R4F groups. Many other toxicological endpoints evaluated did not show CHTP1.2 aerosol exposure-related effects, and no effects not seen for 3R4F were observed. These observations were consistent with findings from previous studies in which rats were exposed to MRTP aerosols containing similar nicotine concentrations.

Alain Sewer - One of the best experts on this subject based on the ideXlab platform.

  • multi omics Systems Toxicology study of mouse lung assessing the effects of aerosols from two heat not burn tobacco products and cigarette smoke
    Computational and structural biotechnology journal, 2020
    Co-Authors: Bjoern Titz, Ashraf Elamin, Thomas Schneider, Sophie Dijon, Alain Sewer, Catherine Nury, Justyna Szostak, Blaine Phillips, Oksana Lavrynenko, Emmanuel Guedj
    Abstract:

    Abstract Cigarette smoke (CS) causes adverse health effects and, for smoker who do not quit, modified risk tobacco products (MRTPs) can be an alternative to reduce the risk of developing smoking-related diseases. Standard toxicological endpoints can lack sensitivity, with Systems Toxicology approaches yielding broader insights into toxicological mechanisms. In a 6-month Systems Toxicology study on ApoE−/− mice, we conducted an integrative multi-omics analysis to assess the effects of aerosols from the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2—a potential and a candidate MRTP based on the heat-not-burn (HnB) principle—compared with CS at matched nicotine concentrations. Molecular exposure effects in the lungs were measured by mRNA/microRNA transcriptomics, proteomics, metabolomics, and lipidomics. Integrative data analysis included Multi-Omics Factor Analysis and multi-modality functional network interpretation. Across all five data modalities, CS exposure was associated with an increased inflammatory and oxidative stress response, and lipid/surfactant alterations. Upon HnB aerosol exposure these effects were much more limited or absent, with reversal of CS-induced effects upon cessation and switching to CHTP 1.2. Functional network analysis revealed CS-induced complex immunoregulatory interactions across the investigated molecular layers (e.g., itaconate, quinolinate, and miR-146) and highlighted the engagement of the heme–Hmox–bilirubin oxidative stress axis by CS. This work exemplifies how multi-omics approaches can be leveraged within Systems Toxicology studies and the generated multi-omics data set can facilitate the development of analysis methods and can yield further insights into the effects of toxicological exposures on the lung of mice.

  • application of a multi layer Systems Toxicology framework for in vitro assessment of the biological effects of classic tobacco e liquid and its corresponding aerosol using an e cigarette device with mesh technology
    Archives of Toxicology, 2019
    Co-Authors: Anita Iskandar, Vincenzo Belcastro, Diego Marescotti, Alain Sewer, Patrice Leroy, Filippo Zanetti, Laura Ortega Torres, Bjorn Titz, Athanasios Kondylis, Stefano Acali
    Abstract:

    We previously proposed a Systems Toxicology framework for in vitro assessment of e-liquids. The framework starts with the first layer aimed at screening the potential toxicity of e-liquids, followed by the second layer aimed at investigating the toxicity-related mechanism of e-liquids, and finally, the third layer aimed at evaluating the toxicity-related mechanism of the corresponding aerosols. In this work, we applied this framework to assess the impact of the e-liquid MESH Classic Tobacco and its aerosol compared with that of cigarette smoke (CS) from the 3R4F reference cigarette. In the first layer, we evaluated the cytotoxicity profile of the MESH Classic Tobacco e-liquid (containing humectants, nicotine, and flavors) and its Base e-liquid (containing humectant and nicotine only) in comparison with total particulate matter (TPM) of 3R4F CS using primary bronchial epithelial cell cultures. In the second layer, the same culture model was used to explore changes in specific markers using high-content screening assays to identify potential toxicity-related mechanisms induced by the MESH Classic Tobacco and Base e-liquids beyond cell viability in comparison with the 3R4F CS TPM-induced effects. Finally, in the third layer, we compared the impact of exposure to the MESH Classic Tobacco or Base aerosols with 3R4F CS using human organotypic air–liquid interface buccal and small airway epithelial cultures. The results showed that the cytotoxicity of the MESH Classic Tobacco liquid was similar to the Base liquid but lower than 3R4F CS TPM at comparable nicotine concentrations. Relative to 3R4F CS exposure, MESH Classic Tobacco aerosol exposure did not cause tissue damage and elicited lower changes in the mRNA, microRNA, and protein markers. In the context of tobacco harm reduction strategy, the framework is suitable to assess the potential-reduced impact of electronic cigarette aerosol relative to CS.

  • comparative biological impacts of an aerosol from carbon heated tobacco and smoke from cigarettes on human respiratory epithelial cultures a Systems Toxicology assessment
    Food and Chemical Toxicology, 2018
    Co-Authors: Anita R Iskandar, Florian Martin, Thomas Schneider, Walter K Schlage, Patrice Leroy, Carole Mathis, Bjorn Titz, Athanasios Kondylis, Gregory Vuillaume, Alain Sewer
    Abstract:

    Abstract The biological impact of an aerosol of a potential modified-risk tobacco product, carbon heated tobacco product 1.2 (CHTP1.2), was comprehensively assessed for the first time in vitro using human small airway and nasal epithelial models following a Systems Toxicology approach. The potentially reduced effects of CHTP1.2 aerosol exposure were benchmarked against those of 3R4F cigarette smoke at similar nicotine concentrations. Experimental repetitions were conducted for which new batches of small airway and nasal cultures were exposed to CHTP1.2 aerosol or 3R4F smoke for 28 minutes. The biological impacts were determined based on a collection of endpoints including morphology, cytotoxicity, proinflammatory mediator profiles, cytochrome P450 1A1/1B1 activity, global mRNA and microRNA changes and proteome profiles. Alterations in mRNA expression were detected in cultures exposed to CHTP1.2 aerosol, without noticeable morphological changes and cytotoxicity, and minimal impact on proinflammatory mediator and proteome profiles. The changes linked to CHTP1.2 aerosol exposure, when observed, were transient. However, the impact of 3R4F smoke exposure persisted long post-exposure and greater than CHTP1.2 aerosol. Morphological changes were observed only in cultures exposed to 3R4F smoke. The lower biological effects of CHTP1.2 aerosol than 3R4F smoke exposure were observed similarly in both small airway and nasal epithelial cultures.

  • comparative effects of a candidate modified risk tobacco product aerosol and cigarette smoke on human organotypic small airway cultures a Systems Toxicology approach
    Toxicology Research, 2017
    Co-Authors: Anita R Iskandar, Florian Martin, Alain Sewer, Walter K Schlage, Shoaib Majeed, Patrice Leroy, Yannick Martinez, Laura Ortega Torres, Celine Merg, Keyur Trivedi
    Abstract:

    Using an in vitro human small airway epithelium model, we assessed the biological impact of an aerosol from a candidate modified-risk tobacco product, the tobacco heating system (THS) 2.2, to investigate the potential reduced risk of THS2.2 aerosol exposure compared with cigarette smoke. Following the recommendations of the Institute of Medicine and the Tobacco Product Assessment Consortium, in which modified-risk tobacco products assessment should be performed in comparison with standard conventional products, the effects of the THS2.2 aerosol exposure on the small airway cultures were compared with those of 3R4F cigarette smoke. We used a Systems Toxicology approach whereby elucidation of toxic effects is derived not only from functional assay readouts but also from omics technologies. Cytotoxicity, ciliary beating function, secretion of pro-inflammatory mediators and histological assessment represented functional assays. The omics data included transcriptomic and miRNA profiles. Exposure-induced perturbations of causal biological networks were computed from the transcriptomic data. The results showed that THS2.2 aerosol exposure at the tested doses elicited lower cytotoxicity levels and lower changes in the secreted pro-inflammatory mediators than 3R4F smoke. Although THS2.2 exposure elicited alterations in the gene expression, a higher transcriptome-induced biological impact was observed following 3R4F smoke: The effects of THS2.2 aerosol exposure, if observed, were mostly transient and diminished more rapidly after exposure than those of 3R4F smoke. The study demonstrated that the Systems Toxicology approach can reveal changes at the cellular level that would be otherwise not detected from functional assays, thus increasing the sensitivity to detect potential toxicity of a treatment/exposure.

  • Systems Toxicology meta analysis of in vitro assessment studies biological impact of a candidate modified risk tobacco product aerosol compared with cigarette smoke on human organotypic cultures of the aerodigestive tract
    Toxicology Research, 2017
    Co-Authors: Anita Iskandar, Bjoern Titz, Ashraf Elamin, Thomas Schneider, Alain Sewer, Patrice Leroy, Carole Mathis, Filippo Zanetti, Stefan Frentzel, Walter K Schlage
    Abstract:

    Systems biology combines comprehensive molecular analyses with quantitative modeling to understand the characteristics of a biological system as a whole. Leveraging a similar approach, Systems Toxicology aims to decipher complex biological responses following exposures. This work reports a Systems Toxicology meta-analysis in the context of in vitro assessment of a candidate modified-risk tobacco product (MRTP) using three human organotypic cultures of the aerodigestive tract (buccal, bronchial, and nasal epithelia). Complementing a series of functional measures, a causal network enrichment analysis of transcriptomic data was used to compare quantitatively the biological impact of aerosol from the Tobacco Heating System (THS) 2.2, a candidate MRTP, with 3R4F cigarette smoke (CS) at similar nicotine concentrations. Lower toxicity was observed in all cultures following exposure to THS2.2 aerosol compared with 3R4F CS. Because of their morphological differences, a smaller exposure impact was observed in the buccal (stratified epithelium) compared with the bronchial and nasal (pseudostratified epithelium). However, the causal network enrichment approach supported a similar mechanistic impact of CS across the three cultures, including the impact on xenobiotic, oxidative stress, and inflammatory responses. At comparable nicotine concentrations, THS2.2 aerosol elicited reduced and more transient effects on these processes. To demonstrate the benefits of additional data modalities, we employed a newly established targeted mass-spectrometry marker panel to further confirm the reduced cellular stress responses elicited by THS2.2 aerosol compared with 3R4F CS in the nasal culture. Overall, this work demonstrates the applicability and robustness of the Systems Toxicology approach for in vitro inhalation toxicity assessment.