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Relationship: 2942

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

Activation of MEK, ERK1/2 leads to Increase, intracellular calcium

Upstream event

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

Activation of MEK, ERK1/2

Downstream event

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

Increase, intracellular calcium

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
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release	adjacent	Moderate		Travis Karschnik (send email)	Under development: Not open for comment. Do not cite
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis	adjacent	Moderate		Travis Karschnik (send email)	Under development: Not open for comment. Do not cite

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
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI
Mus musculus	Mus musculus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Female	Moderate
Mixed	Moderate

Life Stage Applicability

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

Term	Evidence
Birth to < 1 month	Moderate
1 to < 3 months	Moderate
Pregnancy	Moderate

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

Astrocytes are networked together by a series of gap junctions permitting to propagate Ca²⁺ waves through the linked network (Lobsiger and Cleveland 2007), and Ca2+-mediated intercellular communication is a mechanism by which astrocytes communicate with each other and modulate the activity of adjacent cells (Verderio et al., 2001). Metal mixture (MM) induced alteration in astrocyte morphology may influence [Ca²⁺]i (Barres et al., 1989); in contrast, an increase in [Ca²⁺]_i may also play a key role in altering astrocyte cytoskeleton, affecting the glia-neuron interaction (Shelton et al., 2000).

Inhibition of GFAP immunoreactivity by MM in developing brain appears to be caused by astrocyte apoptosis. In primary cultures of astrocytes, our data show that MM synergistically induced apoptosis (Rai and others 2010). This was manifested by the activation of MEK/ERK, followed by the activation of JNK pathways, which then enhanced intracellular Ca2+ levels and subsequently ROS generation.

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 identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

This evidence was assembled from a literature search relying on standard search engines such as PubMed, Web of Science, Google Scholar, Environmental Index, Scopus, Toxline, and Toxnet and the search strategy included terms related to metal mixtures, individual metals (e.g., arsenic, lead, manganese, and cadmium), neurodevelopmental health outcomes, and associated Medical Subject Headings (MeSH) terms.

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

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

We treated the astrocytes with a metal-mixture (MM) of arsenic, cadmium, and lead and observed that the MM triggered [Ca²⁺]_i release (Rai and others 2010). The [Ca2+]_i release reached its peak after 30 min of MM treatment. Similarly, MM triggered ROS generation, and the ROS generation reached its peak after 1 h of MM treatment. To investigate whether the [Ca²⁺]_i release was ROS, ERK1/2, or JNK1/2 –dependent, we incubated the MM-treated astrocytes with an antioxidant (a-tocopherol, 200 lg/ml), PD98059 (10lM), or SP600125 (10lM). a-Tocopherol itself was nontoxic. We observed that PD98059 (10lM) or SP600125 (10lM) suppressed [Ca²⁺]_i release, but a-tocopherol (200 lg/ml) did not. This suggested that [Ca²⁺]_i release in MM-treated astrocytes was ERK1/2 and JNK1/2 dependent (Rai and others 2010).

Yael and Breitbart (2015) demonstrated for the first time that mouse sperm ERK1/2 is activated upon ZP addition, and that ERK1/2 mediates the elevation of intracellular Ca2+ in the sperm cell prior to the occurrence of the acrosome reaction. The fact that the acrosome reaction, induced by the Ca²⁺-ionophore A23187, was not inhibited by U0126 suggests that ERK1/2 mediates the acrosome reaction by activating Ca2+ transport into the cell. Direct determination of intracellular [Ca²⁺] revealed that Ca2+ influx induced by EGF or ZP was completely blocked by U0126. Thus, it has been established that the increase in ERK1/2 phosphorylation/activation in response to ZP or by activation of the EGF receptor (EGFR) by EGF, is a key event for intracellular Ca²⁺ elevation and the subsequent occurrence of the acrosome reaction (Jaldety et al., 2015).

To examine the relationship between Ca²⁺ and Erk1/2 signaling, Levin and Borodinsky (2022) inhibited Mek1/2 with PD0325901 and found that this prevents the injury-induced increase in Ca²⁺ activity in cells lateral to the axial musculature across the entire 800 µm-wide region measured. This suggests that injury-induced Erk1/2 activation recruits Ca²⁺ activity to promote regeneration of the larval tail. Consistent with recruitment of Ca²⁺ activity across a wide region of tail, activated Erk1/2 is also present in at least the posterior 800 µm of stump (Levin et al., 2022). However, unlike Ca²⁺ activity, Erk1/2 signaling at 20 mpa is activated in a gradient. This could mean that even the lowest level of Erk1/2 signal measured in 800 µm of amputated tail is sufficient to induce the Ca²⁺ response, or that a signal is propagated anteriorly from the cells adjacent to the amputation where injury induces high Erk1/2 activation (Levin et al., 2022).

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

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

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

Response-response Relationship

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

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

Exposures were conducted for 2 min, 5 min, 10 min, 30 min, 1 h, 2 h, and 24 h. The [Ca2+]_i release reached its peak after 30 min of MM treatment (Rai and others 2010).

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

The activity of many protein kinases is modulated by Ca2+ and/or Ca2+/calmodulin either directly (PKC, CaM kinase II) or indirectly (PKA via stimulation of adenylyl cyclase and phosphodiesterase by Ca2+/calmodulin) (Kern et al., 1995). Therefore, the effects of Ca2+ and protein kinases on cytoskeletal proteins and neurite initiation are likely to be mediated, at least in part, by changes in protein phosphorylation (Kern et al., 1995).

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

References

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

Asit Rai and others, Characterization of Developmental Neurotoxicity of As, Cd, and Pb Mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions, Toxicological Sciences, Volume 118, Issue 2, December 2010, Pages 586–601, https://doi.org/10.1093/toxsci/kfq266

Barres, B. A., L. L. Chun, and Corey. "Calcium current in cortical astrocytes: induction by cAMP and neurotransmitters and permissive effect of serum factors." Journal of Neuroscience 9.9 (1989): 3169-3175.

Jaldety, Yael, and Haim Breitbart. "ERK1/2 mediates sperm acrosome reaction through elevation of intracellular calcium concentration." Zygote 23.5 (2015): 652-661.

Kern, Marcey, and Gerald Audesirk. "Inorganic lead may inhibit neurite development in cultured rat hippocampal neurons through hyperphosphorylation." Toxicology and applied pharmacology 134.1 (1995): 111-123.

Levin, Jacqueline B., and Laura N. Borodinsky. "Injury-induced Erk1/2 signaling tissue-specifically interacts with Ca2+ activity and is necessary for regeneration of spinal cord and skeletal muscle." Cell calcium 102 (2022): 102540.

Lobsiger, C. S., and Cleveland, D. W. (2007). Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat. Neuro-sci. 10, 1355–1360.

Shelton, Marilee K., and Ken D. McCarthy. "Hippocampal astrocytes exhibit Ca2+‐elevating muscarinic cholinergic and histaminergic receptors in situ." Journal of neurochemistry 74.2 (2000): 555-563.

Verderio, Claudia, and Michela Matteoli. "ATP mediates calcium signaling between astrocytes and microglial cells: modulation by IFN-γ." The Journal of Immunology 166.10 (2001): 6383-6391.