Aop: 442

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

Inhibition of voltage gate sodium channels leading to impairment in learning and memory during development

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Inhibition of voltage gate during development is leading to cognitive disorders

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
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Authors

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

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
Andrea Terron   (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
  • Andrea Terron
  • Martina Panzarea
  • Nikolaos Tagaras
  • Timothy Shafer

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
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.91 Included in OECD Work Plan
This AOP was last modified on October 21, 2022 11:39

Revision dates for related pages

Page Revision Date/Time
Inhibit, voltage-gated sodium channel March 21, 2022 08:41
Disruption of sodium channel gating kinetics September 13, 2022 20:44
Disruption, action potential March 31, 2022 06:46
Altered neurotransmission in development May 18, 2022 11:39
Hippocampal anatomy, Altered May 20, 2022 05:45
Altered function of the brain July 06, 2022 10:34
Impairment, Learning and memory July 12, 2022 09:02
Inhibit, voltage-gated sodium channel leads to Altered kinetics of sodium channel March 31, 2022 06:51
Altered kinetics of sodium channel leads to Disruption in action potential generation March 31, 2022 06:54
Pyrethrins and Pyrethroids November 29, 2016 18:42

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

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 1353 Inhibit, voltage-gated sodium channel Inhibit, voltage-gated sodium channel
KE 1977 Disruption of sodium channel gating kinetics Altered kinetics of sodium channel
KE 1983 Disruption, action potential Disruption in action potential generation
KE 2005 Altered neurotransmission in development neurotrasmission in development
KE 757 Hippocampal anatomy, Altered Hippocampal anatomy, Altered
KE 2022 Altered function of the brain brain function
AO 341 Impairment, Learning and memory Impairment, Learning and memory

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

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

Essentiality of MIE and KE1: 

Evidence from mutation and knockout models demonstrates that perturbation of VGSC function during development impairs nervous system structure and function. Knockout and mutant mouse models of sodium channel α subunits demonstrate varying degrees of adverse outcomes associated with loss or alteration of specific channel subunits. When mRNA for the Nav 1.2 subunit was reduced by approximately 85%, mice exhibited reduced levels of electrical excitability, had high levels of apoptotic neurons in the brainstem and cortex, and died from severe hypoxia within 1–2 days of birth (Planells-Cases et al., 2000). 

In insects, only VGSCα are codified. Pyrethroid resistant, or knockdown-resistant houseflies are well known. As this mutation does not alter expression or localisation of the VGSC, it was suspected to alter the affinity of the channel for pyrethroids. Expression of this mutant channel in Xenopus laevis oocytes resulted in VGSCs that were 10-fold less sensitive to cismethirin as assessed using voltage-clamp experiments (Wakeling et al., 2012). 

In humans, some mutations have been identified in genes coding for VGSC subunits that result in neuronal hyperexcitability due to subtle changes in channel gating and inactivation (Meisler et al., 2001), these mutations have been linked to various forms of epilepsy (Shafer et al., 2005; Chahine 2018). 

Pyrethroids, like these mutations, alter VGSC activation, inactivation and neuronal excitability. However, the mechanisms and magnitude of mutational versus pyrethroid effects are different as well as the duration of the effect. 

Essentiality of KE1 and KE2: 

The sodium channel modulator veratridine (VTD) produce the same effect as deltamethrin. In patch recording, this compound rapidly reduced the number of sEPSC without affecting the number of individual burst, but at higher concentration (1 mM) completely removed all sEPSC activity without affecting mEPSC frequency, similar to treatment to TTX (Meyer et al., 2008). Both events – sE(I)PSCs and mE(I)PSCs – are similar in the fact that they occur without any artificial stimulation. The difference between sE(I)PSCs and mE(I)PSCs is coming from the fact that for the sE(I)PSCs there is a chance of action potential-driven events due to intrinsic properties of presynaptic cell and/or network activity. All the mE(I)PSCs, in turn, are recorded in the presence of tetrodotoxin (TTX) which blocks action potential formation and its propagation, therefore mE(I)PSCs are more ‘spontaneous’ events than sE(I)PSCs and can be further used for the quantification of readily releasable pool size. So, it is useful to take both sE(I)PSCs and mE(I)PSCs from the same cell. First, one can record the sE(I)PSCs and then, by adding TTX into the bath solution the mE(I)PSCs. Having both sE(I)PSCs and mE(I)PSCs can help to understand where the changes in synaptic transmission are coming from, i.e. whether it is from the presynaptic side, or postsynaptic or both (Mayer et al., 2008). Titration with tetrodotoxin (TTX) produces a concentration-dependent reduction in the deltamethrin dependent calcium influx, indicating that the alteration in firing rate is consequent to the disruption in the VGSC (Cao et al., 2011).

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