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Relationship: 3242

Title

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

Disruption in action potential generation leads to neurotrasmission in development

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Disruption in action potential generation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

neurotrasmission in development

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			Iris Mangas (send email)	Under development: Not open for comment. Do not cite	WPHA/WNT Endorsed

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	High	NCBI
Invertebrates	Invertebrates	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

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

Term	Evidence
During brain development	High

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

Stimulation of neurons by neurotransmitters or sensory input activates the opening of different ion channels and permits current flow across the membrane. As ion currents move across the membrane, the membrane potential is changed. Depending on the ion channel, this change in membrane potential can be either excitatory to depolarize, or inhibitory to hyperpolarize the cell. Neurons integrate the barrage of both excitatory and inhibitory signals they receive. When this integration leads to a net sum depolarization, voltage gated sodium channels open and an action potential is triggered. The action potential through a series of successive openings of additional VGSCs, allows the transmission of the electrical impulses to move along the length of the axon to the nerve terminal. The synapse describes the location where the presynaptic nerve terminal meets the postsynaptic cell. The postsynaptic cell can be another neuron, muscle or gland. At the synapse the electrical signal at the presynaptic terminal is transduced to a chemical signal to span the spatial gap and communicate information from one cell to the next. On arrival of the depolarizing action potential (AP) at the presynaptic terminal, voltage gated calcium channels are activated and vesicles containing chemical neurotransmitters are released into the synaptic cleft – the space between the neurons. The frequency and duration of the action potentials determine how many neurotransmitter vesicles are released. The neurotransmitters act on the postsynaptic cell by interaction with neurotransmitter-specific receptors that depolarize or hyperpolarize the membrane of the receiving cell. This transduction of electrical to chemical and back again to electrical signaling across neurons is the basis of neurotransmission. This sequence of events is portrayed in Figure 4.

Figure 4. Sequence of Events from action potential generation to synaptic transmission. Self produced by EFSA WG.

It is well established that neurotransmission can be disrupted through several different mechanisms, including disruptions of ion channels, release machinery, post-synaptic response and disruption of neurotransmitter re-uptake or degradation (Atchison, 1988; Vester and Caudle, 2016). It is also well accepted that neurotransmission occurs in the mature and developing brain and can be similarly disrupted by the same mechanisms.

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

This KER was originally created as part of an evidence-based AOP informed IATA for deltamethrin for developmental neurotoxicity hazard characterization. The IATA case study was developed to support human health risk assessment of deltamethrin pesticide active substance and as a proof-of-concept on the applicability of the data provided in the Developmental Neurotoxicity In vitro Battery to apply mechanistic understanding of toxicity pathways for regulatory decision making (DNT IVB OECD., 2023). Using systematic searches and expert knowledge the initial KER was updated by an EFSA Working Group.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The evidence supporting this KER a well-established tenant of neurobiology (Foundations of Neuroscience by Casey Henley; https://openbooks.lib.msu.edu/neuroscience/chapter/drug-and-toxin-effects/ ; more detailed in Cellular and Molecular Neurophysiology There is abundant evidence that disruption of action potentials leads to altered neurotransmission by drugs and environmental agents, including VGSC blockers (Meng et al., 2016; Shafer et al., 2008; Hossain et al., 2008; for review, see Soderlund et al., 2002). There are also numerous examples of peer-reviewed studies demonstrating alterations in action potential activity leading to altered neurotransmission during development (Čechová and Šlamberová, 2021; Latchney et al., 2021).

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

The process of disruption of action potentials leading to changes in neurotransmission represents a very well-established principle of neurobiology that is widely described in the published literature and basic neuroscience textbooks. This process is the basis of routine neurophysiological studies investigating the development, function and disturbance of neuronal networks. It is not only biologically plausible that alterations in action potential shape, duration and patterns could lead to altered neurotransmission, but also that this occurs in adult and developing nervous systems.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The empirical evidence of KER3 is strong. There is abundant empirical evidence in the published literature supporting the basic biology underlying this KER. A variety of insults can alter action potential generation and impair synaptic transmission (e.g. Seabrook et al., 1989; Joy et al., 1990; Hong et al., 1986; Gilbert et al., 1989. Eells and Dubocovich, 1988; Hossain et al., 2008; Shafer et al., 2008). These data have been generated in a wide variety of different models from insects to mammalian models, including embryonic neurons and adult neuronal preparations. For a more detailed explanation, and examples of chemicals and mechanisms leading to altered neurotransmission, the readers are referred to https://openbooks.lib.msu.edu/neuroscience/chapter/drug-and-toxin-effects/

Dose and temporal concordance

Because of the challenges of measuring this KER, dose concordance is not well established. However, there is no indication of discontinuity between dose levels that alter action potential activity and synaptic transmission. In addition, dose-concordance is observed at both earlier and later KERs, indicating that it likely is maintained for this KER.

Action potential stimulation of neurotransmission occurs in a very rapid millisecond time scale. There is strong evidence for temporal concordance between alterations in action potential activity and changes in neurotransmission. The sequence of events from presynaptic action potential generation and postsynaptic response as depicted above in Figure 4, clearly demonstrates the time concordance between these two KEs.

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 biological processes that regulate the generation and propagation of action potential and neuronal transmission are very well known and changes in this KER are well documented for chemical insults. This KER is supported by both in vitro and in vivo data.

The literature directly demonstrating the relationship between action potential generation and neurotransmission during development is less robust. However, given the fundamental properties of neurotransmission that exist in both mature and developing nervous system and the extensive literature of chemical stressors derived from a wide variety of preparations of varying ages, this uncertainty is small.

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

The description of the KER provided here is a generic description, but the basic biology described is maintained across species, developmental stage, brain regions and sex. There are a number of factors that can modulate this relationship, including, but not limited to, temperature; region/pathway/neuronal subtype, type of synaptic structure, age of the animal and preceding activity at that synapse.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Currently, quantitative models for this KER were not found in the peer-reviewed literature.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

The overall relationship between action potential firing leading to release of neurotransmitter release and a response in the post-synaptic cell is well established in neurobiology. One simple example is the firing of a motor neuron, leading to release of acetylcholine, followed by muscle contraction. The sequence of events from presynaptic action potential generation and postsynaptic response as depicted above in Figure 1, clearly demonstrates the response-response concordance between these two KEs. The precise form of the response-response relationships in terms of the either excitation or inhibition and strength of that effect is dependent on the neuron type and its location and function within the nervous system.

Time-scale

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

The KER is active within milli-seconds and the upstream event occurs before the downstream events (see Figure 4 above).

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

There are currently no known Feedforward/Feedback loops influencing this KER.

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

Male, females, all life stages, starting from foetal stage (Smith and Walsh 2020).

References

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

Atchison WD. Effects of neurotoxicants on synaptic transmission: lessons learned from electrophysiological studies. Neurotoxicol Teratol. 1988 Sep-Oct;10(5):393-416. doi: 10.1016/0892-0362(88)90001-3.PMID: 2854607

Čechová B, Šlamberová R. Methamphetamine, neurotransmitters and neurodevelopment. Physiol Res. 2021 Dec 31;70(S3):S301-S315. doi: 10.33549/physiolres.934821. PMID: 35099249; PMCID: PMC8884400.

Cellular and Molecular Neurophysiology book, 4th edition. 2015. Soderlund et al., 2002

Eells JT, Dubocovich ML. Pyrethroid insecticides evoke neurotransmitter release from rabbit striatal slices. J Pharmacol Exp Ther. 1988 Aug;246(2):514-21. PMID: 3404444.

Foundations of Neuroscience by Casey Henley; https://openbooks.lib.msu.edu/neuroscience/chapter/drug-and-toxin-effects/

Gilbert ME, Mack CM, Crofton KM. Pyrethroids and enhanced inhibition in the hippocampus of the rat. Brain Res. 1989 Jan 16;477(1-2):314-21. doi: 10.1016/0006-8993(89)91420-0. PMID: 2702491.

Hong JS, Herr DW, Hudson PM, Tilson HA. Neurochemical effects of DDT in rat brain in vivo. Arch Toxicol Suppl. 1986;9:14-26. doi: 10.1007/978-3-642-71248-7_2. PMID: 2434059.

Hossain MM, Suzuki T, Unno T, Komori S, Kobayashi H. Differential presynaptic actions of pyrethroid insecticides on glutamatergic and GABAergic neurons in the hippocampus. Toxicology. 2008 Jan 14;243(1-2):155-63. doi: 10.1016/j.tox.2007.10.003. Epub 2007 Oct 10. PMID: 18023957.

Hossain, M.M.; Suzuki, T.; Unno, T.; Komori, S.; Kobayashi, H. Differential presynaptic actions of pyrethroid insecticides on glutamatergic and gabaergic neurons in the hippocampus. Toxicology 2008, 243, 155–163.

Joy RM, Lister T, Ray DE, Seville MP. Characteristics of the prolonged inhibition produced by a range of pyrethroids in the rat hippocampus. Toxicol Appl Pharmacol. 1990 May;103(3):528-38. doi: 10.1016/0041-008x(90)90325-o. PMID: 2339424.

Latchney SE, Majewska AK. Persistent organic pollutants at the synapse: Shared phenotypes and converging mechanisms of developmental neurotoxicity. Dev Neurobiol. 2021 Jul;81(5):623-652. doi: 10.1002/dneu.22825. Epub 2021 May 2. PMID: 33851516; PMCID: PMC8364477.

Meng L, Meyer PF, Leary ML, Mohammed YF, Ferber SD, Lin JW. Neurosci Lett. 2016. Effects of Deltamethrin on crayfish motor axon activity and neuromuscular transmission. Mar 23;617:32-8. doi: 10.1016/j.neulet.2016.01.061. Epub 2016 Feb 6.PMID: 26861201

Seabrook GR, Duce IR, Irving SN. Spontaneous and evoked quantal neurotransmitter release at the neuromuscular junction of the larval housefly, Musca domestica. Pflugers Arch. 1989 May;414(1):44-51. doi: 10.1007/BF00585625. PMID: 2566966.

Shafer TJ, Rijal SO, Gross GW. Complete inhibition of spontaneous activity in neuronal networks in vitro by deltamethrin and permethrin. Neurotoxicology. 2008 Mar;29(2):203-12. doi: 10.1016/j.neuro.2008.01.002. Epub 2008 Jan 19. PMID: 18304643.

Shafer TJ, Rijal SO, Gross GW. Neurotoxicology. 2008. Complete inhibition of spontaneous activity in neuronal networks in vitro by deltamethrin and permethrin. Mar;29(2):203-12. doi: 10.1016/j.neuro.2008.01.002. Epub 2008 Jan 19.PMID: 18304643

Smith RS, Walsh CA. Ion Channel Functions in Early Brain Development. Trends Neurosci. 2020 Feb;43(2):103-114. doi: 10.1016/j.tins.2019.12.004. Epub 2020 Jan 17. PMID: 31959360; PMCID: PMC7092371.

Soderlund., 2002. Cellular and Molecular Neurophysiology book, 4th edition. 2015.

Vester A, Caudle MW. The Synapse as a Central Target for Neurodevelopmental Susceptibility to Pesticides Toxics. 2016 Aug 26;4(3):18.