Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models

Lade...
Vorschaubild
Dateien
Capinha_2-1eitsp4n7hrih6.pdf
Capinha_2-1eitsp4n7hrih6.pdfGröße: 3.04 MBDownloads: 17
Datum
2023
Autor:innen
Capinha, Liliana
Zhang, Yaran
Zana, Melinda
Carta, Giada
Murphy, Cormac
Baldovini, Jenna
Mazidi , Zahra
et al.
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
ArXiv-ID
Internationale Patentnummer
Angaben zur Forschungsförderung
European Union (EU): 964537
European Union (EU): 681002
Projekt
EUToxRisk21
Open Access-Veröffentlichung
Open Access Hybrid
Sammlungen
Core Facility der Universität Konstanz
Gesperrt bis
Titel in einer weiteren Sprache
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
Archives of Toxicology. Springer. 2023, 97(2), pp. 523-545. ISSN 0370-8497. eISSN 1432-0738. Available under: doi: 10.1007/s00204-022-03436-6
Zusammenfassung

Environmental or occupational exposure of humans to trichloroethylene (TCE) has been associated with different extrahepatic toxic effects, including nephrotoxicity and neurotoxicity. Bioactivation of TCE via the glutathione (GSH) conjugation pathway has been proposed as underlying mechanism, although only few mechanistic studies have used cell models of human origin. In this study, six human derived cell models were evaluated as in vitro models representing potential target tissues of TCE-conjugates: RPTEC/TERT1 (kidney), HepaRG (liver), HUVEC/TERT2 (vascular endothelial), LUHMES (neuronal, dopaminergic), human induced pluripotent stem cells (hiPSC) derived peripheral neurons (UKN5) and hiPSC-derived differentiated brain cortical cultures containing all subtypes of neurons and astrocytes (BCC42). A high throughput transcriptomic screening, utilizing mRNA templated oligo-sequencing (TempO-Seq), was used to study transcriptomic effects after exposure to TCE-conjugates. Cells were exposed to a wide range of concentrations of S-(1,2-trans-dichlorovinyl)glutathione (1,2-DCVG), S-(1,2-trans-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)glutathione (2,2-DCVG), and S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC). 1,2-DCVC caused stress responses belonging to the Nrf2 pathway and Unfolded protein response in all the tested models but to different extents. The renal model was the most sensitive model to both 1,2-DCVC and 1,2-DCVG, with an early Nrf2-response at 3 µM and hundreds of differentially expressed genes at higher concentrations. Exposure to 2,2-DCVG and 2,2-DCVC also resulted in the upregulation of Nrf2 pathway genes in RPTEC/TERT1 although at higher concentrations. Of the three neuronal models, both the LUHMES and BCC42 showed significant Nrf2-responses and at higher concentration UPR-responses, supporting recent hypotheses that 1,2-DCVC may be involved in neurotoxic effects of TCE. The cell models with the highest expression of γ-glutamyltransferase (GGT) enzymes, showed cellular responses to both 1,2-DCVG and 1,2-DCVC. Little to no effects were found in the neuronal models from 1,2-DCVG exposure due to their low GGT-expression. This study expands our knowledge on tissue specificity of TCE S-conjugates and emphasizes the value of human cell models together with transcriptomics for such mechanistic studies.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
Cytotoxicity; Glutathione conjugation pathway; Hazard identification; Multi-organ toxicity; Transcriptomics
Konferenz
Rezension
undefined / . - undefined, undefined
Zitieren
ISO 690CAPINHA, Liliana, Yaran ZHANG, Anna-Katharina HOLZER, Anna-Katharina ÜCKERT, Melinda ZANA, Giada CARTA, Cormac MURPHY, Jenna BALDOVINI, Zahra MAZIDI , Marcel LEIST, 2023. Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models. In: Archives of Toxicology. Springer. 2023, 97(2), pp. 523-545. ISSN 0370-8497. eISSN 1432-0738. Available under: doi: 10.1007/s00204-022-03436-6
BibTex
@article{Capinha2023Trans-59658,
  year={2023},
  doi={10.1007/s00204-022-03436-6},
  title={Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models},
  number={2},
  volume={97},
  issn={0370-8497},
  journal={Archives of Toxicology},
  pages={523--545},
  author={Capinha, Liliana and Zhang, Yaran and Holzer, Anna-Katharina and Ückert, Anna-Katharina and Zana, Melinda and Carta, Giada and Murphy, Cormac and Baldovini, Jenna and Mazidi , Zahra and Leist, Marcel}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/59658">
    <dc:creator>Mazidi , Zahra</dc:creator>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:contributor>Zana, Melinda</dc:contributor>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2023-01-10T10:07:46Z</dc:date>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dc:creator>Zhang, Yaran</dc:creator>
    <dc:creator>Carta, Giada</dc:creator>
    <dc:creator>Leist, Marcel</dc:creator>
    <dc:contributor>Capinha, Liliana</dc:contributor>
    <dcterms:title>Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models</dcterms:title>
    <dc:contributor>Ückert, Anna-Katharina</dc:contributor>
    <dcterms:issued>2023</dcterms:issued>
    <dc:contributor>Mazidi , Zahra</dc:contributor>
    <dc:contributor>Baldovini, Jenna</dc:contributor>
    <dc:creator>Baldovini, Jenna</dc:creator>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/59658/1/Capinha_2-1eitsp4n7hrih6.pdf"/>
    <dc:contributor>Holzer, Anna-Katharina</dc:contributor>
    <dc:contributor>Murphy, Cormac</dc:contributor>
    <dc:contributor>Leist, Marcel</dc:contributor>
    <dc:contributor>Zhang, Yaran</dc:contributor>
    <dc:contributor>Carta, Giada</dc:contributor>
    <dc:language>eng</dc:language>
    <dc:creator>Ückert, Anna-Katharina</dc:creator>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:creator>Holzer, Anna-Katharina</dc:creator>
    <dc:creator>Capinha, Liliana</dc:creator>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:rights>terms-of-use</dc:rights>
    <dc:creator>Murphy, Cormac</dc:creator>
    <dc:creator>Zana, Melinda</dc:creator>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2023-01-10T10:07:46Z</dcterms:available>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/59658/1/Capinha_2-1eitsp4n7hrih6.pdf"/>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/59658"/>
    <dcterms:abstract xml:lang="eng">Environmental or occupational exposure of humans to trichloroethylene (TCE) has been associated with different extrahepatic toxic effects, including nephrotoxicity and neurotoxicity. Bioactivation of TCE via the glutathione (GSH) conjugation pathway has been proposed as underlying mechanism, although only few mechanistic studies have used cell models of human origin. In this study, six human derived cell models were evaluated as in vitro models representing potential target tissues of TCE-conjugates: RPTEC/TERT1 (kidney), HepaRG (liver), HUVEC/TERT2 (vascular endothelial), LUHMES (neuronal, dopaminergic), human induced pluripotent stem cells (hiPSC) derived peripheral neurons (UKN5) and hiPSC-derived differentiated brain cortical cultures containing all subtypes of neurons and astrocytes (BCC42). A high throughput transcriptomic screening, utilizing mRNA templated oligo-sequencing (TempO-Seq), was used to study transcriptomic effects after exposure to TCE-conjugates. Cells were exposed to a wide range of concentrations of S-(1,2-trans-dichlorovinyl)glutathione (1,2-DCVG), S-(1,2-trans-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)glutathione (2,2-DCVG), and S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC). 1,2-DCVC caused stress responses belonging to the Nrf2 pathway and Unfolded protein response in all the tested models but to different extents. The renal model was the most sensitive model to both 1,2-DCVC and 1,2-DCVG, with an early Nrf2-response at 3 µM and hundreds of differentially expressed genes at higher concentrations. Exposure to 2,2-DCVG and 2,2-DCVC also resulted in the upregulation of Nrf2 pathway genes in RPTEC/TERT1 although at higher concentrations. Of the three neuronal models, both the LUHMES and BCC42 showed significant Nrf2-responses and at higher concentration UPR-responses, supporting recent hypotheses that 1,2-DCVC may be involved in neurotoxic effects of TCE. The cell models with the highest expression of γ-glutamyltransferase (GGT) enzymes, showed cellular responses to both 1,2-DCVG and 1,2-DCVC. Little to no effects were found in the neuronal models from 1,2-DCVG exposure due to their low GGT-expression. This study expands our knowledge on tissue specificity of TCE S-conjugates and emphasizes the value of human cell models together with transcriptomics for such mechanistic studies.</dcterms:abstract>
  </rdf:Description>
</rdf:RDF>
Interner Vermerk
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Kontakt
URL der Originalveröffentl.
Prüfdatum der URL
Prüfungsdatum der Dissertation
Finanzierungsart
Kommentar zur Publikation
Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Ja
Diese Publikation teilen