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Relationship: 2605

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Inhibit, voltage-gated sodium channel leads to Altered kinetic of sodium channel

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of voltage gate sodium channels leading to impairment in learning and memory during development adjacent Andrea Terron (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates NCBI
Invertebrates Invertebrates NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Male
Female

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  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.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). 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. https://doi.org/10.1289/ehp.7254.

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. https://doi.org/10.1016/S0300–483X(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: https://doi.org/10.1124/mol.51.4.651

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. http://dx.doi.org/10.5772/50330