Publikation:

Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants

Lade...
Vorschaubild

Dateien

Magel_2-1ttw5rmuqnwx54.pdf
Magel_2-1ttw5rmuqnwx54.pdfGröße: 3.47 MBDownloads: 21

Datum

2024

Herausgeber:innen

Kontakt

ISSN der Zeitschrift

Electronic ISSN

ISBN

Bibliografische Daten

Verlag

Schriftenreihe

Auflagebezeichnung

ArXiv-ID

Internationale Patentnummer

Link zur Lizenz

Angaben zur Forschungsförderung

Deutsche Forschungsgemeinschaft (DFG): DFG TRR353
Institutionen der Bundesrepublik Deutschland: 161L0243B
Institutionen der Bundesrepublik Deutschland: 016LW0146K

Projekt

Open Access-Veröffentlichung
Open Access Gold
Core Facility der Universität Konstanz

Gesperrt bis

Titel in einer weiteren Sprache

Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published

Erschienen in

Cells. MDPI. 2024, 13(24), 2057. eISSN 2073-4409. Verfügbar unter: doi: 10.3390/cells13242057

Zusammenfassung

Cell-based test methods with a phenotypic readout are frequently used for toxicity screening. However, guidance on how to validate the hits and how to integrate this information with other data for purposes of risk assessment is missing. We present here such a procedure and exemplify it with a case study on neural crest cell (NCC)-based developmental toxicity of picoxystrobin. A library of potential environmental toxicants was screened in the UKN2 assay, which simultaneously measures migration and cytotoxicity in NCC. Several strobilurin fungicides, known as inhibitors of the mitochondrial respiratory chain complex III, emerged as specific hits. From these, picoxystrobin was chosen to exemplify a roadmap leading from cell-based testing towards toxicological predictions. Following a stringent confirmatory testing, an adverse outcome pathway was developed to provide a testable toxicity hypothesis. Mechanistic studies showed that the oxygen consumption rate was inhibited at sub-µM picoxystrobin concentrations after a 24 h pre-exposure. Migration was inhibited in the 100 nM range, under assay conditions forcing cells to rely on mitochondria. Biokinetic modeling was used to predict intracellular concentrations. Assuming an oral intake of picoxystrobin, consistent with the acceptable daily intake level, physiologically based kinetic modeling suggested that brain concentrations of 0.1–1 µM may be reached. Using this broad array of hazard and toxicokinetics data, we calculated a margin of exposure ≥ 80 between the lowest in vitro point of departure and the highest predicted tissue concentration. Thus, our study exemplifies a hit follow-up strategy and contributes to paving the way to next-generation risk assessment.

Zusammenfassung in einer weiteren Sprache

Fachgebiet (DDC)
570 Biowissenschaften, Biologie

Schlagwörter

neural crest cells, mitochondria, developmental toxicity, strobilurin fungicides, nextgeneration risk assessment, toxicokinetics, hit confirmation, adverse outcome pathway, data integration

Konferenz

Rezension
undefined / . - undefined, undefined

Forschungsvorhaben

Organisationseinheiten

Zeitschriftenheft

Zugehörige Datensätze in KOPS

Zitieren

ISO 690MAGEL, Viktoria, Jonathan BLUM, Xenia DOLDE, Heidrun LEISNER, Karin GRILLBERGER, Hiba KHALIDI, Iain GARDNER, Giorgia PALLOCCA, Nadine DRESER, Marcel LEIST, 2024. Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants. In: Cells. MDPI. 2024, 13(24), 2057. eISSN 2073-4409. Verfügbar unter: doi: 10.3390/cells13242057
BibTex
@article{Magel2024-12-12Inhib-71892,
  title={Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants},
  year={2024},
  doi={10.3390/cells13242057},
  number={24},
  volume={13},
  journal={Cells},
  author={Magel, Viktoria and Blum, Jonathan and Dolde, Xenia and Leisner, Heidrun and Grillberger, Karin and Khalidi, Hiba and Gardner, Iain and Pallocca, Giorgia and Dreser, Nadine and Leist, Marcel},
  note={Article Number: 2057}
}
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/123456789/71892">
    <dc:creator>Leist, Marcel</dc:creator>
    <dc:contributor>Magel, Viktoria</dc:contributor>
    <dc:contributor>Grillberger, Karin</dc:contributor>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/71892/1/Magel_2-1ttw5rmuqnwx54.pdf"/>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:creator>Khalidi, Hiba</dc:creator>
    <dc:creator>Dolde, Xenia</dc:creator>
    <dc:contributor>Pallocca, Giorgia</dc:contributor>
    <dc:creator>Pallocca, Giorgia</dc:creator>
    <dcterms:issued>2024-12-12</dcterms:issued>
    <dc:contributor>Leisner, Heidrun</dc:contributor>
    <dc:contributor>Gardner, Iain</dc:contributor>
    <dc:creator>Blum, Jonathan</dc:creator>
    <dc:contributor>Blum, Jonathan</dc:contributor>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:contributor>Leist, Marcel</dc:contributor>
    <dc:language>eng</dc:language>
    <dc:contributor>Khalidi, Hiba</dc:contributor>
    <dc:creator>Leisner, Heidrun</dc:creator>
    <dc:creator>Grillberger, Karin</dc:creator>
    <dc:contributor>Dolde, Xenia</dc:contributor>
    <dc:creator>Gardner, Iain</dc:creator>
    <dc:rights>Attribution 4.0 International</dc:rights>
    <dcterms:title>Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants</dcterms:title>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/71892"/>
    <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by/4.0/"/>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2025-01-15T10:25:06Z</dcterms:available>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/71892/1/Magel_2-1ttw5rmuqnwx54.pdf"/>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2025-01-15T10:25:06Z</dc:date>
    <dc:creator>Magel, Viktoria</dc:creator>
    <dcterms:abstract>Cell-based test methods with a phenotypic readout are frequently used for toxicity screening. However, guidance on how to validate the hits and how to integrate this information with other data for purposes of risk assessment is missing. We present here such a procedure and exemplify it with a case study on neural crest cell (NCC)-based developmental toxicity of picoxystrobin. A library of potential environmental toxicants was screened in the UKN2 assay, which simultaneously measures migration and cytotoxicity in NCC. Several strobilurin fungicides, known as inhibitors of the mitochondrial respiratory chain complex III, emerged as specific hits. From these, picoxystrobin was chosen to exemplify a roadmap leading from cell-based testing towards toxicological predictions. Following a stringent confirmatory testing, an adverse outcome pathway was developed to provide a testable toxicity hypothesis. Mechanistic studies showed that the oxygen consumption rate was inhibited at sub-µM picoxystrobin concentrations after a 24 h pre-exposure. Migration was inhibited in the 100 nM range, under assay conditions forcing cells to rely on mitochondria. Biokinetic modeling was used to predict intracellular concentrations. Assuming an oral intake of picoxystrobin, consistent with the acceptable daily intake level, physiologically based kinetic modeling suggested that brain concentrations of 0.1–1 µM may be reached. Using this broad array of hazard and toxicokinetics data, we calculated a margin of exposure ≥ 80 between the lowest in vitro point of departure and the highest predicted tissue concentration. Thus, our study exemplifies a hit follow-up strategy and contributes to paving the way to next-generation risk assessment.</dcterms:abstract>
    <dc:creator>Dreser, Nadine</dc:creator>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:contributor>Dreser, Nadine</dc:contributor>
  </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