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Relationship: 3140

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

Increase, intracellular calcium leads to Increase, Mitochondrial dysfunction

Upstream event

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

Increase, intracellular calcium

Downstream event

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

Increase, Mitochondrial dysfunction

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 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 Do not cite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
Homo sapiens	Homo sapiens	Moderate	NCBI
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

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

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

One of the better characterized apoptotic cascade pathways has mitochondrial dysfunction as its initiator. Mitochondrial dysfunction initiated by the opening of the mitochondrial transition pore leads to mitochondrial depolarization, release of cytochrome C, activation of a variety of caspases and cleavage of downstream death effector proteins, and ultimately results in apoptotic cell death. While a variety of stimuli can trigger opening of the mitochondrial transition pore and cause apoptosis, a sustained intracellular increase in Ca2+ is one of the better-known triggers (Mattson 2000).

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

Intracellular calcium overload may be related to the mitochondrial dysfunction (Yuan et al., 2013). Mitochondria are vital organelles for cellular metabolism and bioenergetics, but they are also key regulators of cell death (Fantin and Leder 2006). Since mitochondria are the major site of ATP production and mitochondrial ΔΨ is the driving force of ATP synthesis, a breakdown in the mitochondrial ΔΨ could lead to a fall in the ATP levels (Chakraborti et al., 1999). The resulting reduction in cellular ATP levels can disrupt ionic homeostasis which can cause an increase in [Ca²⁺]_i and subsequent cellular apoptosis/necrosis (Grammatopoulos et al., 2004). Notably, in many (if not all) paradigms of apoptosis, ΔΨm represents the point of no return in the cascade of events that ultimately leads to cell death (Kroemer et al., 2007).

The effector phase of apoptosis involves increased mitochondrial Ca²⁺ and oxyradical levels, the formation of permeability transition pores (PTP) in the mitochondrial membrane, and release of cytochrome c into the cytosol (Mattson 2000).

The increase of free radicals and Ca²⁺ levels associated to Cd exposure may induce mitochondrial disruption (Fern et al., 1996).

Intracellular calcium homeostasis is very important in maintaining the normal function of the cell, in that variations in the concentration of calcium in cells can determine cell survival or death. For example, a high [Ca²⁺]i can cause disruption of mitochondrial Ca²+ equilibrium, which results in reactive oxygen species (ROS) formation due to the stimulation of electron flux along the electron transport chain (ETC) (Chacon and Acosta 1991). Under oxidative stress, mitochondrial Ca²⁺ accumulation can switch from a physiologically beneficial process to a cell death signal (Ermak and Davies 2002).

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

Yuan, Yan, et al. 2013 found that BAPTA-AM significantly blocked disruption of Δψm in cells exposed to Cd (5, 10 and 20 µM) for 12 h. Furthermore, cleavage of caspase-9, caspase-3 and PARP were significantly attenuated by BAPTA-AM, which was in agreement with thier observation that BAPTA-AM profoundly prevented Cd-induced apoptosis and cell death of cerebral cortical neurons. However, increased Bax and decreased Bcl-2 levels were not blocked by BAPTA-AM . These data suggest that calcium-mediated mitochondria-caspase b is involved in Cd-induced apoptosis. Moreover, thier results collectively suggested that Cd-induced apoptosis of cerebral cortical neurons occurs through a calcium-mitochondria signaling pathway (Yuan et al., 2013).

Yuan, Yan, et al. 2013 also noted that reduced expression of Bcl-2 increases the expression of Bax, which results in an overload of Ca²⁺ in the mitochondria and promotes the opening of permeability transition pores causing mitochondria to swell, with their outer membranes collapsing and exiting into the cytoplasm, which would consequently trigger apoptosis.

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

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

References

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

Chacon E, Acosta D (1991) Mitochondrial regulation of superoxide by Ca2+: an alternate mechanism for the cardiotoxicity of doxorubicin. Toxicol Appl Pharmacol 107: 117–128.

Chakraborti T, Das S, Mondal M, Roychoudhury S, Chakraborti S (1999) Oxidant, mitochondria and calcium: an overview. Cell Signal 11: 77–85.

Ermak G, Davies KJ (2002) Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol 38: 713–721.

Fantin VR, Leder P (2006) Mitochondriotoxic compounds for cancer therapy. Oncogene 25: 4787–4797.

Grammatopoulos TN, Johnson V, Moore SA, Andres R, Weyhenmeyer JA (2004) Angiotensin type 2 receptor neuroprotection against chemical hypoxia is dependent on the delayed rectifier K+ channel, Na+/Ca2+ exchanger and Na+/K+ ATPase in primary cortical cultures. Neurosci Res 50: 299–306.

Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87: 99–163.

Lidsky, Theodore I., and Jay S. Schneider. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126.1 (2003): 5-19.

Mattson, M. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1, 120–130 (2000). https://doi.org/10.1038/35040009.

R. Fern, J.A. Black, B.R. Ransom, S.G. Waxman Cd+-induced injury in CNS white matter J. Neurophysiol., 76 (1996), pp. 3264-3273

Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330.