Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

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2021
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Cediel-Ulloa, Andrea
Kranaster, Petra
van Vugt-Lussenburg, Barbara M.A.
Munic Kos, Vesna
van der Stel, Wanda
Carta, Giada
Bennekou, Susanne Hougaard
Leist, Marcel
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Archives of Toxicology. Springer. 2021, 95(2), pp. 591-615. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-020-02970-5
Zusammenfassung

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.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
In vitro neurotoxicity, Mitotoxicity, TempO-Seq, High-content imaging, AOP:3, Mechanistic safety assessment
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ISO 690DELP, Johannes, Andrea CEDIEL-ULLOA, Ilinca SUCIU, Petra KRANASTER, Barbara M.A. VAN VUGT-LUSSENBURG, Vesna MUNIC KOS, Wanda VAN DER STEL, Giada CARTA, Susanne Hougaard BENNEKOU, Marcel LEIST, 2021. Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. In: Archives of Toxicology. Springer. 2021, 95(2), pp. 591-615. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-020-02970-5
BibTex
@article{Delp2021-02Neuro-52689,
  year={2021},
  doi={10.1007/s00204-020-02970-5},
  title={Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors},
  number={2},
  volume={95},
  issn={0340-5761},
  journal={Archives of Toxicology},
  pages={591--615},
  author={Delp, Johannes and Cediel-Ulloa, Andrea and Suciu, Ilinca and Kranaster, Petra and van Vugt-Lussenburg, Barbara M.A. and Munic Kos, Vesna and van der Stel, Wanda and Carta, Giada and Bennekou, Susanne Hougaard and Leist, Marcel}
}
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