Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors
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| Title: | Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors |
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| Authors: | Anna Forsby, Andrea Cediel-Ulloa, Susanne Hougaard Bennekou, Petra Kranaster, Johannes Delp, Giada Carta, Bob van de Water, Marcel Leist, Ilinca Suciu, Wanda van der Stel, Vesna Munic Kos, Barbara M.A. van Vugt-Lussenburg, Paul Jennings |
| Source: | Arch Toxicol Delp, J, Cediel-Ulloa, A, Suciu, I, Kranaster, P, van Vugt-Lussenburg, B M, Munic Kos, V, van der Stel, W, Carta, G, Bennekou, S H, Jennings, P, van de Water, B, Forsby, A & Leist, M 2021, ' Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors ', Archives of Toxicology, vol. 95, pp. 591–615 . https://doi.org/10.1007/s00204-020-02970-5 Delp, J, Cediel-Ulloa, A, Suciu, I, Kranaster, P, van Vugt-Lussenburg, B M, Munic Kos, V, van der Stel, W, Carta, G, Bennekou, S H, Jennings, P, van de Water, B, Forsby, A & Leist, M 2021, ' Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors ', Archives of Toxicology, vol. 95, pp. 591–615 . https://doi.org/10.1007/s00204-020 |
| Publisher Information: | Springer Science and Business Media LLC, 2021. |
| Publication Year: | 2021 |
| Subject Terms: | 0301 basic medicine, Drug-Related Side Effects and Adverse Reactions, Pharmacology and Toxicology, 3, Dopaminergic Neurons/metabolism [MeSH], Mitochondria/metabolism [MeSH], Humans [MeSH], Enzyme Inhibitors/toxicity [MeSH], Electron Transport Chain Complex Proteins/antagonists, Electron Transport Complex I/antagonists, Electron Transport Complex III/antagonists, Mitochondria/drug effects [MeSH], Electron Transport Complex II/antagonists, Transcriptome [MeSH], Pesticides/toxicity [MeSH], Biomarkers [MeSH], TempO-Seq, Dopaminergic Neurons/drug effects [MeSH] [Cell Line, Tumor [MeSH], Drug-Related Side Effects and Adverse Reactions [MeSH], Risk Assessment [MeSH], Mechanistic safety assessment, In Vitro Systems, Proteostasis/drug effects [MeSH], Cell Line [MeSH], In vitro neurotoxicity, Electron Transport/drug effects [MeSH], Mitotoxicity, High-content imaging, AOP], Risk Assessment, Cell Line, Electron Transport, Electron Transport Complex III, 03 medical and health sciences, in vitro neurotoxicity, AOP:3, Cell Line, Tumor, Humans, Enzyme Inhibitors, Pesticides, AOP, 0303 health sciences, Electron Transport Complex I, Dopaminergic Neurons, Electron Transport Complex II, Farmakologi och toxikologi, Mitochondria, 3. Good health, Electron Transport Chain Complex Proteins, 13. Climate action, Proteostasis, Transcriptome, Biomarkers |
| Description: | Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1432-0738 0340-5761 |
| DOI: | 10.1007/s00204-020-02970-5 |
| Access URL: | https://link.springer.com/content/pdf/10.1007/s00204-020-02970-5.pdf https://pubmed.ncbi.nlm.nih.gov/33512557 https://scholarlypublications.universiteitleiden.nl/access/item%3A3204449/view https://www.narcis.nl/publication/RecordID/oai%3Aresearch.vu.nl%3Apublications%2Fe2a77ca0-56d1-4217-8605-0713f925d927 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870626 https://europepmc.org/article/PMC/PMC7870626 https://pubmed.ncbi.nlm.nih.gov/33512557/ https://www.ncbi.nlm.nih.gov/pubmed/33512557 https://orbit.dtu.dk/en/publications/ae35a386-b950-4048-afe3-b249274e27d2 https://repository.publisso.de/resource/frl:6451713 https://hdl.handle.net/1887/3204448 http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-449992 |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....b61f9e7082c9e7401241b565844c2030 |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency. |
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| ISSN: | 14320738 03405761 |
| DOI: | 10.1007/s00204-020-02970-5 |