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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
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

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

(c) US Army Corps of Engineers, Engineering Research and Development Center

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

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on September 03, 2023 05:47

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 September 10, 2023 19:16
ACh Synaptic Accumulation leads to Activation, Muscarinic Acetylcholine Receptors September 03, 2023 02:35
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure September 03, 2023 02:55
Occurrence, Focal Seizure leads to Increased, glutamate September 03, 2023 03:04
Increased, glutamate leads to Overactivation, NMDARs September 03, 2023 03:06
Overactivation, NMDARs leads to Status epilepticus September 03, 2023 03:19
Status epilepticus leads to Increased, glutamate September 03, 2023 03:26
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload September 10, 2023 20:11
Status epilepticus leads to Increased, Intracellular Calcium overload July 24, 2023 22:52
Increased, Intracellular Calcium overload leads to Cell injury/death September 03, 2023 05:11
Cell injury/death leads to N/A, Neurodegeneration September 10, 2023 19:25

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

Epidemiological studies concerning OP pesticides estimated approximately 3 million cases of acute severe poisoning, as well as 300,000 deaths annually. Most of those deaths occur in developing countries of the Asia-Pacific region (Bertolote et al., 2006). These OP compounds can also be used as chemical warfare nerve agents. The improper use of OP chemicals has tragic consequences such as neurodegeneration, brain damage, and death underscoring the need for safety measures that protect both human health and the environment.

Bertolote, J. M., Fleischmann, A., Eddleston, M. & Gunnell, D. 2006. Deaths from pesticide poisoning: A global response. British Journal of Psychiatry, 189, 201-203. DOI: 10.1192/bjp.bp.105.020834.

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

Construction of AOP 281 started from the bottom up, and involved searching the literature and consultation with experts in neuroscience.  Extensive literature searches were conducted in Scopus and Pubmed using keywords such as, “acetylcholinesterase inhibition”, “muscarinic acetylcholine receptor”, “calcium dysregulation”, “organophosphate”, “glutamate”, and “cell death” with an initial focus on zebrafish data.  Over 300 papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP.  An Excel spreadsheet was used to record reviewed papers and which part(s) of the AOP they supported.

AOP 281 was developed primarily by the authors and experts in this publication, except when existing KEs or KERs are used in the AOP.  These existing KEs and KERs have additional authors who are not explicitly cited herein. Three KEs of the 10 in AOP 281 (including the MIE and AO as key events), and eight KERs of eleven were developed specifically for this AOP.  The remaining KEs and KERs were modified accordingly to include additional data specific for AOP 281.

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
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
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. More help

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

Sex: The AOP is not sex-specific

Life stages: the AOP is relevant to all life stages. Immature or developing populations may be more sensitive due to their increased susceptibility to seizures and developing cholinergic systems.

Taxonomic: given that both cholinergic and glutamatergic systems are highly conserved among vertebrates, this AOP is likely to be applicable to all vertebrates.

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

All KEs in AOP 281 rank high for essentiality.  The provided studies demonstrate direct evidence and include experiments involving inhibition of AChE through the application of various inhibitors, gene-knockout experiments, receptor antagonist studies, and anticonvulsant treatments which are shown to result in the reduction of neurodegeneration.

  • AChE Inhibition (MIE) evidence is high. This is supported by several studies that measured increases in ACh after inhibition of AChE by a variety of inhibitors (Del Pino et al., 2017, Karanth et al., 2007, Kim et al., 2003, Kosasa et al., 1999, Ray et al., 2009). Additionally, researchers have demonstrated that pretreatment with a combination of reversible AChE inhibitors, nicotinic and mAChR receptor antagonists prior to exposure to soman resulted in a significantly higher survival rate and overall reduced brain ACh levels compared to controls (Harris et al., 1980).
  • ACh accumulation in synapses (KE 1) evidence is high. Blocking the effects of ACh with atropine, an mAChR antagonist, was demonstrated to significantly reduce the pathological effects and neurodegeneration associated with soman intoxication (McDonough et al., 1989).
  • Activation of mAChRs (KE 2) evidence is high. M1-mAChR deficient mice through gene-knockout studies were shown to be resistant to seizures induced by pilocarpine, an mAChR agonist (Hamilton et al., 1997).
  • Occurrence of Focal Seizure (KE 3) evidence is high. Treatment with diazepam, a GABAA receptor agonist and known anticonvulsant, both prevented seizures and resulted in significantly reduced brain pathology (McDonough et al., 1989).
  • Increased Glutamate (KE 4) evidence is high. Application of 500 µM of glutamate showed in reduction in neuron survival, however if NMDA antagonist MK-801 was used in conjunction with glutamate, neuron survival returned to control levels (Michaels and Rothman, 1990). Other in vivo experiments using MK-801 or ketamine demonstrated a reduction in seizure activity and reduced neurodegeneration (Borris et al., 2000, Braitman and Sparenborg, 1989, Sparenborg et al., 1992).
  • Overactivation of NMDARs (KE 5) evidence is high. Multiple experiments using ketamine and MK-801, both NMDA receptor antagonists, have been demonstrated to terminate or reduce both seizure activity and neurodegeneration (Borris et al., 2000, Braitman and Sparenborg, 1989, Sparenborg et al., 1992).
  • Increased Intracellular Calcium Overload (KE 6) evidence is high. Calcium chelation in zebrafish models of organophosphate exposure significantly reduced neurodegeneration (Faria et al., 2015). Additionally, Deshpande et al. (2008) demonstrated that cell death could be significantly reduced given a low extracellular calcium solution in an in vitro model of SE in rat hippocampal neurons.
  • Status Epilepticus (KE 7) evidence follows that of KE 3 and is considered high. Anticonvulsant treatment using diazepam was demonstrated to significantly reduce neurodegeneration (McDonough et al., 1989).
  • Cell Injury/Death (KE 8) evidence is considered high. Cell death in the context of the brain is considered a form of neurodegeneration (Przedborski et al., 2003).  Therefore, prevention of cell death directly results in the prevention of the adverse outcome.

Evidence Assessment

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

Biological plausibility: Biological plausibility refers to the structural or functional relationship between the key events based on our fundamental understanding of "normal biology". The evidence for biological plausibility throughout this AOP from inhibition of AChE to neurodegeneration is high. It is well understood that inhibition of AChE is followed by an accumulation of ACh, which subsequently leads to activation of muscarinic acetylcholine receptors and focal seizures. The seizures then lead to increased glutamate, which binds to and overactivates NMDARs. Following that step, we find the highest biological uncertainty in the pathway, with moderate biological plausibility (from overactivation of NMDARs leading to status epilepticus to increased glutamate). The rest of the pathway is considered of high biological plausibility all the way to neurodegeneration.

Concordance of dose-response relationships: Dose response concordance considers the degree to which upstream events are shown to occur at test concentrations equal to or lower than those that cause significant effects on downstream key events, the underlying assumption being that all KEs can be measured with equal precision. There is a significant amount of quantitative data providing dose and temporal concordance for multiple species between AChE inhibitors and the resulting percent AChE inhibition and ACh concentration (Kosasa et al., 1999). Dose-response relationships have been well stablished by showing that AChE inhibition resulted in the progressive accumulation of extracellular ACh. Furthermore, the relationship between increased intracellular calcium and cell death through dose and temporal concordance has also been demonstrated. Additionally, Faria et al. (2015) demonstrated a dose-response relationship between increasing doses of the organophosphate chlorpyrifos-oxon and the prevalence of a severe phenotype marked by measurably increased necrosis.

Temporal concordance: Temporal concordance refers to the degree to which the data support the hypothesized sequence of the key events; i.e., the effect on KE1 is observed before the effect on KE2, which is observed before the effect on KE3 and so on. Temporal concordance has been shown between seizure activity and increasing levels of glutamate (KE4 and KE7). Furthermore, temporal concordance has also been established between status epilepticus and increased intracellular calcium in rats. The relationship between increased intracellular calcium and cell death through dose and temporal concordance has also been demonstrated.

Consistency: We are not aware of cases where the whole chain of key events described was observed without also observing a significant impact on neurodegeneration. Nevertheless, the final adverse outcome is not specific to this AOP. Many of the key events included in this AOP overlap with AOPs linking other molecular initiating events to other adverse outcomes.

Uncertainties, inconsistencies, and data gaps: The current main uncertainties within this AOP are related to seizures and the location of AChE inhibition. Even though it is well known that there are two phases of seizure activity driven by cholinergic and glutamatergic mechanisms, the transition between these phases is not well understood. Additionally, the levels of increasing glutamate post-AChE inhibition appear to be dependent on the location of inhibition as well as stressor specific.

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
Modulating Factor (MF) Influence or Outcome KER(s) involved
butylcholinesterase enzyme Competes with acetylcholinesterase (ACh) for substrate 1

Quantitative Understanding

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

At present, the quantitative understanding of this AOP varies by level of biological organization. While the initial KEs leading to activation of muscarinic acetylcholine receptors have a high level of quantitative understanding, following KEs leading all the way to the Adverse Outcome (Cell Injury / Death Leading to Neurodegeneration) have a much lower quantitative understanding. The exception would be KE5 (Increased Glutamate leading to Overactivation of NMDARs), that has multiple kinetic models available to evaluate quantitative relationships. Overall, better quantitative relationships need to be developed to be able to quantitively and effectively predict the adverse outcome.

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

Borris, D. J., Bertram, E. H. & Kapur, J. 2000. Ketamine controls prolonged status epilepticus. Epilepsy Res, 42, 117-22. DOI: 10.1016/s0920-1211(00)00175-3.

Braitman, D. J. & Sparenborg, S. 1989. MK-801 protects against seizures induced by the cholinesterase inhibitor soman. Brain Research Bulletin, 23, 145-148. DOI: 10.1016/0361-9230(89)90173-1.

Del Pino, J., Moyano, P., Díaz, G. G., Anadon, M. J., Diaz, M. J., García, J. M., Lobo, M., Pelayo, A., Sola, E. & Frejo, M. T. 2017. Primary hippocampal neuronal cell death induction after acute and repeated paraquat exposures mediated by AChE variants alteration and cholinergic and glutamatergic transmission disruption. Toxicology, 390, 88-99. DOI: 10.1016/j.tox.2017.09.008.

Deshpande, L. S., Lou, J. K., Mian, A., Blair, R. E., Sombati, S., Attkisson, E. & DeLorenzo, R. J. 2008. Time course and mechanism of hippocampal neuronal death in an in vitro model of status epilepticus: role of NMDA receptor activation and NMDA dependent calcium entry. Eur J Pharmacol, 583, 73-83. DOI: 10.1016/j.ejphar.2008.01.025.

Faria, M., Garcia-Reyero, N., Padrós, F., Babin, P. J., Sebastián, D., Cachot, J., Prats, E., Arick Ii, M., Rial, E., Knoll-Gellida, A., Mathieu, G., Le Bihanic, F., Escalon, B. L., Zorzano, A., Soares, A. M. & Raldúa, D. 2015. Zebrafish Models for Human Acute Organophosphorus Poisoning. Sci Rep, 5, 15591. DOI: 10.1038/srep15591.

Hamilton, S. E., Loose, M. D., Qi, M., Levey, A. I., Hille, B., McKnight, G. S., Idzerda, R. L. & Nathanson, N. M. 1997. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proceedings of the National Academy of Sciences, 94, 13311-13316. DOI: 10.1073/pnas.94.24.13311.

Harris, L. W., Stitcher, D. L. & Heyl, W. C. 1980. The effects of pretreatments with carbamates, atropine and mecamylamine on survival and on soman-induced alterations in rat and rabbit brain acetylcholine. Life Sci, 26, 1885-91. DOI: 10.1016/0024-3205(80)90617-7.

Karanth, S., Liu, J., Ray, A. & Pope, C. 2007. Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats. Toxicology, 239, 167-179. DOI: https://doi.org/10.1016/j.tox.2007.07.004.

Kim, Y. K., Koo, B. S., Gong, D. J., Lee, Y. C., Ko, J. H. & Kim, C. H. 2003. Comparative effect of Prunus persica L. BATSCH-water extract and tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) on concentration of extracellular acetylcholine in the rat hippocampus. J Ethnopharmacol, 87, 149-54. DOI: 10.1016/s0378-8741(03)00106-5.

Kosasa, T., Kuriya, Y., Matsui, K. & Yamanishi, Y. 1999. Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. European Journal of Pharmacology, 380, 101-107. DOI: 10.1016/S0014-2999(99)00545-2.

McDonough, J. H., Jr., Jaax, N. K., Crowley, R. A., Mays, M. Z. & Modrow, H. E. 1989. Atropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fundam Appl Toxicol, 13, 256-76. DOI: 10.1016/0272-0590(89)90262-5.

Michaels, R. L. & Rothman, S. M. 1990. Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci, 10, 283-92. DOI: 10.1523/jneurosci.10-01-00283.1990.

Przedborski, S., Vila, M. & Jackson-Lewis, V. 2003. Neurodegeneration: what is it and where are we? J Clin Invest, 111, 3-10. DOI: 10.1172/jci17522.

Ray, A., Liu, J., Karanth, S., Gao, Y., Brimijoin, S. & Pope, C. 2009. Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats. Toxicology and Applied Pharmacology, 236, 341-347. DOI: 10.1016/j.taap.2009.02.022.

Sparenborg, S., Brennecke, L. H., Jaax, N. K. & Braitman, D. J. 1992. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacology, 31, 357-68. DOI: 10.1016/0028-3908(92)90068-z.