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  1. Article ; Online: Effects of the nerve agent VX on hiPSC-derived motor neurons.

    Schaefers, Catherine / Schmeißer, Wolfgang / John, Harald / Worek, Franz / Rein, Theo / Rothmiller, Simone / Schmidt, Annette

    Archives of toxicology

    2024  

    Abstract: Poisoning with the organophosphorus nerve agent VX can be life-threatening due to limitations of the standard therapy with atropine and oximes. To date, the underlying pathomechanism of VX affecting the neuromuscular junction has not been fully ... ...

    Abstract Poisoning with the organophosphorus nerve agent VX can be life-threatening due to limitations of the standard therapy with atropine and oximes. To date, the underlying pathomechanism of VX affecting the neuromuscular junction has not been fully elucidated structurally. Results of recent studies investigating the effects of VX were obtained from cells of animal origin or immortalized cell lines limiting their translation to humans. To overcome this limitation, motor neurons (MN) of this study were differentiated from in-house feeder- and integration-free-derived human-induced pluripotent stem cells (hiPSC) by application of standardized and antibiotic-free differentiation media with the aim to mimic human embryogenesis as closely as possible. For testing VX sensitivity, MN were initially exposed once to 400 µM, 600 µM, 800 µM, or 1000 µM VX and cultured for 5 days followed by analysis of changes in viability and neurite outgrowth as well as at the gene and protein level using µLC-ESI MS/HR MS, XTT, IncuCyte, qRT-PCR, and Western Blot. For the first time, VX was shown to trigger neuronal cell death and decline in neurite outgrowth in hiPSC-derived MN in a time- and concentration-dependent manner involving the activation of the intrinsic as well as the extrinsic pathway of apoptosis. Consistent with this, MN morphology and neurite network were altered time and concentration-dependently. Thus, MN represent a valuable tool for further investigation of the pathomechanism after VX exposure. These findings might set the course for the development of a promising human neuromuscular test model and patient-specific therapies in the future.
    Language English
    Publishing date 2024-03-30
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-024-03708-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Phosphonylated tyrosine and lysine residues as biomarkers of local exposure of human hair to the organophosphorus nerve agents sarin and VX.

    John, Harald / Lindl, Tamara / Reuter, Henrik / Schmeißer, Wolfgang / Schrader, Michael / Thiermann, Horst

    Drug testing and analysis

    2023  Volume 15, Issue 7, Page(s) 730–744

    Abstract: We herein present for the first time a micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (μLC-ESI MS/HR MS) procedure to detect phosphonylated tyrosine (Tyr) and lysine (Lys) residues obtained from human hair ... ...

    Abstract We herein present for the first time a micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (μLC-ESI MS/HR MS) procedure to detect phosphonylated tyrosine (Tyr) and lysine (Lys) residues obtained from human hair exposed to organophosphorus nerve agents (OPNA). In general, toxic OPNA react with endogenous blood proteins causing the formation of adducts representing well-known targets for biomedical analysis to prove exposure. In contrast, no protein-derived biomarker has been introduced so far to document local exposure of hair. Accordingly, we developed and characterized a μLC-ESI MS/HR MS method for the analysis of scalp hair exposed to OPNA in vitro. Type I and Type II keratin from hair was dissolved during lysis, precipitated and subjected to pronase-catalyzed hydrolysis yielding single adducted Lys and in a much higher amount Tyr residues. Exposure to sarin caused the adduction of an isopropyl methylphosphonic acid moiety and exposure to VX yielded adducts of ethyl methylphosphonic acid, well suited as biomarkers of exposure. These were of appropriate stability in the autosampler for 24 h. The biomarker yield obtained from hair of six individuals as well as from hair of six different parts of the body of one individual (armpit, beard, leg, arm, scalp, and pubic) differed reasonably indicating the variable individual protein composition and structure of hair. Exposed hair stored at ambient temperature for 9 weeks with contact to air and daylight showed stability of all adducts and therefore their suitability for verification of exposure.
    MeSH term(s) Humans ; Nerve Agents/metabolism ; Sarin ; Lysine ; Organophosphorus Compounds ; Tyrosine/chemistry ; Spectrometry, Mass, Electrospray Ionization/methods ; Biomarkers ; Hair/chemistry ; Chemical Warfare Agents/analysis
    Chemical Substances Nerve Agents ; Sarin (B4XG72QGFM) ; VX (9A4381183B) ; Lysine (K3Z4F929H6) ; Organophosphorus Compounds ; Tyrosine (42HK56048U) ; Biomarkers ; Chemical Warfare Agents
    Language English
    Publishing date 2023-02-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2462336-2
    ISSN 1942-7611 ; 1942-7603
    ISSN (online) 1942-7611
    ISSN 1942-7603
    DOI 10.1002/dta.3459
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Highly stable peptide adducts from hard keratins as biomarkers to verify local sulfur mustard exposure of hair by high-resolution mass spectrometry.

    Schmeißer, Wolfgang / Siegert, Markus / Thiermann, Horst / Rein, Theo / John, Harald

    Archives of toxicology

    2022  Volume 96, Issue 8, Page(s) 2287–2298

    Abstract: In the recent past, the blister agent sulfur mustard (SM) deployed by the terroristic group Islamic State has caused a huge number of civilian and military casualties in armed conflicts in the Middle East. The vaporized or aerolized agent might be ... ...

    Abstract In the recent past, the blister agent sulfur mustard (SM) deployed by the terroristic group Islamic State has caused a huge number of civilian and military casualties in armed conflicts in the Middle East. The vaporized or aerolized agent might be inhaled and have direct contact to skin and hair. Reaction products of SM with plasma proteins (adducts) represent well-established systemic targets for the bioanalytical verification of exposure. The SM-derived hydroxyethylthioethyl (HETE)-moiety is attached to nucleophilic amino acid side chains and allows unambiguous adduct detection. For shipping of common blood and plasma samples, extensive packaging rules are to be followed as these matrices are considered as potentially infectious material. In contrast, hair is considered as non-infectious thus making its handling and transportation much less complicated. Therefore, we addressed this matrix to develop a procedure for bioanalytical verification. Following optimized lysis of SM-treated human scalp hair and pepsin-catalyzed proteolysis of adducts of keratin type I and II, microbore liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HR MS) was used to detect three alkylated keratin-derived biomarker peptides: AE(-HETE)IRSDL, FKTIE(-HETE)EL, and LE(-HETE)TKLQF simultaneously. All bear the HETE-moiety bound to a glutamic acid residue. Protein adducts were stable for at least 14 weeks at ambient temperature and contact to air, and were not affected by washing the hair with shampoo. The biomarker peptides were also obtained from beard, armpit, abdominal, and pubic hair. This is the first report introducing stable local peptide adduct biomarkers from hair, that is easily accessible by a non-invasive sampling process.
    MeSH term(s) Biomarkers ; Chemical Warfare Agents/chemistry ; Hair/chemistry ; Humans ; Hydroxyeicosatetraenoic Acids ; Keratins ; Mustard Gas/chemistry ; Mustard Gas/toxicity ; Peptides ; Serum Albumin, Human/chemistry ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry/methods
    Chemical Substances Biomarkers ; Chemical Warfare Agents ; Hydroxyeicosatetraenoic Acids ; Peptides ; Keratins (68238-35-7) ; Mustard Gas (T8KEC9FH9P) ; Serum Albumin, Human (ZIF514RVZR)
    Language English
    Publishing date 2022-05-16
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-022-03307-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Transthyretin as a target of alkylation and a potential biomarker for sulfur mustard poisoning: Electrophoretic and mass spectrometric identification and characterization.

    Schmeißer, Wolfgang / Lüling, Robin / Steinritz, Dirk / Thiermann, Horst / Rein, Theo / John, Harald

    Drug testing and analysis

    2021  Volume 14, Issue 1, Page(s) 80–91

    Abstract: For the verification of exposure to the banned blister agent sulfur mustard (SM) and the better understanding of its pathophysiology, protein adducts formed with endogenous proteins represent an important field of toxicological research. SM and its ... ...

    Abstract For the verification of exposure to the banned blister agent sulfur mustard (SM) and the better understanding of its pathophysiology, protein adducts formed with endogenous proteins represent an important field of toxicological research. SM and its analogue 2-chloroethyl ethyl sulfide (CEES) are well known to alkylate nucleophilic amino acid side chains, for example, free-thiol groups of cysteine residues. The specific two-dimensional thiol difference gel electrophoresis (2D-thiol-DIGE) technique making use of maleimide dyes allows the staining of free cysteine residues in proteins. As a consequence of alkylation by, for example, SM or CEES, this staining intensity is reduced. 2D-thiol-DIGE analysis of human plasma incubated with CEES and subsequent matrix-assisted laser desorption/ionization time-of-flight (tandem) mass-spectrometry, MALDI-TOF MS(/MS), revealed transthyretin (TTR) as a target of alkylating agents. TTR was extracted from SM-treated plasma by immunomagnetic separation (IMS) and analyzed after tryptic cleavage by microbore liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (μLC-ESI MS/HR MS). It was found that the Cys
    MeSH term(s) Alkylation ; Biomarkers/metabolism ; Chemical Warfare Agents/analysis ; Chemical Warfare Agents/poisoning ; Chromatography, Liquid/methods ; Electrophoresis/methods ; Humans ; Mustard Gas/analogs & derivatives ; Mustard Gas/analysis ; Mustard Gas/poisoning ; Prealbumin/metabolism ; Spectrometry, Mass, Electrospray Ionization/methods ; Tandem Mass Spectrometry/methods ; Time Factors
    Chemical Substances Biomarkers ; Chemical Warfare Agents ; Prealbumin ; TTR protein, human ; 2-chloroethyl ethyl sulfide (693-07-2) ; Mustard Gas (T8KEC9FH9P)
    Language English
    Publishing date 2021-08-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 2462336-2
    ISSN 1942-7611 ; 1942-7603
    ISSN (online) 1942-7611
    ISSN 1942-7603
    DOI 10.1002/dta.3146
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Identification of creatine kinase and alpha-1 antitrypsin as protein targets of alkylation by sulfur mustard.

    Lüling, Robin / Schmeißer, Wolfgang / Siegert, Markus / Mückter, Harald / Dietrich, Alexander / Thiermann, Horst / Gudermann, Thomas / John, Harald / Steinritz, Dirk

    Drug testing and analysis

    2020  Volume 13, Issue 2, Page(s) 268–282

    Abstract: Sulfur mustard (SM) is a toxic chemical warfare agent deployed in several conflicts within the last 100 years and still represents a threat in terroristic attacks and warfare. SM research focuses on understanding the pathophysiology of SM and identifying ...

    Abstract Sulfur mustard (SM) is a toxic chemical warfare agent deployed in several conflicts within the last 100 years and still represents a threat in terroristic attacks and warfare. SM research focuses on understanding the pathophysiology of SM and identifying novel biomarkers of exposure. SM is known to alkylate nucleophilic moieties of endogenous proteins, for example, free thiol groups of cysteine residues. The two-dimensional-thiol-differences in gel electrophoresis (2D-thiol-DIGE) technique is an initial proteomics approach to detect proteins with free cysteine residues. These amino acids are selectively labeled with infrared-maleimide dyes visualized after GE. Cysteine residues derivatized by alkylating agents are no longer accessible for the maleimide-thiol coupling resulting in the loss of the fluorescent signal of the corresponding protein. To prove the applicability of 2D-thiol-DIGE, this technology was exemplarily applied to neat human serum albumin treated with SM, to lysates from human cell culture exposed to SM as well as to human plasma exposed to CEES (chloroethyl ethyl sulfide, an SM analogue). Exemplarily, the most prominent proteins modified by SM were identified by matrix-assisted laser desorption/ionization time-of-flight (tandem) mass spectrometry, MALDI-TOF MS(/MS), as creatine kinase (CK) from human cells and as alpha-1 antitrypsin (A1AT) from plasma samples. Peptides containing the residue Cys
    MeSH term(s) Alkylation/drug effects ; Chemical Warfare Agents/adverse effects ; Creatine Kinase/chemistry ; Creatine Kinase/metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Mustard Gas/adverse effects ; alpha 1-Antitrypsin/chemistry ; alpha 1-Antitrypsin/metabolism
    Chemical Substances Chemical Warfare Agents ; alpha 1-Antitrypsin ; Creatine Kinase (EC 2.7.3.2) ; Mustard Gas (T8KEC9FH9P)
    Language English
    Publishing date 2020-09-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2462336-2
    ISSN 1942-7611 ; 1942-7603
    ISSN (online) 1942-7611
    ISSN 1942-7603
    DOI 10.1002/dta.2916
    Database MEDical Literature Analysis and Retrieval System OnLINE

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