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Aop: 281
Title
A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.
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Acetylcholinesterase Inhibition Leading to Neurodegeneration
Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters.
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AChE Inhibition Leading to Neurodegeneration
Graphical Representation
A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs.
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Point of Contact
The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.
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Allie Always
(email point of contact)
Contributors
Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact.
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- Kendra Conrow
- Karen Watanabe
- Natalia Reyero
- Priscilla Pacheco
- Dennis Sinitsyn
- Allie Always
Status
Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators.
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| Author status | OECD status | OECD project | SAAOP status |
|---|---|---|---|
| Under development: Not open for comment. Do not cite |
This AOP was last modified on July 16, 2022 18:37
Revision dates for related pages
| Page | Revision Date/Time |
|---|---|
| Acetylcholinesterase (AchE) Inhibition | April 29, 2020 17:21 |
| Acetylcholine accumulation in synapses | June 26, 2020 13:06 |
| Activation, Muscarinic Acetylcholine Receptors | April 17, 2020 13:09 |
| Overactivation, NMDARs | June 26, 2020 04:38 |
| Increased, Intracellular Calcium overload | June 26, 2020 04:45 |
| Cell injury/death | July 15, 2022 09:46 |
| Occurrence, Focal Seizure | May 20, 2020 01:40 |
| N/A, Neurodegeneration | February 23, 2021 05:07 |
| Status epilepticus | May 21, 2020 18:26 |
| Increased, glutamate | October 11, 2021 14:58 |
| AchE Inhibition leads to ACh Synaptic Accumulation | December 19, 2019 15:57 |
| Status epilepticus leads to Overactivation, NMDARs | May 21, 2020 18:20 |
| ACh Synaptic Accumulation leads to Activation, Muscarinic Acetylcholine Receptors | February 13, 2019 17:46 |
| Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure | April 22, 2019 15:19 |
| Occurrence, Focal Seizure leads to Overactivation, NMDARs | November 13, 2019 15:33 |
| Overactivation, NMDARs leads to Increased, Intracellular Calcium overload | November 29, 2016 20:08 |
| Increased, Intracellular Calcium overload leads to Cell injury/death | February 19, 2019 16:25 |
| Cell injury/death leads to N/A, Neurodegeneration | November 29, 2016 20:08 |
| Increased, Intracellular Calcium overload leads to Status epilepticus | May 21, 2020 18:19 |
Abstract
A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance.
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The enzyme acetylcholinesterase (AChE) hydrolyzes acetylcholine (ACh) in order to eliminate it from the body. When AChE is inhibited ACh levels increase. An excess of ACh at cholinergic synapses overstimulates both muscarinic- and nicotinic- receptors (1,2). These receptors are found in most organs in the body, thus the effects of AChE inhibition can result in multiple adverse outcomes affecting a wide variety of functions (1). This AOP focuses upon an acute outcome of neurodegeneration due to AChE inhibition specifically through calcium dysregulation as that has been identified as central to the development of the most severe phenotype caused by acute organophosphate poisoning (3).
1. United States., Environmental Protection Agency., Office of Pesticide Programs. (2000). The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and Carbamate Pesticides. https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf accessed Nov. 2018.
2. Quick, M. W., & Lester, R. A. J. (2002). Journal of Neurobiology, 53(4), 457-478. doi:10.1002/neu.10109.
3. Faria et al. (2015). Scientific Reports, 5. doi:10.1038/srep15591.
AOP Development Strategy
Context
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.
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Strategy
Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used).
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Summary of the AOP
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Events:
Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP.
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Key Events (KE)
A measurable event within a specific biological level of organisation.
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Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP.
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| Type | Event ID | Title | Short name |
|---|
| MIE | 12 | Acetylcholinesterase (AchE) Inhibition | AchE Inhibition |
| KE | 10 | Acetylcholine accumulation in synapses | ACh Synaptic Accumulation |
| KE | 1602 | Activation, Muscarinic Acetylcholine Receptors | Activation, Muscarinic Acetylcholine Receptors |
| KE | 1623 | Occurrence, Focal Seizure | Occurrence, Focal Seizure |
| KE | 1350 | Increased, glutamate | Increased, glutamate |
| KE | 388 | Overactivation, NMDARs | Overactivation, NMDARs |
| KE | 389 | Increased, Intracellular Calcium overload | Increased, Intracellular Calcium overload |
| KE | 1788 | Status epilepticus | Status epilepticus |
| KE | 55 | Cell injury/death | Cell injury/death |
| AO | 352 | N/A, Neurodegeneration | N/A, Neurodegeneration |
Relationships Between Two Key Events (Including MIEs and AOs)
This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page.
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| Title | Adjacency | Evidence | Quantitative Understanding |
|---|
| Status epilepticus leads to Overactivation, NMDARs | non-adjacent |
Network View
This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs.
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Prototypical Stressors
A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented.
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Life Stage Applicability
The life stage for which the AOP is known to be applicable.
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Taxonomic Applicability
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Sex Applicability
The sex for which the AOP is known to be applicable.
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Overall Assessment of the AOP
Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment).
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Domain of Applicability
Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context.
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Essentiality of the Key Events
The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.
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Evidence Assessment
Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP.
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Known Modulating Factors
Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs.
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Quantitative Understanding
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Considerations for Potential Applications of the AOP (optional)
Addressess 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.
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References
List of the literature that was cited for this AOP.
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