Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants
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...
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2024-12-01
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| author | Viktoria Magel Jonathan Blum Xenia Dolde Heidrun Leisner Karin Grillberger Hiba Khalidi Iain Gardner Gerhard F. Ecker Giorgia Pallocca Nadine Dreser Marcel Leist |
| author_facet | Viktoria Magel Jonathan Blum Xenia Dolde Heidrun Leisner Karin Grillberger Hiba Khalidi Iain Gardner Gerhard F. Ecker Giorgia Pallocca Nadine Dreser Marcel Leist |
| author_sort | Viktoria Magel |
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| description | 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-f484bcc052ee4a0fb1338d7a51c7fede2024-12-27T14:16:28ZengMDPI AGCells2073-44092024-12-011324205710.3390/cells13242057Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial ToxicantsViktoria Magel0Jonathan Blum1Xenia Dolde2Heidrun Leisner3Karin Grillberger4Hiba Khalidi5Iain Gardner6Gerhard F. Ecker7Giorgia Pallocca8Nadine Dreser9Marcel Leist10In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyIn Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyIn Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyIn Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyDepartment of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, AustriaCertara Predictive Technologies, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UKCertara Predictive Technologies, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UKDepartment of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, AustriaIn Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyIn Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyIn Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78464 Konstanz, GermanyCell-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.https://www.mdpi.com/2073-4409/13/24/2057neural crest cellsmitochondriadevelopmental toxicitystrobilurin fungicidesnext-generation risk assessmenttoxicokinetics |
| spellingShingle | Viktoria Magel Jonathan Blum Xenia Dolde Heidrun Leisner Karin Grillberger Hiba Khalidi Iain Gardner Gerhard F. Ecker Giorgia Pallocca Nadine Dreser Marcel Leist Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants Cells neural crest cells mitochondria developmental toxicity strobilurin fungicides next-generation risk assessment toxicokinetics |
| title | Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants |
| title_full | Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants |
| title_fullStr | Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants |
| title_full_unstemmed | Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants |
| title_short | Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants |
| title_sort | inhibition of neural crest cell migration by strobilurin fungicides and other mitochondrial toxicants |
| topic | neural crest cells mitochondria developmental toxicity strobilurin fungicides next-generation risk assessment toxicokinetics |
| url | https://www.mdpi.com/2073-4409/13/24/2057 |
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