Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants
- Author(s)
- Viktoria Magel, Jonathan Blum, Xenia Dolde, Heidrun Leisner, Karin Grillberger, Hiba Khalidi, Iain Gardner, Gerhard F. Ecker, Giorgia Pallocca, Nadine Dreser, Marcel Leist
- 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.
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Universität Konstanz, Simcyp (a Certara company)
- Journal
- Cells
- Volume
- 13
- ISSN
- 2073-4409
- DOI
- https://doi.org/10.3390/cells13242057
- Publication date
- 12-2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301207 Pharmaceutical chemistry, 301215 Drug safety
- Keywords
- ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/f274d255-de0f-483c-b622-e1b3a12d6b44