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

• Published in: Archives of toxicology Vol. 92; no. 1; pp. 41 - 82
• Main Authors: Terron, Andrea, Bal-Price, Anna, Paini, Alicia, Monnet-Tschudi, Florianne, Bennekou, Susanne Hougaard, Leist, Marcel, Schildknecht, Stefan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2018; Springer Nature B.V
• Subjects: Adverse Outcome Pathways; Agrochemicals; Animals; Archives & records; Basal ganglia; Biomedical and Life Sciences; Biomedicine; Central nervous system diseases; Degeneration; Dopamine receptors; Electron transport chain; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - metabolism; Environmental Health; Epidemiology; Exposure; Health risks; Humans; Inflammation; Inhibition; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Movement disorders; NADH-ubiquinone oxidoreductase; Neurodegeneration; Occupational Medicine/Industrial Medicine; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - etiology; Pesticides; Pesticides - toxicity; Pharmacology/Toxicology; Review; Review Article; Rotenone - toxicity; Substantia nigra; Toxicology; Pesticide exposure; Regulatory decision-making; MPTP; Mitochondrial complex I inhibitor; Parkinson’s disease; Adverse outcome pathway; Rotenone
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-017-2133-4

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.