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Cited by 124Parkinson's Disease Mechanisms and TreatmentsPesticide Exposure and ToxicityNuclear Receptors and Signaling

An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition

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EFSA WG EPI1 Members, Terron, Andrea, Bal-Price, Anna, Paini, Alicia, Monnet-Tschudi, Florianne, Bennekou, Susanne Hougaard, Leist, Marcel, Schildknecht, Stefan·2018·Archives of Toxicology
DOI 10.1007/s00204-017-2133-4PMC PMC5773657
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Abstract

Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson's disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i.e., the MIE) with the onset of parkinsonian motor deficits (i.e., the AO). This AOP was developed according to the Organisation for Economic Co-operation and Development guidelines and uploaded to the AOP database. The KEs linking complex I inhibition to parkinsonian motor deficits are mitochondrial dysfunction, impaired proteostasis, neuroinflammation, and the degeneration of dopaminergic neurons of the substantia nigra. These KEs, by convention, were linearly organized. However, there was also evidence of additional feed-forward connections and shortcuts between the KEs, possibly depending on the intensity of the insult and the model system applied. The present AOP demonstrates mechanistic plausibility for epidemiological observations on a relationship between pesticide exposure and an elevated risk for Parkinson's disease development.

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  • The AOP concept fosters development or selection of assays allowing quantitative detection of individual key events, thereby enabling definition of threshold levels.

    “The AOP concept fosters the development or selection of assays allowing a quantitative detection of individual KEs, thereby enabling the definition of threshold levels (Leist et al., 2017; Terron et al., 2018).”

    From In Vitro research Reproducibility: Keeping up High Standards (2019) · cites this paper as Terron et al., 2018

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Authors
Members, E. W. E., Terron, A., Bal-Price, A., Paini, A., Monnet-Tschudi, F., Bennekou, S. H., Leist, M., & Schildknecht, S.
Affiliations
  • European Food Safety Authority (IT)
  • Joint Research Centre (IT)
  • University of Konstanz (DE)
Corresponding author
Schildknecht, Stefan
ORCID
Venue
Archives of Toxicology
Publisher
Springer Science and Business Media LLC
Published
2017-12-05
Volume
92
Issue
1
Pages
41-82
ISSN
  • 0340-5761 (ISSN-L)
  • 1432-0738
DOI
10.1007/s00204-017-2133-4
PMC
PMC5773657
OpenAlex
W2775495274
Cited by
124
References
31
Citations by year
2026: 7 · 2025: 16 · 2024: 13 · 2023: 13 · 2022: 14 · 2021: 18 · 2020: 12 · 2019: 20 · 2018: 8 · 2016: 1 · 2012: 1
FWCI
1.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Archives of Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KOPS (University of Konstanz) (submittedVersion, cc-by)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Joint Research Centre (European Commission) (submittedVersion)
Funders
  • EU-ToxRisk
  • RTG 1331
  • BMBF
  • Doerenkamp-Zbinden Foundation
  • KoRS Chemical Biology
  • CRC 969, Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
adverse outcome pathways, Parkinson's disease, mitochondrial complex I inhibition, pesticide exposure, mitochondrial dysfunction, proteostasis, neuroinflammation, dopaminergic neuron loss, substantia nigra, molecular initiating events, key events
MeSH terms
Adverse Outcome Pathways, Animals, Humans, Mitochondria, Pesticides, Rotenone, Parkinsonian Disorders, Electron Transport Complex I

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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