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Relationship: 2605


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Binding to VGSC leads to Altered kinetics of sodium channel

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Binding to voltage gate sodium channels during development leads to cognitive impairment adjacent Arthur Author (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates NCBI
Invertebrates Invertebrates NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

VGSCs are critical in generation and conduction of electrical signals in multiple excitable tissues. Natural and synthetic toxins are known to interact with VGSC by altering the gate kinetic of the channel by slowing the activation and deactivation rate of the VGSC and shift to a more hyperpolarised potentials the membrane potential at which the VGSC activate.

The detailed mechanism of voltage sensing and voltage-dependent activation of the voltage sensor of sodium channels through a series of resting and activated states is known at the atomic level.

There is evidence supporting that the binding of pyrethroids to VGSC (Trainer et al., 1997; O’Reilly et al., 2006) induces disruption of the sodium channel gate kinetics (Meyer et al., 2008; Soderlund et al., 2002).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

It is well known that ion channels are integral membrane proteins that are critical for the execution of action potential and therefore for neuronal function and activation. Action potentials are the electrical impulses that travel along the axons of neurons and result from the movement of Na+ and potassium (K+) ions across the membrane. Binding of excitatory neurotransmitters to their receptors opens cation-permeable ion channels causing the membrane to depolarise or become more positive. This depolarisation activates (opens) VGSCs allowing Na+ to enter the neuron further depolarising the membrane. This increase in membrane permeability to Na+ is responsible for the rising phase of the action potential, eventually causing the membrane polarity to reverse (overshoot phase). The falling phase of the action potential is caused by the inactivation of the VGSCs and the opening of voltage-gated potassium channels allowing K+ to leave the cell. The efflux of K+ ions results in hyperpolarisation (undershoot phase) of the membrane. Ultimately the voltage-gated K+ channels close and the membrane potential returns to its resting state. Type I and II pyrethroids cause stimulus dependent membrane depolarisation and conduction block.

It is therefore biologically plausible that binding of a chemical substance to a VGSC leads sodium channels to open at more hyperpolarised potentials and kept open longer (disruption of channel kinetic), allowing more sodium ions to cross and depolarise the neuronal membrane (Shafer et al., 2005)

Expression of VGSC are spatially and temporally dependent; however, it is biologically plausible that also in developing brain pyrethroids would bind to VGSC isoforms and disrupt the channel gating kinetic (Shafer et al., 2005; Soderlund et al., 2002).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The fact that binding of pyrethroids to VGSCs results in altered sodium channel gate kinetics is well accepted and supported by some evidence. However, some minor uncertainties can be detected as reported below.

Uncertainties in the overall knowledge remain as the sodium channels’ ontogeny is a complex process. Since brain development in both humans and rodents extends from early gestation through lactation it is not possible to state with certainty which isoform of the sodium channels’ α subunits is preferentially affected by deltamethrin.

For in vitro methodologies, there is still a lack of knowledge on stability of deltamethrin in the medium and the partitioning of this compound with plastic, lipid and protein. Indeed, the high lipophilicity of pyrethroids is still a limitation for the sensitivity of the assays and for the identification of a single binding site on any given sodium channel and its mediated action this may affect the sensitivity of the assays (Ruigt et al., 1987). Also, the metabolic competence of the test systems used in various assays is unknown.

Moreover, the study from Meyer et al. (2008) is an indirect measurement of the interaction between the prototype stressor, deltamethrin and VGSCs. Also, the exact temperature at which the patch clamp recording was made is uncertain (in the publication it is stated at room temperature) and it is well documented that pyrethroids effects on VGSCs are negatively temperature dependent (reviewed in Narahashi, 2000). Finally, Meyer and colleagues used hippocampal cell culture from rats PND 2–4 which were not characterised and did not contain microglia or oligodendrocyte precursors cells, therefore there are still uncertainties in the knowledge of the interaction between pyrethroids and microglia or oligodendrocytes precursor VGSC.

Some inconsistencies can be observed in experimental studies. They are associated with the electrophysiological technique used to study ionic currents in individual isolated living cells, tissue sections or patches of cells. The solution used in the bath can be similar to cytoplasm composition or completely different, they can be changed by adding ions or drugs to study the ion channels under different conditions. In the study of Meyer et al. (2008) different effects, i.e. burst duration, were observed for permethrin (type I) and deltamethrin (type II) and it was not clear if this represents a true difference in the mode of action between type I and type II pyrethroids or simply a difference between the two compounds. This could only be determined by the examination of additional chemicals.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


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

Chahine M (ed.), 2018. Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Vol. 246. Springer.

Meisler MH, Kearney J, Ottman R and Escayg A, 2001. Identification of epilepsy genes in human and mouse. Annual Review of Genetics, 35(1), 567–588.

Meyer DA and Shafer TJ, 2006. Permethrin, but not deltamethrin, increases spontaneous glutamate release from hippocampal neurons in culture. Neurotoxicology, 27, 594–603.

Meyer DA, Carter JM, Johnstone AF and Shafer TJ, 2008. Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture. Neurotoxicology, 29(2), 213–225. doi: 10.1016/j.neuro.2007.11.005.

Narahashi T, 2000. Neuroreceptors and ion channels as the basis for drug action: past, present, and future. J Pharmacol Exp Ther, 294, 1–26.

O'Reilly AO, Khambay BP, Williamson MS, Field LM, Wallace BA and Davies TG, 2006. Modelling insecticide-binding sites in the voltage-gated sodium channel. Biochemical Journal, 396(2), 255–263.

Planells-Cases R, Caprini M, Zhang J, Rockenstein EM, Rivera RR, Murre C, … and Montal M, 2000. Neuronal death and perinatal lethality in voltage-gated sodium channel αII-deficient mice. Biophysical Journal, 78(6), 2878–2891.

Shafer TJ, Meyer DA and Crofton KM, 2005. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environmental Health Perspectives, 113(2), 123–136.

Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, … and Weiner ML, 2002. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology, 171(1), 3–59.–483X(01)00569–8

Trainer VL, McPhee JC, Boutelet-Bochan H, Baker C, Scheuer T, Babin D, and Catterall WA, 1997. High affinity binding of pyrethroids to the α subunit of brain sodium channels. Molecular Pharmacology, 51(4), 651–657. doi:

Wakeling EN, Neal AP and Atchison WD, 2012. Pyrethroids and their effects on ion channels. Pesticides—Advances in Chemical and Botanical Pesticides. Rijeka, Croatia: InTech, pp. 39–66.