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Aop: 17

AOP Title

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Binding to SH/selen-proteins can trigger neuroinflammation leading to neurodegeneration

Short name:

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Neuroinflammation to Neurodegeneration 2

Authors

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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


Point of Contact Florianne Tschudi-Monnet


Contributors

  • Florianne Tschudi-Monnet

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.13 Included in OECD Work Plan


This AOP was last modified on May 23, 2017 04:21

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Revision dates for related pages

Page Revision Date/Time
Binding, SH-/selen-proteins December 03, 2016 16:37
N/A, Interferences with SH-/selen-proteins December 03, 2016 16:37
Depletion, GSH December 03, 2016 16:37
N/A, Oxidative stress December 03, 2016 16:37
N/A, Neuronal dysfunction November 29, 2016 19:00
N/A, Neuroinflammation May 22, 2017 10:13
N/A, Neurodegeneration May 22, 2017 10:28
Binding, SH-/selen-proteins leads to N/A, Interferences with SH-/selen-proteins December 03, 2016 16:37
N/A, Interferences with SH-/selen-proteins leads to Depletion, GSH December 03, 2016 16:37
Depletion, GSH leads to N/A, Oxidative stress December 03, 2016 16:37
N/A, Oxidative stress leads to N/A, Neuronal dysfunction December 03, 2016 16:37
N/A, Neuronal dysfunction leads to N/A, Neuroinflammation November 29, 2016 19:59
N/A, Neuroinflammation leads to N/A, Neurodegeneration May 23, 2017 04:16
N/A, Neurodegeneration leads to N/A, Neuroinflammation May 23, 2017 04:21

Abstract

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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.


Background (optional)

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This optional section should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Instructions To add background information, click Edit in the upper right hand menu on the AOP page. Under the “Background (optional)” field, a text editable form provides ability to edit the Background.  Clicking ‘Update AOP’ will update these fields.

Summary of the AOP

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Stressors

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Describes stressors known to trigger the MIE and provides evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. The evidence supporting the stressor will typically consist of a brief description and citation of literature showing that particular stressors can trigger the MIE. Instructions To add a stressor associated with an AOP, under “Summary of the AOP” click ‘Add Stressor’ will bring user to the “New Aop Stressor” page. In the Name field, user can search for stressor by name. Choosing a stressor from the resulting drop down populates the field. Selection of an Evidence level from the drop down menu and add any supporting evidence in the text box. Click ‘Add stressor’ to add the stressor to the AOP page.

Molecular Initiating Event

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Title Short name
Binding, SH-/selen-proteins Binding, SH-/selen-proteins

Key Events

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Title Short name
N/A, Interferences with SH-/selen-proteins N/A, Interferences with SH-/selen-proteins
Depletion, GSH Depletion, GSH
N/A, Oxidative stress N/A, Oxidative stress
N/A, Neuronal dysfunction N/A, Neuronal dysfunction
N/A, Neuroinflammation N/A, Neuroinflammation

Adverse Outcome

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Title Short name
N/A, Neurodegeneration N/A, Neurodegeneration

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Is the AOP specific to certain tissues, life stages / age classes? Indicate if there are critical life stages, where exposure must occur, to results in the final adverse effect. Or specify if there are key events along the pathway which are dependent on the life stage although the AOP is known to be initiated regardless of life stage. Indicate also if the AOP is associated also with age- or sex-dependence. Instructions To add a life stage term to an AOP page, under “Life Stage Applicability” select ‘add life stage term.’ User will be directed to a page entitled “Add Life Stage to AOP.” This page will list the AOP name, with drop down menu options to select a Life Stage term and Evidence. Evidence can be left blank and added later. To edit a life stage term on an AOP page, under “Life Stage Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Life Stage” where they can edit the Evidence field using the drop down menu. Clicking ‘Update Aop life stage’ will update the Evidence field and redirect the user back to the AOP page.

Taxonomic Applicability

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Indicate the relevant domain of applicability in terms of taxa. Instructions To add a taxonomic term to an AOP page, under “Taxonomic Applicability” select ‘add taxonomic term.’ User will be directed to a page entitled “Adding Taxonomic Term to AOP.” The user can search for and select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, click ‘Request New Taxon Term’ to request a term from AOP-Wiki administrators. Click ‘Add taxonomic term’ to add this term to the AOP page. Evidence can be left blank and added later. To edit a taxonomic term on an AOP page, under “Taxonomic Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Taxonomic Term” where they can edit the Evidence field using the drop down menu. Clicking ‘Update taxonomic term’ will update the Evidence field and redirect the user back to the AOP page.

Sex Applicability

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Indicate the relevant domain of applicability with respect to sex. Instructions To add a taxonomic term to an AOP page, under “Taxonomic Applicability” select ‘add taxonomic term.’ User will be directed to a page entitled “Adding Taxonomic Term to AOP.” The user can search for and select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, click ‘Request New Taxon Term’ to request a term from AOP-Wiki administrators. Click ‘Add taxonomic term’ to add this term to the AOP page. Evidence can be left blank and added later. To edit a taxonomic term on an AOP page, under “Taxonomic Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Taxonomic Term” where they can edit the Evidence field using the drop down menu. Clicking ‘Update taxonomic term’ will update the Evidence field and redirect the user back to the AOP page.

Graphical Representation

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Click to download graphical representation template

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Overall Assessment of the AOP

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This section addresses the relevant domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and weight of evidence for the overall hypothesised AOP (i.e., including the MIE, KEs and AO) as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). It draws upon the evidence assembled for each KER as one of several components which contribute to relative confidence in supporting information for the entire hypothesised pathway. An important component in assessing confidence in supporting information as a basis to consider regulatory application of AOPs beyond that described in Section 6 is the essentiality of each of the key events as a component of the entire pathway. This is normally investigated in specifically-designed stop/reversibility studies or knockout models (i.e., those where a key event can be blocked or prevented). Assessment of the overall AOP also contributes to the identification of KEs for which confidence in the quantitative relationship with the AO is greatest (i.e., to facilitate determining the most sensitive predictor of the AO). Instructions To edit the “Overall Assessment of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Overall Assessment of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Overall Assessment of the AOP” section on the AOP page.

Domain of Applicability

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The relevant domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Domain of applicability is informed by the “Description” and “Taxonomic Relevance” section of each KE description and the “Description of the KER” section of each KER description. The relevant domain of applicability of the AOP as a whole will most often be defined based on the most narrowly restricted of its KEs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the domain of applicability of the AOP as a whole would generally be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE descriptions, the rationale for defining the relevant domain of applicability of the overall AOP should be briefly summarised on the AOP page. Instructions To edit the “Domain of Applicability” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Domain of Applicability” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Domain of Applicability” section on the AOP page.

Essentiality of the Key Events

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The essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1). Instructions To edit the “Essentiality of the Key Events” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Essentiality of the Key Events” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Essentiality of the Key Events” section on the AOP page.

Weight of Evidence Summary

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Summary Table
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.'



Quantitative Considerations

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The extent of quantitative understanding of the various KERs in the overall hypothesised AOP is also critical in consideration of potential regulatory application. For some applications (e.g. doseresponse analysis in in depth risk assessment), quantitative characterisation of downstream KERs may be essential while for others, quantitative understanding of upstream KERs may be important (e.g., QSAR modelling for category formation for testing). Because evidence that contributes to quantitative understanding of the KER is generally not mutually exclusive with the empirical support for the KER, evidence that contributes to quantitative understanding should generally be considered as part of the evaluation of the weight of evidence supporting the KER (see Annex 1, footnote b). General guidance on the degree of quantitative understanding that would be characterised as weak, moderate, or strong is provided in Annex 2. Instructions To edit the “Quantitative Considerations” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Quantitative Considerations” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Quantitative Considerations” section on the AOP page.

Considerations for Potential Applications of the AOP (optional)

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At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application. Instructions To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page.

References

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List the bibliographic references to original papers, books or other documents used to support the AOP. Instructions To edit the “References” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “References” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “References” section on the AOP page.