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Florianne Tschudi-Monner, Department of Physiology, University of Lausanne, Switzerland, and Swiss Center for Applied Human Toxicology (SCAHT), Florianne.Tschudi-Monnet@unil.ch
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OECD Project 1.13: Neurotoxicant-induced Neuroinflammation: a converging key event in an adverse outcome pathway.
This AOP was last modified on 12/5/2016.
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This AOP describes the cascade of events initiated by binding to selenoproteins causing a depletion of glutathione (GSH), one of the most important anti-oxidants in the brain. This will lead to oxidative stress which is deleterious to neurons. Neuroinflammation, characterized by microglial and astrocyte reactivity, will be triggered in response to neuronal damage. When neuroinflammation induces a 'neurodegenerative phenotype' associated with the production of pro-inflammatory cytokines and the expression of specific microglial markers, it can lead to neurodegeneration, the adverse outcome. Neurodegeneration will amplify the inflammatory response and lead to a self-sustained neuroinflammation that exacerbates the neurodegenerative process. Such a self-sustained neuroinflammation-neurodegenerative loop is involved in neurodegenerative diseases such as Alzheimer's and Parkinson’s diseases.
This AOP is relevant for neurotoxicity and developmental neurotoxicity testing following low dose and long term exposure and for delayed adverse outcome, according to the Landrigan et al (2005) hypothesis of early origins of neurodegenerative disease in later life. It is part of a broader effort initiated by JRC/Seurat to describe several AOPs relevant for neurotoxicity, that will be published in « Critical Reviews in Toxicology ». Currently, the only related endpoint for regulatory purposes is measurement of rodent brain glial fibrillary acidic protein (GFAP), whose increase is a marker of astrocyte reactivity; this is required by the US EPA for fuel additives, but is optional for other chemical hazard evaluations.
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Event||Support for Essentiality|
|Interferences with SH-/selen-proteins, N/A||Strong|
|Oxidative stress, N/A||Strong|
|Neuronal dysfunction, N/A||Strong|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
Overall Assessment of the AOP
Weight of Evidence Summary
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
In the AOP "Neuroinflammation to Neurodegeneration 1" (no.976057), binding to components of the electron transport chain (ETC) in mitochondria leads to oxidative stress, which causes neuronal dysfunction. In the AOP "Neuroinflammation to Neurodegeneration 2" (no.678683), binding to selenoproteins in nervous tissue leads to a decrease of anti-oxidant protection and thus to oxidative stress, which causes neuronal dysfunction. In the AOP "Neuroinflammation to Neurodegeneration 3" (no.348359), agonist binding to NMDAR triggers oxidative stress, which causes neuronal dysfunction. In the AOP "Neuroinflammation to neurodegeneration 4" (no.515292), antagonist binding to NMDAR triggers neuronal dysfunction and microglial /astroglial activation. From these 4 pathways, it becomes clear that neuronal dysfunction is a broad category including a variety of events, appearing alone or concomitantly, such as synapse impairment/loss, cytoskeletal dysfunction (axonal retraction, cytoskeletal instabilities), apoptosis or necrosis. Each of these events is able to trigger a neuroinflammatory response, that may have different characteristics and express different phenotypes. And depending on the extent of the dysfunction/lesion and on the temporal evolution, neuroinflammation may evolve into neurodegeneration. In turn, neurodegeneration exacerbates the neuroinflammatory process in a self-sustained aggravation loop, playing a key role in the onset and progression of several neurodegenerative diseases. The separate AOP entitled "Multiples MIEs trigger neuroinflammation leading to neurodegeneration" (no.1435) includes AOPs 1 to 4 and identifies neuroinflammation as a converging key event.'
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
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Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
Applicability of the AOP
Life Stage Applicability,
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