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Relationship: 1685


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

Oxidative Stress leads to Glutamate dyshomeostasis

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 of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory adjacent Low Low Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite EAGMST Approved

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
rat Rattus norvegicus High NCBI
mouse Mus musculus 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
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

In the central nervous system (CNS), glutamate (Glu) is rapidly taken up at the synaptic cleft to mitigate potential excitotoxicity (Meldrum, 2000). Reuptake is carried out by the electrochemical gradient of Glu across the plasma membrane and is accomplished by Glu transporter proteins, referred to as excitatory amino acid transporters (EAATs). These transporter proteins are predominantly expressed in astrocytes, but they are also be found in other neural cells, such as oligodendrocyte, neuron, and microglia membranes (Danbolt, 2001). Functional Glu transporters are located on cell surface membranes. The activities of these transporters are regulated by a redistribution of these proteins to or from the plasma membrane (Robinson 2002), under the control of several signaling pathways. Five different families of EAATs have been recognized (EAAT1–EAAT5). They vary in Na+ and/or K+ coupling abilities. Their names differ based on the presence of the transporter in human or in other mammals (see Table 1).

Transporter (Human)

Transporter (Mammals)

Occurrence (Cell)



Astrocyte, oligodendrocyte, microglia



Astrocyte, oligodendrocyte



Neuron (somatodendritic), astrocyte (low)



Purkinje cell, astrocyte



Müller cell (retina)

Table 1: Glu transporters in human and mammals and their occurrence in CNS cells. From Rajda et al., 2017

These transporters co-localize with, form physical (co-immunoprecipitable) interactions with, and functionally couple to various 'energy-generating' systems, including the Na(+)/K(+)-ATPase, the Na+/Ca2+ exchanger, glycogen metabolizing enzymes, glycolytic enzymes, and mitochondria/mitochondrial proteins. This functional coupling is bi-directional with many of these systems both being regulated by glutamate transport and providing the 'fuel' to support glutamate uptake (Robinson and Jackson, 2016). The Na+ gradient, which depends on Na/K ATPase pump and consequently of ATP production and intracellular levels, provides the energy to move Glu from the outside into the cells, accompanied by two Na+ and an H+ ; at the same time, K+ moves in the opposite direction (Boron and Boulpaep, 2003). Mitochondrial dysfunction leads to a decrease in ATP synthesis, impaired Ca2+ content, and concomitant increase in the levels of ROS (Reactive Oxygen Species) and RNS (Reactive Nitrogen Species) (Beal, 2005). Free radicals, which are electrically unstable, have a central role in several physiological and pathological processes. Both ROS and RNS originate from endogenous and exogenous sources. Mitochondria, endoplasmic reticulum, peroxisomes, phagocytic cells, and others serve as endogenous sources, and environmental factors, such as alcohol, tobacco, pollution, industrial solvents, pesticides, heavy metals, specified medicines, etc. make up the prepondarance of exogenous factors. Significant amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS,) are formed during oxidative phosphorylation, when the greatest amount of ATP is produced. Cellular antioxidants production serves as a countermeasure against this process (Su et al., 2013; Szalardi et al., 2015). Most cells, including astrocytes, have protective mechanisms against ROS, predominantly in the form of the tripeptide thiol, glutathione (GSH) (Hsie et al., 1996). This process stays in a highly sensitive balance. In the specific case when ROS and RNS synthesis exceeds antioxidant synthesis it results in oxidative stress (Reddy, 2006; Ghafouribar et al., 2008; Su et al., 2013; Szalardi et al., 2015; Valko et al., 2007; Yankovskaya et al., 2003; Senoo-Matsuda et al., 2003;  Schon and Manfredi, 2003).

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

Due to the tight coupling of Glu transporters with energy production, and to the important role of Glu transporters in Glu homeostasis, perturbations of energy metabolism such as mitochondrial dysfunction and increased production of ROS lead to Glu dyshomeostasis  (Boron and Boulpaep, 2003). In particular, it was shown that ROS inhibit glutamate uptake by astrocytes (Sorg et al., 1997), and that  glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels (Liu et al., 2009).

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 relationship between oxidative stress associated to mitochondrial dysfunction and glutamate dyshomeostasis is complex and may be bidirectional. Glutamate dysfunction, due to decreased glutamate uptake, can secondarly induce increased ROS production and consequently oxidative stress.

The astrocytic enzyme glutamine synthetase (GS), transforming glutamate in glutamine, which is taken up by neurons, is also a SH-containing protein, which is inhibited by mercury binding (Kwon and Park, 2003). This participate to glutamate dyshomeostasis  linking this KE directly to the MIE.

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

In case of glutamate dyshomeostasis, when extracellular concentrations are very high (5 – 10 mM), a mechanism of toxicity called oxidative glutamate toxicity can be observed. It is mediated by an inhibition of cystein uptake leading to a depletion of GSH (Kritis et al., 2015). The GSH depletion decreases the protection against oxidative stress and exacerbates oxidative stress, which, in turn, exacerbates glutamate dyshomeostasis.

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

Experimental evidences has been observed mainly in rodent, but due to occurrence of oxidative stress and the presence of glutamate in different taxa, it may be much broader, as suggested by similar observations in C. elegans (Wu et al., 2015).


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

Allen, J. W., H. El-Oqayli, M. Aschner, T. Syversen and U. Sonnewald (2001). "Methylmercury has a selective effect on mitochondria in cultured astrocytes in the presence of [U-(13)C]glutamate." Brain Res 908(2): 149-154.

Beal M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 2005;58:495–505.

Boron WF, Boulpaep EL. 2003. A cellular and molecular approach. Medical Physiology. Updated Edition. Elsevier, Saunders.

Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65:1–105.

Feng, S., Xu, Z., Liu, W., Li, Y., Deng, Y., Xu, B., 2014. Preventive effects of dextromethorphan on methylmercury-induced glutamate dyshomeostasis and oxidative damage in rat cerebral cortex. Biol Trace Elem Res 159, 332-345.

Hediger MA. Glutamate transporters in kidney and brain. Am J Physiol. 1999;277:F487–F492.

 Hsie AW, Recio L, Katz DS, Lee CQ, Wagner M, et al. (1986) Evidence for reactive oxygen species inducing mutations in mammalian cells. Proc Natl Acad Sci U S A 83: 9616–9620

Juarez, B. I., M. L. Martinez, M. Montante, L. Dufour, E. Garcia and M. E. Jimenez-Capdeville (2002). "Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats." Neurotoxicol Teratol 24(6): 767-771.

Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD (2015) Researching glutamate - induced cytotoxicity in different cell lines: a comparative/collective analysis/study. Front Cell Neurosci 9:91 doi:10.3389/fncel.2015.00091

Kwon, O.-S., Park, Y.-J. In vitro and in vivo dose-dependent inhibition of methylmercury on glutamine synthetase in the brain of different species (2003) Environmental Toxicology and Pharmacology, 14 (1-2), pp. 17-24.

Liu HT, Akita T, Shimizu T, Sabirov RZ, Okada Y. 2009. Bradykinin-induced astrocyte–neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels. J Physiol. 587(Pt 10): 2197–2209.

Meldrum BS. 2000. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130(4S Suppl):1007S–1015S.

Porciuncula, L. O., J. B. Rocha, R. G. Tavares, G. Ghisleni, M. Reis and D. O. Souza (2003). "Methylmercury inhibits glutamate uptake by synaptic vesicles from rat brain." Neuroreport 14(4): 577-580.

Rajda C, Pukoli D, Bende Z, Majalath Z, Vécsei L. 2017. Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis. Int J Mol Sci. 2017 Feb; 18(2): 353. doi:  10.3390/ijms18020353.

Reddy P.H. 2006. Mitochondrial oxidative damage in aging and Alzheimer’s disease: Implications for mitochondrially targeted antioxidant therapeutics. J. Biomed. Biotechnol.  doi: 10.1155/JBB/2006/31372.

Robinson MB. 2002. Regulated trafficking of neurotransmitter transporters: common notes but different melodies. J Neurochem. 80(1):1-11.

Robinson, M. B. and J. G. Jackson (2016). "Astroglial glutamate transporters coordinate excitatory signaling and brain energetics." Neurochem Int 98: 56-71.

Roos, D. H., R. L. Puntel, M. M. Santos, D. O. Souza, M. Farina, C. W. Nogueira, M. Aschner, M. E. Burger, N. B. Barbosa and J. B. Rocha (2009). "Guanosine and synthetic organoselenium compounds modulate methylmercury-induced oxidative stress in rat brain cortical slices: involvement of oxidative stress and glutamatergic system." Toxicol In Vitro 23(2): 302-307.

Roos, D. H., R. L. Puntel, M. Farina, M. Aschner, D. Bohrer, J. B. Rocha and N. B. de Vargas Barbosa (2011). "Modulation of methylmercury uptake by methionine: prevention of mitochondrial dysfunction in rat liver slices by a mimicry mechanism." Toxicol Appl Pharmacol 252(1): 28-35.

Senoo-Matsuda N., Hartman P.S., Akatsuka A., Yoshimura S., Ishii N. 2003. A complex II defect affects mitochondrial structure, leading to ced-3- and ced-4-dependent apoptosis and aging. J. Biol. Chem. 278:22031–22036. doi: 10.1074/jbc.M211377200.

Schon E.A., Manfredi G. 2003. Neuronal degeneration and mitochondrial dysfunction. J. Clin Investig. 111:303–312. doi: 10.1172/JCI200317741.

Sorg O, Horn TF, Yu N, Gruol DL, Bloom FE. 1997.Inhibition of astrocyte glutamate uptake by reactive oxygen species: role of antioxidant enzymes.Mol Med. 3(7): 431–440.

Valko M., Leibfritz D., Moncol J., Cronin M.T., Mazur M., Telser J. 2007. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39:44–84. doi: 10.1016/j.biocel.2006.07.001.

Wu T, He K, Zhan Q, et al. (2015) MPA-capped CdTe quantum dots exposure causes neurotoxic effects in nematode Caenorhabditis elegans by affecting the transporters and receptors of glutamate, serotonin and dopamine at the genetic level, or by increasing ROS, or both. Nanoscale 7(48):20460-73 doi:10.1039/c5nr05914c

Xu, B., Xu, Z.F., Deng, Y., Liu, W., Yang, H.B., Wei, Y.G., 2012. Protective effects of MK-801 on methylmercury-induced neuronal injury in rat cerebral cortex: involvement of oxidative stress and glutamate metabolism dysfunction. Toxicology 300, 112-120.

Yankovskaya V., Horsefield R., Törnroth S., Luna-Chavez C., Miyoshi H., Léger C., Byrne B., Cecchini G., Iwata S. 2003. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science.299:700–704. doi: 10.1126/science.1079605.