Aop: 450

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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

Inhibition of AChE and activation of CYP2E1 leading to sensory axonal peripheral neuropathy and mortality

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Organo-Phosphate Chemicals leading to sensory axonal peripheral neuropathy and mortality

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Saroj Kumar Amar and Kurt A. Gust*

U.S. Army Engineer Research and Development Center, Environmental Laboratory, 3909 Halls Ferry Road, Vicksburg, Mississippi 39180 Sarojkumaramar@gmail.com, Saroj.K.Amar@erdc.dren.mil *Corresponding Author: Kurt.A.Gust@usace.army.mil

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
SAROJ AMAR   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • SAROJ AMAR
  • Kurt A. Gust

Status

The status section is used to provide AOP-KB 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. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on June 03, 2022 13:49
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Acetylcholinesterase (AchE) Inhibition April 29, 2020 17:21
Activation of Cyp2E1 June 19, 2021 14:19
Oxidative Stress in Brain April 04, 2018 14:24
N/A, Neurodegeneration February 23, 2021 05:07
Decreased, Neuronal network function in adult brain September 16, 2017 10:15
Increased Mortality September 08, 2021 07:07
Sensory axonal peripheral neuropathy January 29, 2019 10:08
AchE Inhibition leads to Activation of Cyp2E1 May 16, 2022 20:18
Sensory axonal peripheral neuropathy leads to Increased Mortality May 16, 2022 20:22
Activation of Cyp2E1 leads to Oxidative Stress in Brain May 16, 2022 20:19
Oxidative Stress in Brain leads to N/A, Neurodegeneration May 16, 2022 20:20
N/A, Neurodegeneration leads to Decreased, Neuronal network function in adult brain November 29, 2016 20:24
Decreased, Neuronal network function in adult brain leads to Sensory axonal peripheral neuropathy May 16, 2022 20:21
Paraoxon June 24, 2021 18:47
Methyl parathion June 24, 2021 18:49
Ethyl Parathion June 24, 2021 18:52
Organophosphates November 29, 2016 21:20

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Organophosphate compounds (OP) such as paraoxon, ethyl parathion, methyl parathion and others are widely used insecticides. OP compounds are also being developed as warfare nerve agents like soman, sarin and tabun etc. The present adverse outcome pathway (AOP) utilizing the existing key events (KEs) and describes the risk associated with a characteristics OP exposure via acetylcholinesterase (AChE) inhibition as molecular initiating event (MIE), which roots a series of KEs that ultimately manifest the adverse outcomes (AO) of sensory axonal peripheral neuropathy and mortality. The MIE of inhibited AChE triggers the KEs: activation of CYP2E1 (aopwiki.org/events/1508), oxidative stress in brain (aopwiki.org/events/1510), neurodegeneration (aopwiki.org/events/352), decreased neuronal network function in adult brain (aopwiki.org/events/618), sensory axonal peripheral neuropathy (aopwiki.org/events/1583) and increased mortality (aopwiki.org/events/351).  The OP insecticides inhibits AChE by inhibition of serine esterases and proteases via phosphorylation (Amitai G et al., 1998, Petroianu GA et al., 2001). Farm workers exposed with commonly used OP showed sharp decrease in blood AChE (MIE) level simultaneously over expression of CYP2E1 (KE1) at mRNA level (Sharma RK et al., 2013). CYP2E1-induced oxidative stress (KE2) by over activation of JNK signaling (Schattenberg JM et al., 2014). Literature further supported that oxidative stress causes neurodegeneration (KE3) by targeting different cellular macromolecules including membrane lipid peroxidation, mitochondrial dysfunction and oxidation of protein and nucleic acid (Gandhi S et al., 2012). Thus neurodegeneration and oxidative stress are inherently related phenomena, since microglia and astrocytes are the main sources of reactive oxygen species in CNS degenerative disorders consequently oxidative stress in brain caused neurodegeneration (Mendonca HR et al., 2020, Wakatsuki S et al., 2015, Mishra V et al., 2015, Kim M et al., 2019). Neurodegeneration leads to impairment of retrograde axonal transport that prohibits the growth factor supply to long-range projection neurons, causing synapse loss, and post-synaptic dendrite retraction that leads to decrease of the neuronal network in adult brain (KE 4) (aopwiki.org/relationships/647, Seeley WW et al., 2009). Palop et al (2006) also advocated that neurodegeneration leads to neural network dysfunction. Consequently, loss of neuronal network function in adult brain leads to an important adverse outcome sensory axonal peripheral neuropathy and symptoms include numbness, lack of coordination, impairment of motor nerve, dizziness, burning sensation etc. (Diantonio et al., 2019, Valek L et al., 2019, Persson AK et al., 2016, Topp KS et al., 2000). Thus this AO represents a disparate group of diseases where epidemiological features indicate the potential for a secondary AO of mortality as final adverse outcome (Taverner T et al., 2019, Martyn CN et al., 1997, Hughes RA et al., 1995). Thus this AOP established the connection between OP chemicals and sensory axonal peripheral neuropathy including mortality to endorse predictive toxicology.

Background (optional)

This optional subsection 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. 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 stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 12 Acetylcholinesterase (AchE) Inhibition AchE Inhibition
2 KE 1391 Activation of Cyp2E1 Activation of Cyp2E1
3 KE 1510 Oxidative Stress in Brain Oxidative Stress in Brain
4 KE 352 N/A, Neurodegeneration N/A, Neurodegeneration
5 KE 618 Decreased, Neuronal network function in adult brain Decreased, Neuronal network function in adult brain
6 AO 1583 Sensory axonal peripheral neuropathy Sensory axonal peripheral neuropathy
7 AO 351 Increased Mortality Increased Mortality

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises 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.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and 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

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. 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. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help
Name Evidence Term
Paraoxon Moderate
Methyl parathion Moderate
Ethyl Parathion Moderate
Organophosphates High

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
Juvenile High
Adults Moderate

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 in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Male High
Female Moderate

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Exposure to OP toxicants is the major source of poisoning worldwide, which affecting approximately 3 million populations early, out of which nearly 15% die as a consequence of poisoning (Farizatto KLG et al., 2017; Eddleston et al., 2008). Exposure route of OP pesticide may be drinking contaminated water, breathing vapors of the toxicants, or direct exposure to a person’s skin with the toxicant. Stressor OPs causes inhibition of MIE (AChE) is well documented in literatures. OP pesticides like parathion and chlorpyrifos exercise their toxicity by irreversible inhibition of AChE (Amitai G et al., 1998). Irreversible inhibition of AChE by OPs in birds, insects, fish, and mammals causes neurotoxicity via characteristics cholinergic toxicity (Cao J et al., 2020; Pundir, C. S et al., 2012). AChE hydrolyses acetylcholine into acetic acid and choline, thus terminates the action of the neurotransmitter acetylcholine.  This hydrolysis is inhibited by OP pesticides as OP interfere with the breakdown of acetylcholine by binding to the AChE, which resulted in accumulation of acetylcholine in the nerve synapses and triggered interrupted neurotransmission (Thapa S et al., 2017). Thus OP-induced synaptotoxicity is directly associated with MIE (inhibition of AChE). Inhibition of AChE activates the expression of Cytochrome P450 2E1 i.e CYP2E1 (KE1) as reported in farm workers exposed with OP (Sharma RK et al., 2013). A correlation study between inhibited AChE and CYP2E1 induction in mouse brain is reported by Ma JQ et al., 2016. Enzymology study showed that AChE reactivator’s oxime were tested positive for their potential to inhibit CYP2E1 (Spicakova A et al., 2016; Veinlichova A et al., 2009). As previous study reported CYP2E1 a free enzyme with significant pro-oxidant activity is rich source of oxidative stress (Ma JQ, et al., 2016). Thus, in brain the expression of CYP2E1 results in the formation of oxygen radical intermediates and increased oxidative stress (KE2) in the astrocytes of CNS via JNK signaling (Schattenberg JM et al., 2014, Lu Y et al., 2008 Jin, M et al., 2013). Neurodegeneration are characterized by oxidative stress associated disorder with slow and gradual deterioration of structure and function of neurons (Uddin MS et al., 2020). Recent study reported that oxidative stress (KE2) mediated the neurodegeneration (KE3) via mitochondrial dysfunction and excitotoxicity (Uddin MS et al., 2020). Since the main source of oxidative stress in CNS is microglia and astrocytes thus oxidative stresses and neurodegeneration are associated together (Gandhi S et al., 2012). In vitro and in vivo study by Wakatsuki S, et al. (2015) revealed that oxidative stress induced two major pathways of neurodegeneration, neuronal apoptosis and axonal degeneration via phosphorylation dependent ZNFR1 signaling. Previous study suggested that in transgenic mouse model, neurological defects and network dysfunction are associated with neurological diseases (Palop et al., 2006). As per neuropathological inferences, neuroimaging technique, patients suffering from neurodegeneration and the supporting proof from transgenic animal models of neurodegeneration, it’s recommended that neurodegeneration is largely associated with decreased neural network function in adult brain. (aopwiki.org/relationships/647, Palop et al., 2007; Seeley WW et al., 2009). Thus neurodegeneration induced loss of neuronal network function in adult brain. Degeneration of injured axons is characteristics features of peripheral neuropathy as animal models demonstrated that blocking axon degeneration can prevent the development of peripheral neuropathy (DiAntonio. 2019). Axonal degeneration of peripheral sensory neurons is a main clinical index of peripheral sensory neuropathy (Liu H et al., 2017). Axonal degeneration induced peripheral neuropathy via self-destructive pathways and mechanistic study in mammalian model highlighted the three distinct pathways i.e wallerian degeneration, apoptosis-induced axon degeneration and pruning-induced axon degeneration (Geden MJ et al., 2016; DiAntonio et al., 2019). As per existing AOP relationship, impaired axonial transport leads to sensory axonal peripheral neuropathy (aopwiki.org/relationships/1835). The loss of neuronal network function in adult brain (KE4) leads to sensory axonal peripheral neuropathy (AO) with symptoms of numbness, lack of coordination, impairment of motor nerve, dizziness, burning sensation etc. (DiAntonio et al., 2019, Valek L et al., 2019, Persson AK et al., 2016,  Topp KS et al., 2000). Axonal neuropathy in childhood causes wasting, weakness and delayed development which impacts nervous system and other systemic manifestation, eventually causes mortality (Yiu EM et al., 2012). Peripheral neuropathy is generally irreversible disease with principle of treatment to prevent the progress of disease and related complications (Azhary H et al., 2010, Hicks CW et al., 2019). Since peripheral neuropathy is desperate group of diseases including several common and rare disease thus possess significant contribution in burden of disease and fatal disability in population (Martyn CN and Hughes RA, 1997). As per latest report Peripheral neuropathy was independently allied with mortality in the U.S. population, conclude that decreased sensation in the foot may be an unpredictable risk factor for death and the incident rate of mortality due to peripheral neuropathy is 34.3 % in the general population (Hicks CW et al., 2021). Consequently this evidence reveals the relation between AO (peripheral neuropathy) with enhanced mortality as terminal AO. Thus this AOP can open the route between MIE and AO that is important to scan the human health assessment specially the individual with potential pesticides exposure risk.

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Life Stage Applicability The key molecular target is the AChE enzyme, which appears to be available in all life stages of different species.

Life Stage

Evidence

Child

High

Adult

Moderate

Taxonomic Applicability

Term

Scientific Term

Evidence

Links

Homo sapiens

Homo sapiens

Moderate

Rattus norvegicus

Rattus norvegicus

High

Mus musculus

Mus musculus

High

Sex Applicability

Sex*

Evidence

Female

Moderate

Male

High

*Study with 44 children for scanning the OP pesticide exposure risk witnessed differences for sex of the child, with male levels higher than female levels (Loewenherz C et al., 1997).

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. 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.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

    Rationale for essentiality calls:

  • MIE: Inhibition, AChE: AChE hydrolyses acetylcholine into acetic acid and choline, thus terminates the action of the neurotransmitter acetylcholine.  This hydrolysis is inhibited by OP pesticides as OP interfere with the breakdown of acetylcholine by binding to the AChE, which resulted in accumulation of acetylcholine in the nerve synapses and triggered interrupted neurotransmission (Thapa S et al., 2017). Previous studies with vertebrate and invertebrate validate the dependence of AChE activity to the dose of OP and increasing inhibition of AChE in dose dependent manner with OP as reported in fish, birds, nematodes, rodents and mollusk (https://aopwiki.org/events/12). Inhibition of acetylcholine binding at the serine site results in an accumulation of acetylcholine in synapses with muscarinic and nicotinic receptors which resulting in unregulated excitation at junctions (https://aopwiki.org/events/10).
  • Key Event 1: Activation, CYP2E1: CYP2E1 can define as a P450 monooxygenase that activates the substrates by the addition of oxygen and producing an electrophilic metabolite (https://aopwiki.org/aops/220; Smith, et al. 2016). CYP2E1 in its catalytic cycle produce reactive oxygen species and expressed in the different part of human brain including cortex, cerebellum, hippocampus, thalamus and stratum and produce reactive oxygen species in its catalytic cycle. CYP2E1 is linked with oxidative damage of the brain (Jin, M et al., 2013). Activation of CYP2E1 is ultimately associated with the increase production of ROS (aopwiki.org/relationships/1726). Maneb and Paraquate a neurodegenerative pesticide enhanced the expression of CYP2E1 in male wistar rat which causes oxidative stress (Ahmad I et al., 2014). Activity of CYP2E1 is increasing with drugs, anesthetic agents, pesticides and related disorder (García-Suástegui WA et al., 2017) and linked with AChE inhibition as reported in farm worker (Sharma RK et al., 2013).  The highest level of CYP2E1 is found in the mitochondria and the endoplasmic reticulum of rat’s brain cells. Expression of CYP2E1 was found in the amygdala and prefrontal cortex in human brain (aopwiki.org/events/1508).
  • Key Event 2: Increased, oxidative stress in brain: The association between activation of CYP2E1 and the formation of ROS, which eventually leads to oxidative stress are well documented (https://aopwiki.org/relationships/1726). Study by Haorah et al. (2008) showed that CYP2E1 indeed produces ROS. Oxidative stress leads to neuronal apoptosis and neuronal degeneration by activating ZNRF1 via epidermal growth factor receptor (EGFR)–mediated phosphorylation (Wakatsuki S et al., 2015). ROS is closely associated to neuronal death in several neurological disorders including Parkinson’s and Alzheimer’s disease (Guglielmotto M et al., 2009). Acute injury of the brain including brain trauma and cerebral ischemia (Chen SD et al., 2011) or psychiatric disorders like autism, attention deficit, depression and schizophrenia (Michel TM et al., 2012) are also linked with ROS. ROS may target several different substrates and organelle of the cell like DNA, RNA oxidation, or lipid peroxidation (Gandhi S et al., 2012). ROS induced DNA mutation, DNA-protein crosslinks, DNA strand break and transformed purine and pyridine bases is documented (Gandhi S et al., 2012).
  • Key Event 3:  Neurodegeneration: Neurodegeneration is the loss of neuron cells in the brain and spinal cord. The loss of neurons can be define in term of ataxia and dementia i.e. functional loss and sensory dysfunction respectively. Each parts of the brain have their own individual function, thus the neurodegeneration is dependent to individual neuronal loss (Uttara, B et al., 2009). Neurodegeneration is a key aspect of a number of diseases called   “neurodegenerative diseases". All of these conditions lead to progressive brain damage and neurodegeneration due to decrease of neuronal function. Neurodegeneration and oxidative stress are inherently related phenomena, since microglia and astrocytes are the main sources of reactive oxygen species in CNS degenerative disorders thus oxidative stress in brain caused neurodegeneration (KE5) (Mendonca HR et al., 2020, Wakatsuki S et al., 2015, Mishra V et al., 2015, Kim M et al., 2019). Hence oxidative stress in brain is the requirement for downstream key event Neurodegeneration.
  •  Key Event 4: Decreased, neuronal function in adult brain: The interaction of neurons is generally consists of a network of several axon terminals connected through synapses to dendrites on other neurons. Once neuron activated, resulted in firing of an electrochemical signal along the axon and it fires only if the total signal received is above firing threshold (aopwiki.org/events/618). In the brain, neurons create a network where the activity of one cell directly influences many others.  Neurotransmitters are released at synaptic transmission by presynaptic neuron which further activate the receptors of the postsynaptic neuron (aopwiki.org/events/618). Synaptic transmission relies on: the availability of the neurotransmitter and the binding of the postsynaptic receptor by the neurotransmitter. Once nerve impulse attains at the synapse, the neurotransmitters releases, which influence postsynaptic neuron. The postsynaptic neurons obtain inputs from both excitatory and inhibitory neurons. The excitatory and inhibitory stimuluses all together causing inhibition or "firing" and the inhibition of AChE resulted in decrease of neuronal function (Kolb and Whishaw, 2003). Previous study confirm the inhibition of AChE by OP pesticides paraoxon and chlorpyrifos and study further reported that environmental exposure of chlorpyrifos may leads to sensory peripheral neuropathy  in human (Amitai G et al., 1998).
  • Adverse Outcome: Sensory axonal peripheral neuropathy: The most common neurodegenerative syndrome affecting millions of patients worldwide is Peripheral neuropathy. Peripheral neuropathy affect the motor and autonomic systems are due to  axonal loss, consequently loss of neuronal function in adult brain leads to an important adverse outcome Sensory axonal peripheral neuropathy (DiAntonio et al., 2019, Valek L et al., 2019, Persson AK et al., 2016, Topp KS et al., 2000). Depending on the exposure level, some of the acute effects of OPs may leads to excessive secretions, cardiorespiratory depression and life threatening seizures. A number of long-term neurological and psychiatric consequences have been observed in survivors with acute OP exposure (Naughton SX et al., 2018). The symptoms may include sustained attention, motor impairments, psychotic episodes, depressed mood and cognitive flexibility (Steenland K et al., 1994; Pereira EF et al., 2014; Rosenstock et al., 1991; Dassanayake et al., 2007). Reversibility of neuropathy upon discontinuation of treatment is also reported (Brown, T et al., 1991). Peripheral neuropathies mostly affect sensory neurons in a length-dependent manner and therefore characterized by a stocking-and-glove distribution of the symptoms and numbness and paresthesia like   sensory symptoms (Forsyth, P.a., et al. 1997, aopwiki.org/events/1583).
  • Adverse Outcome Terminal: Increased, Mortality Increased mortality refers to an increase in the number of individuals dying in an experimental replicate group or in a population over a specific period of time (aopwiki.org/events/351). It has been estimated that there are 258,234 (plausible range 233,997 to 325,907) deaths from pesticide self-poisoning worldwide yearly, accounting for 30% (range 27% to 37%) of suicides globally (Gunnell D et al., 2007). Peripheral neuropathies are a disparate group of diseases their contribution to the burden of disease and disability is plausible, however there are limited epidemiological evidence that quantitatively connecting the previous AO to mortality rates with regard to the final adverse outcome (Taverner T et al., 2019, Martyn CN et al., 1997, Hughes RA et al., 1995). As per latest report Peripheral neuropathy was independently allied with mortality in the U.S. population, concluded that decreased sensation in the foot may be an unpredictable risk factor for death thus the incident rate of mortality due to peripheral neuropathy is 34.3 % in the general population (Hicks CW et al., 2021). Study in vertebrate and invertebrate showed that 70 to 80 % inhibition of AChE in brain leads to significant increase in mortality via accumulation of ACh (Russom CL et al., 2014).

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

"'Biological Plausibility"'

OP induced inhibition of AChE leads to accumulation of acetylcholine (ACh) at the cholinergic synaptic clefts, resulting in to long-term activation of the nicotinic and muscarinic ACh receptors (AChR) and overstimulation of cholinergic neurons with hyper excitation and seizures (Faria, M et al., 2015; Peña Llopis, S. & Pena, 2005). OP induced seizures can grow to status epilepticus causing severe damage of brain (Weissman, B. A. & Raveh, L et al., 2008). Inhibition of AChE is associated with wide range of adverse effect including fatality, hence it’s dependent to concentration and half-life of OP dose. Major adverse effects with accumulation of ACh in peripheral system includes glandular secretions, skeletal muscle twitching, smooth muscle contractions and flaccid paralysis, simultaneously centrally mediated impacts associated with learning, memory and behavioral impairments (https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf). Oxidative stress is the key mechanisms involved in OP induced neurotoxicity, which can caused by over-production of reactive oxygen species (ROS) in the electron transport system and metabolism of agents by cytochrome P450 (Farkhondeh T et al., 2020). Thus the oxidative stress is inducer of neuronal apoptosis and axonal degeneration. Since it activate the ZNRF1 by inducing epidermal growth factor receptor (EGFR)–mediated phosphorylation at the 103rd tyrosine residue thus the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration (Wakatsuki S et al., 2015). As per neuropathological outcomes and neuroimaging of patients suffering from neurodegeneration as well as complementary evidence from transgenic animal models of neurodegeneration, it has been recommended that neurodegeneration is related to neural network dysfunction (aopwiki.org/relationships/368; Palop et al., 2007b; Seeley WW et al., 2009). Neurodegeneration leads to impairment of retrograde axonal transport that prohibits the growth factor supply to long-range projection neurons, causing synapse loss and post-synaptic dendrite retraction that leads to decreases of the neuronal network (Seeley WW et al., 2009) (https://aopwiki.org/relationships/647). Defective axonal transport are the major cause for peripheral neuropathies as the length-dependent and distal neurologic deficits observed in patients with axonal loss, which are often linked to axonal transport defects ( https://aopwiki.org/relationships/1835 ; Rowinsky, E.K et al., 1995). Mutations linked to axonal transport are known cause of Charcot-Marie-Tooth disease (a peripheral neuropathy) (Zhao, C et al., 2001). Thus the function of axon survival and axon degeneration proteins play an important role in the mechanistic insight. Usually, the clinical presentation reflects an axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, collective with the features indicative of nerve hyper excitability includes paresthesia, dysesthesia, and pain.  Symptoms like proprioceptive and motor effects may be prolonged, severe disabling and adversely affect activities of daily living and quality of life (Bhutani M et al., 2010).

"'Concordance of dose-response relationships:"'

Impairments in axonal transport could be detected even at concentrations that did not inhibit AChE activity and they were not blocked by cholinergic receptor antagonists (Naughton SX et al., 2018). Both neuronal culture and animal studies have reported that OP- induced axonal transport deficits as a potential non-cholinesterase mechanism for the long-term deleterious neurological effects (Naughton SX et al., 2021). Physostigmine was establish to strongly inhibit the purified eel AChE with an IC50 of 0.02 μM but not impaired axonal transport (Naughton SX et al., 2021).

"'Temporal concordance among the key events and adverse effect:"'

Sufficient literature evident that around 25 -32% of the US veterans deployed in Persian Gulf War was reported with chronic health symptoms like headache, respiratory problems, musculoskeletal pain and a number of neurological and neuropsychiatric illness including cognitive defects (Naughton SX et al., 2018; Sullivan et al., 2018), inline  with exposure of OP based inhibitors of AChE (Winkenwerder, 2003). Depending to exposure level, the effect of OP exposure may include cardiorespiratory depression, life threatening seizures and long term neurological and psychiatric consequences in survival including motor impairment (Naughton SX et al., 2018; Pereira et al., 2014). As per previous report the animal models have been largely appreciated to reveal the effects of anti- AChE abuses and their connection to brain damage in humans. Harrison et al., (2004) establish that OP (Paraoxon) caused seizures in guinea pigs similar to those caused by the nerve gas soman in humans. Similarly, the anti-AChE strength of Paraoxon was similar in macaques and humans (Worek et al., 2011). Moreover, Rosenberg et al., (2017) showed that anti- AChE exposed macaques presented severe signs of toxicity such as fasciculations, miosis, salivation and convulsions including fatality in less than seven hours of application.

"'Consistency:"'

The cholinergic phase typically last within 48 hrs including medical emergency in intensive care unit (Senanayake N et al., 1987). OP induced inhibition of AChE caused accumulation of ACh at muscarinic sites and resulted in secretions, bronchoconstriction, blur vision and bradycardia. Accumulation of ACh at nicotinic sites triggered flaccid paralysis, insomnia, confusion, drowsiness convulsions, coma, and respiratory depression (PMCID: PMC6357250, EJIFCC. 1999). Peripheral neuropathy is the most common neurodegenerative disorder, caused by damaging to peripheral nerves and is an important cause of neuropathic pain including hyperalgesia, allodynia, and dysesthesias (DiAntonio et AL et al., 2019). Acute exposure of organophosphate induced delayed neuropathy is well reported which is characterized by distal degeneration of axons of CNS and PNS. Non excitability of the nerve with electromyographical signs of denervation has been noticed with progression of disease and the experimental date with human shows recovery in the young (Lotti M., 2005).  Transcutaneous intoxication with OP showed the nicotinic effect in young children (Pavlovic M., 2015). A study by Yonggang Li et al (2012) reported that Adult male Sprague Dawley rats treated with acute exposure of OP (diisopropylfluorophosphate) showed that almost all animals developed severe seizures and died within 30 minutes but with delayed neuronal injury model, animal survived and delayed neuronal injury was observed till 4-72 hrs (Li Y et al., 2011). Furthermore the role of oxidative stress in neuronal injury and oxidative stress-mediated protein damage in the brains of diisopropylfluorophosphate -intoxicated rats is also documented (Li Y et al., 2012).

"'Uncertainties, inconsistencies, and data gaps:"'

Cholinergic hyper stimulation which affect nervous system via AChE inhibition is very common mode of action of OP (Pope CN et al., 1999), simultaneously the mouse lacking AChE also showed hyper sensitive of OP via non AChE mechanisms of action (Duysen EG et al., 2001). Unfortunately, the very limited evidence are available for the measurement of AChE inhibition in peripheral neural tissues or neuro-effector junctions. Reductions in neural AChE activity may not always associated with obvious clinical signs because critical functions of those specific neurons may not be sufficiently evaluated to identify associated changes or tolerance developed. The time at which potential functional effects are evaluated may also contribute to an apparent lack of concordance between functional effects and cholinesterase inhibition. Thus it is difficult to determine, with accuracy or consistently, the degree of cholinesterase inhibition that will cause specific physiological or behavioral changes (https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf). The existing evidence mostly focused on the whole brain AChE activity, but not usually regional brain measurements, or time-course data, mainly with acute exposures. Thus this is a major limitation, and  also the distribution of cholinergic pathways, their concentration and molecular form of AChE in different brain regions is not uniform. Thus, whole brain measurements of AChE inhibition may tell little or no change in activity, while masking significant changes in specific brain regions linked with particular cholinergically-mediated functions can tell more (https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf).

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

OP is commonly used as insecticides because it inhibits the AChE of insects (Tomlin C et al., 1994) and the same characteristic mode of cholinergic toxicity has been reported in human (Taylor P et al., 1996). Previous study showed that OP is more effective inhibitor of AChE than neuropathy target esterage (NTE) which causing delayed polyneuropathy at higher dose (Lotti M et al., 1992; Moretto A et al., 1998), simultaneously patients with low level repeated exposure of OP developed sensory neuropathy (Kaplan JG et al., 1993; Moretto A et al., 1998).  Inhibition of AChE (MIE) is considered a vital event in the mechanism of cholinergic toxicity, the AChE-inhibiting OP causes a broad range of adverse effects including sensory, cognitive, and psychological effects (Reigart, R. and Roberts, 1999). Decreasing AChE level and increasing CYP2E1 (KE1) is reported in farm worker (Sharma RK et al., 2013). CYP2E1-induced oxidative stress (KE2) (Schattenberg JM et al., 2014) causes neurodegeneration (KE3) (Gandhi S et al., 2012) that leads to dysfunction of neuronal function (Palop et al., 2006). Subsequently, the loss of neuronal network function (KE4) leads to an adverse outcome of sensory axonal peripheral neuropathy (AO) and the symptoms may include lack of coordination, impairment of motor nerve, dizziness, burning sensation, numbness etc. (DiAntonio et al., 2019). This desperate group of diseases due to peripheral neuropathy causes fatal disability and mortality (AO) in population (Martyn CN and Hughes RA, 1997). As per latest report Peripheral neuropathy was self-sufficiently allied with mortality in the U.S. population, concluded that decreased sensation in the foot may be an unpredictable risk factor for death and the rate of mortality associated with peripheral neuropathy is 34.3 % in the general population (Hicks CW et al., 2021). Thus clinical symptoms with behavioral or physiological effects is the most direct evidence of the potential adverse consequences of human exposure to anticholinesterase pesticides like OP (https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf).

Considerations for Potential Applications of the AOP (optional)

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.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 or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

The potential application of this AOP includes risk assessment in predictive modeling of OP pesticide toxicity via AChE dependent pathways. Thus this AOP is an attempt to create the mechanism of organophosphorus (OP) pesticides induced sensory peripheral neuropathy and mortality as an adverse outcome. Supplementary evidence may help this AOP to fully elucidate the mechanistic approach and the neurotoxic potential of OP pesticide. 

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

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