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Article ; Online: Effects of cigarette smoke exposure on a mouse model of multiple sclerosis

Ho, Jenny / Koshibu, Kyoko / Xia, Wenhao / Luettich, Karsta / Kondylis, Athanasios / Garcia, Llenalia / Phillips, Blaine / Peitsch, Manuel / Hoeng, Julia

Toxicology Reports. 2022, v. 9 p.597-610

2022

Abstract: Multiple sclerosis (MS) is an inflammatory autoimmune disease associated with genetic and environmental factors. Cigarette smoking is harmful to health and may be one of the risk factors for MS. However, there have been no systematic investigations under ...

Abstract	Multiple sclerosis (MS) is an inflammatory autoimmune disease associated with genetic and environmental factors. Cigarette smoking is harmful to health and may be one of the risk factors for MS. However, there have been no systematic investigations under controlled experimental conditions linking cigarette smoke (CS) and MS. The present study is the first inhalation study to correlate the pre-clinical and pathological manifestations affected by different doses of CS exposure in a mouse experimental autoimmune encephalomyelitis (EAE) model. Female C57BL/6 mice were whole-body exposed to either fresh air (sham) or three concentrations of CS from a reference cigarette (3R4F) for 2 weeks before and 4 weeks after EAE induction. The effects of exposure on body weight, clinical symptoms, spinal cord pathology, and serum biochemicals were then assessed. Exposure to low and medium concentrations of CS exacerbated the severity of symptoms and spinal cord pathology, while the high concentration had no effect relative to sham exposure in mice with EAE. Interestingly, the clinical chemistry parameters for metabolic profile as well as liver and renal function (e.g. triglycerides and creatinine levels, alkaline phosphatase activity) were lower in these mice than in naïve controls. Although the mouse EAE model does not fully recapitulate the pathology or symptoms of MS in humans, these findings largely corroborate previous epidemiological findings that exposure to CS can worsen the symptoms and pathology of MS. Furthermore, the study newly highlights the possible correlation of clinical chemistry findings such as metabolism and liver and renal function between MS patients and EAE mice.
Keywords	air ; alkaline phosphatase ; autoimmune diseases ; blood serum ; body weight ; cigarettes ; creatinine ; encephalitis ; females ; liver ; metabolism ; mice ; models ; renal function ; risk ; sclerosis ; smoke ; spinal cord ; toxicology ; AAALAC ; BBB ; CFA ; CNS ; CO ; CS ; DAPI ; EAE ; eGFR ; GAM ; IACUC ; ISO ; MOG ; MS ; nAChR ; OCT ; PFA ; PMI ; PTX ; QC ; s.c. ; STAT3 ; TPM ; US ; Multiple sclerosis ; Experimental autoimmune encephalomyelitis ; Cigarette smoke ; Inhalation ; Clinical chemistry
Language	English
Size	p. 597-610.
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2805786-7
ISSN	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2022.03.032
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Effects of cigarette smoke exposure on a mouse model of multiple sclerosis.

Ho, Jenny / Koshibu, Kyoko / Xia, Wenhao / Luettich, Karsta / Kondylis, Athanasios / Garcia, Llenalia / Phillips, Blaine / Peitsch, Manuel / Hoeng, Julia

Toxicology reports

2022 Volume 9, Page(s) 597–610

Abstract	Multiple sclerosis (MS) is an inflammatory autoimmune disease associated with genetic and environmental factors. Cigarette smoking is harmful to health and may be one of the risk factors for MS. However, there have been no systematic investigations under controlled experimental conditions linking cigarette smoke (CS) and MS. The present study is the first inhalation study to correlate the pre-clinical and pathological manifestations affected by different doses of CS exposure in a mouse experimental autoimmune encephalomyelitis (EAE) model. Female C57BL/6 mice were whole-body exposed to either fresh air (sham) or three concentrations of CS from a reference cigarette (3R4F) for 2 weeks before and 4 weeks after EAE induction. The effects of exposure on body weight, clinical symptoms, spinal cord pathology, and serum biochemicals were then assessed. Exposure to low and medium concentrations of CS exacerbated the severity of symptoms and spinal cord pathology, while the high concentration had no effect relative to sham exposure in mice with EAE. Interestingly, the clinical chemistry parameters for metabolic profile as well as liver and renal function (e.g. triglycerides and creatinine levels, alkaline phosphatase activity) were lower in these mice than in naïve controls. Although the mouse EAE model does not fully recapitulate the pathology or symptoms of MS in humans, these findings largely corroborate previous epidemiological findings that exposure to CS can worsen the symptoms and pathology of MS. Furthermore, the study newly highlights the possible correlation of clinical chemistry findings such as metabolism and liver and renal function between MS patients and EAE mice.
Language	English
Publishing date	2022-03-29
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	2805786-7
ISSN	2214-7500 ; 2214-7500
ISSN (online)	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2022.03.032
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Article ; Online: Investigation and comparison of the transfer of TSNA from tobacco to cigarette mainstream smoke and to the aerosol of a heated tobacco product, THS2.2.

Jaccard, Guy / Kondylis, Athanasios / Gunduz, Irfan / Pijnenburg, Johannes / Belushkin, Maxim

Regulatory toxicology and pharmacology : RTP

2018 Volume 97, Page(s) 103–109

Abstract: Tobacco-specific nitrosamines (TSNA) levels in tobacco cut filler and cigarette smoke were measured in more than 1000 commercially available cigarettes sampled between 2008 and 2014. Relative contributions to their transfer from tobacco to the mainstream ...

Abstract	Tobacco-specific nitrosamines (TSNA) levels in tobacco cut filler and cigarette smoke were measured in more than 1000 commercially available cigarettes sampled between 2008 and 2014. Relative contributions to their transfer from tobacco to the mainstream smoke in terms of direct transfer by distillation, pyrorelease, and pyrosynthesis were evaluated on the basis of the comparison with the transfer of nicotine from tobacco to smoke. N'-nitrosonornicotine (NNN) was transferred essentially by distillation, while N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-bipyridyl)-1-butanone (NNK) and N'-nitrosoanabasine (NAB) were transferred by pyrorelease or pyrosynthesis as well. In the case of the Tobacco Heating System 2.2, the transfer of nicotine from tobacco to the aerosol was similar to that observed for cigarettes, while the % transfer of TSNAs from tobacco to THS 2.2 aerosol was 2-3 times lower than in cigarettes. This difference is due to the fact that the tobacco is heated instead of burnt resulting in a lower direct transfer by distillation and a lower if any contribution of pyrosynthesis or pyrorelease.
MeSH term(s)	Aerosols/chemistry ; Aerosols/metabolism ; Hot Temperature ; Nitrosamines/analysis ; Nitrosamines/metabolism ; Smoke/analysis ; Nicotiana/chemistry ; Nicotiana/metabolism ; Tobacco Products/analysis
Chemical Substances	Aerosols ; Nitrosamines ; Smoke
Language	English
Publishing date	2018-06-19
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article
ZDB-ID	604672-1
ISSN	1096-0295 ; 0273-2300
ISSN (online)	1096-0295
ISSN	0273-2300
DOI	10.1016/j.yrtph.2018.06.011
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Article: Nicotine-mediated effects in neuronal and mouse models of synucleinopathy.

Frontiers in neuroscience

2023 Volume 17, Page(s) 1239009

Abstract: Introduction: Alpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson's disease. The plant alkaloid "nicotine" was reported to attenuate α-Syn aggregation in different models, ...

Abstract	Introduction: Alpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson's disease. The plant alkaloid "nicotine" was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear. Methods: In this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice. We also established a novel humanized neuronal model of α-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with α-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action. Results and discussion: Overall, our results showed that nicotine attenuated α-Syn-provoked neuropathology in both models. Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine's neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology
Language	English
Publishing date	2023-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1239009
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Article ; Online: Blood and urine multi-omics analysis of the impact of e-vaping, smoking, and cessation: from exposome to molecular responses.

Poussin, Carine / Titz, Bjoern / Xiang, Yang / Baglia, Laurel / Berg, Rachel / Bornand, David / Choukrallah, Mohammed-Amin / Curran, Timothy / Dijon, Sophie / Dossin, Eric / Dulize, Remi / Etter, Doris / Fatarova, Maria / Medlin, Loyse Felber / Haiduc, Adrian / Kishazi, Edina / Kolli, Aditya R / Kondylis, Athanasios / Kottelat, Emmanuel /

Laszlo, Csaba / Lavrynenko, Oksana / Eb-Levadoux, Yvan / Nury, Catherine / Peric, Dariusz / Rizza, Melissa / Schneider, Thomas / Guedj, Emmanuel / Calvino, Florian / Sierro, Nicolas / Guy, Philippe / Ivanov, Nikolai V / Picavet, Patrick / Spinelli, Sherry / Hoeng, Julia / Peitsch, Manuel C

Scientific reports

2024 Volume 14, Issue 1, Page(s) 4286

Abstract: Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for ... ...

Abstract	Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study.
MeSH term(s)	Humans ; Vaping ; Smoking Cessation ; Cross-Sectional Studies ; Exposome ; Multiomics ; Tobacco Products ; Electronic Nicotine Delivery Systems
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-54474-2
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Article ; Online: Delivery efficiencies of constituents of combustion-derived aerosols across the air-liquid interface during in vitro exposures.

Steiner, Sandro / Diana, Pierrick / Dossin, Eric / Guy, Philippe / Vuillaume, Grégory / Kondylis, Athanasios / Majeed, Shoaib / Frentzel, Stefan / Hoeng, Julia

Toxicology in vitro : an international journal published in association with BIBRA

2018 Volume 52, Page(s) 384–398

Abstract: In vitro aerosol exposure of epithelial cells grown at the air-liquid interface is an experimental methodology widely used in respiratory toxicology. The exposure depends to a large part on the physicochemical properties of individual aerosol ... ...

Abstract	In vitro aerosol exposure of epithelial cells grown at the air-liquid interface is an experimental methodology widely used in respiratory toxicology. The exposure depends to a large part on the physicochemical properties of individual aerosol constituents, as they determine the transfer kinetics from the aerosol into the cells. We characterized the transfer of 70 cigarette smoke constituents from the smoke into aqueous samples exposed in the Vitrocell® 24/48 aerosol exposure system. The amounts of these compounds in the applied smoke were determined by trapping whole smoke in N,N-dimethylformamide and then compared with their amounts in smoke-exposed, phosphate-buffered saline, yielding compound specific delivery efficiencies. Delivery efficiencies of different smoke constituents differed by up to five orders of magnitude, which indicates that the composition of the applied smoke is not necessarily representative for the delivered smoke. Therefore, dose metrics for in vitro exposure experiments should, if possible, be based on delivered and not applied doses. A comparison to literature on in vivo smoke retention in the respiratory tract indicated that the same applies for smoke retention in the respiratory tract.
MeSH term(s)	Aerosols ; Cell Culture Techniques ; Epithelial Cells/drug effects ; Smoke/adverse effects ; Smoke/analysis ; Tobacco Products ; Toxicity Tests/methods
Chemical Substances	Aerosols ; Smoke
Language	English
Publishing date	2018-07-09
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2018.06.024
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Article: Ceramide ratios are affected by cigarette smoke but not heat-not-burn or e-vapor aerosols across four independent mouse studies

Lavrynenko, Oksana / Titz, Bjoern / Dijon, Sophie / Santos, Daniel Dos / Nury, Catherine / Schneider, Thomas / Guedj, Emmanuel / Szostak, Justyna / Kondylis, Athanasios / Phillips, Blaine / Ekroos, Kim / Martin, Florian / Peitsch, Manuel C / Hoeng, Julia / Ivanov, Nikolai V

Life sciences. 2020 Dec. 15, v. 263

2020

Abstract: Smoking is an important risk factor for the development of chronic obstructive pulmonary disease and cardiovascular diseases. This study aimed to further elucidate the role of ceramides, as a key lipid class dysregulated in disease states.In this article ...

Abstract	Smoking is an important risk factor for the development of chronic obstructive pulmonary disease and cardiovascular diseases. This study aimed to further elucidate the role of ceramides, as a key lipid class dysregulated in disease states.In this article we developed and validated LC–MS/MS method for ceramides (Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1(15Z)) for the absolute quantification. We deployed it together with proteomics and transcriptomic analysis to assess the effects of cigarette smoke (CS) from the reference cigarette as well as aerosols from heat-not-burn (HnB) tobacco and e-vapor products in apolipoprotein E-deficient (ApoE⁻/⁻) mice over several time points.In the lungs, CS exposure substantially elevated the ratios of Cer(d18:1/24:0) and Cer(d18:1/24:1) to Cer(d18:1/18:0) in two independent ApoE⁻/⁻ mouse inhalation studies. Data from previous studies, in both ApoE⁻/⁻ and wild-type mice, further confirmed the reproducibility of this finding. Elevation of these ceramide ratios was also observed in plasma/serum, the liver, and—for the Cer(d18:1/24:1(15Z)) to Cer(d18:1/18:0) ratio—the abdominal aorta. Also, the levels of acid ceramidase (Asah1) and glucocerebrosidase (Gba)—lysosomal enzymes involved in the hydrolysis of glucosylceramides—were consistently elevated in the lungs after CS exposure. In contrast, exposure to HnB tobacco product and e-vapor aerosols did not induce significant changes in the ceramide profiles or associated enzymes.Our work in mice contributes to the accumulating evidence on the importance of ceramide ratios as biologically relevant markers for respiratory disorders, adding to their already demonstrated role in cardiovascular disease risk assessment in humans.
Keywords	aorta ; blood serum ; cardiovascular diseases ; ceramides ; cigarettes ; glucosylceramidase ; hydrolysis ; liver ; mice ; proteomics ; respiratory tract diseases ; risk assessment ; risk factors ; smoke ; transcriptomics
Language	English
Dates of publication	2020-1215
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-light
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2020.118753
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Article ; Online: Comparison of the basic morphology and function of 3D lung epithelial cultures derived from several donors.

Bovard, David / Giralt, Albert / Trivedi, Keyur / Neau, Laurent / Kanellos, Petros / Iskandar, Anita / Kondylis, Athanasios / Luettich, Karsta / Frentzel, Stefan / Hoeng, Julia / Peitsch, Manuel C

Current research in toxicology

2020 Volume 1, Page(s) 56–69

Abstract: In vitro models of the human lung play an essential role in evaluating the toxicity of inhaled compounds and understanding the development of respiratory diseases. Three-dimensional (3D) organotypic models derived from lung basal epithelial cells and ... ...

Abstract	In vitro models of the human lung play an essential role in evaluating the toxicity of inhaled compounds and understanding the development of respiratory diseases. Three-dimensional (3D) organotypic models derived from lung basal epithelial cells and grown at the air-liquid interface resemble human airway epithelium in multiple aspects, including morphology, cell composition, transcriptional profile, and xenobiotic metabolism. Whether the different characteristics of basal cell donors have an impact on model characteristics and responses remains unknown. In addition, studies are often conducted with 3D cultures from one donor, assuming a representative response on the population level. Whether this assumption is correct requires further investigation. In this study, we compared the morphology and functionality of 3D organotypic bronchial and small airway cultures from different donors at different weeks after air-lift to assess the interdonor variability in these parameters. The thickness, cell type composition, and transepithelial electrical resistance varied among the donors and over time after air-lift. Cilia beating frequency increased in response to isoproterenol treatment in both culture types, independent of the donor. The cultures presented low basal cytochrome P450 (CYP) 1A1/1B1 activity, but 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment induced CYP1A1/1B1 activity regardless of the donor. In conclusion, lung epithelial cultures prepared from different donors present diverse morphology but similar functionality and metabolic activity, with certain variability in their response to stimulation.
Language	English
Publishing date	2020-09-04
Document type	Journal Article
ISSN	2666-027X
ISSN (online)	2666-027X
DOI	10.1016/j.crtox.2020.08.002
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Article ; Online: Ceramide ratios are affected by cigarette smoke but not heat-not-burn or e-vapor aerosols across four independent mouse studies.

Life sciences

2020 Volume 263, Page(s) 118753

Abstract: Aims: Smoking is an important risk factor for the development of chronic obstructive pulmonary disease and cardiovascular diseases. This study aimed to further elucidate the role of ceramides, as a key lipid class dysregulated in disease states.: Main ...

Abstract	Aims: Smoking is an important risk factor for the development of chronic obstructive pulmonary disease and cardiovascular diseases. This study aimed to further elucidate the role of ceramides, as a key lipid class dysregulated in disease states. Main methods: In this article we developed and validated LC-MS/MS method for ceramides (Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1(15Z)) for the absolute quantification. We deployed it together with proteomics and transcriptomic analysis to assess the effects of cigarette smoke (CS) from the reference cigarette as well as aerosols from heat-not-burn (HnB) tobacco and e-vapor products in apolipoprotein E-deficient (ApoE Key findings: In the lungs, CS exposure substantially elevated the ratios of Cer(d18:1/24:0) and Cer(d18:1/24:1) to Cer(d18:1/18:0) in two independent ApoE Significance: Our work in mice contributes to the accumulating evidence on the importance of ceramide ratios as biologically relevant markers for respiratory disorders, adding to their already demonstrated role in cardiovascular disease risk assessment in humans.
MeSH term(s)	Aerosols/adverse effects ; Animals ; Apolipoproteins E/genetics ; Ceramides/analysis ; Ceramides/metabolism ; Chromatography, Liquid/methods ; E-Cigarette Vapor/adverse effects ; Female ; Humans ; Lung/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Proteomics ; Risk Factors ; Smoke/adverse effects ; Tandem Mass Spectrometry/methods ; Time Factors
Chemical Substances	Aerosols ; Apolipoproteins E ; Ceramides ; E-Cigarette Vapor ; Smoke
Language	English
Publishing date	2020-11-12
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Validation Study
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2020.118753
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Article ; Online: In Vivo

Xia, Wenhao / Kolli, Aditya Reddy / Koshibu, Kyoko / Martin, Florian / Kondylis, Athanasios / Kuczaj, Arkadiusz / Tan, Wei Teck / Yeo, Ying Shan / Tan, Glenda / Teng, Charles / Woon, Kaing / Schneider, Thomas / Talikka, Marja / Phillips, Blaine W / Vanscheeuwijck, Patrick / Peitsch, Manuel C / Hoeng, Julia

Journal of natural products

2021 Volume 84, Issue 4, Page(s) 1012–1021

Abstract: Natural alkaloids, a large class of plant-derived substances, have attracted considerable interest because of their pharmacological activities. In this study, ... ...

Abstract	Natural alkaloids, a large class of plant-derived substances, have attracted considerable interest because of their pharmacological activities. In this study, the
MeSH term(s)	Alkaloids/pharmacokinetics ; Alkaloids/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacokinetics ; Anti-Inflammatory Agents/pharmacology ; Brain/metabolism ; Carrageenan ; Cytokines ; Edema/drug therapy ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Rats ; Rats, Wistar
Chemical Substances	Alkaloids ; Anti-Inflammatory Agents ; Cytokines ; Pyridines ; anatabine (5PP654XB7D) ; Carrageenan (9000-07-1)
Language	English
Publishing date	2021-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.0c01044
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