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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. More help

Acetylcholinesterase Inhibition Leading to Neurodegeneration

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

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. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Kendra Conrow (a)

Dennis Sinitsyn (a)

Demetrio Raldua (b)

Natalia Garcia-Reyero (c)

Karen H. Watanabe (a)

(a) Arizona State University

(b) IDAEA-CSIC

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. More help

Karen Watanabe (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Kendra Conrow
Karen Watanabe
Natalia Reyero
Priscilla Pacheco
Dennis Sinitsyn

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

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. More help

Handbook Version	OECD status	OECD project
v2.0

This AOP was last modified on April 29, 2023 16:03

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	January 04, 2023 18:39
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
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 Increased, glutamate	April 22, 2019 15:20
Increased, glutamate leads to Overactivation, NMDARs	February 13, 2019 17:47
Overactivation, NMDARs leads to Status epilepticus	October 12, 2022 19:44
Status epilepticus leads to Increased, glutamate	October 12, 2022 19:46
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload	November 29, 2016 20:08
Status epilepticus leads to Increased, Intracellular Calcium overload	October 12, 2022 19:47
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

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. More help

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. More help

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). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

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. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

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	1788	Status epilepticus	Status epilepticus
KE	389	Increased, Intracellular Calcium overload	Increased, Intracellular Calcium overload
KE	55	Cell injury/death	Cell injury/death

352

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. More help

Title	Adjacency	Evidence	Quantitative Understanding

AchE Inhibition leads to ACh Synaptic Accumulation	adjacent	High	Moderate
ACh Synaptic Accumulation leads to Activation, Muscarinic Acetylcholine Receptors	adjacent	High
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure	adjacent
Occurrence, Focal Seizure leads to Increased, glutamate	adjacent
Increased, glutamate leads to Overactivation, NMDARs	adjacent
Overactivation, NMDARs leads to Status epilepticus	adjacent
Status epilepticus leads to Increased, glutamate	adjacent
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload	adjacent	High
Status epilepticus leads to Increased, Intracellular Calcium overload	adjacent
Increased, Intracellular Calcium overload leads to Cell injury/death	adjacent	High
Cell injury/death leads to N/A, Neurodegeneration	adjacent	High

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. More help

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. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

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). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

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. More help

References

List of the literature that was cited for this AOP. More help