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Relationship: 210


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

N/A, Neuronal dysfunction leads to Neuroinflammation

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

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

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

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

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

Stressed or injured neurons may decrease their synthesis/release of chemokines maintaining microglial cells in a quiescent state (Blank and Prinz, 2013; Chapman et al., 2000; Streit et al., 2001). Consequently microglial cells are becoming reactive, releasing bio-molecules such as cytokines. The pro-inflammatory cytokine IL-6 is known as an inductor of astrocyte reactivity (Chiang et al., 1994).

Neuronal death can lead to the release of intracellular content acting on microglial cells on specific receptors such as DAMPS (Damage Associated Molecular Pathways) (Marin-Teva et al., 2011)

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 accepted that under normal physiological conditions, microglial cells participate in surveillance of neuronal integrity (Nimmerjahn et al., 2005), and that in case of neuronal stress, injury or death, microglial cells are becoming reactive, what is the initiation of the neuroinflammatory process.

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

Following paraquat exposure, it was observed that neuronal dysfunction was observed together with astrocyte reactivity, evidenced by increased expression of glial fibrillary acidic protein (GFAP), whereas microglial reactivity was delayed and occurring despite a partial but important neuronal recovery (Sandström et al., 2014). Such observations suggest that the temporal evolution of the inflammatory process is crucial.

It cannot be excluded that toxicant can affect directly glial cells and induce secondarily neuronal injury.

Cell-cell interactions play a key role in the triggering, evolution and consequences of neuroinflammation.

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
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


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

Blank, T. and M. Prinz (2013). "Microglia as modulators of cognition and neuropsychiatric disorders." Glia 61(1): 62-70.

Chapman, G. A., K. Moores, et al. (2000). "Fractalkine Cleavage from Neuronal Membrans Represents an Acute Event in Inflammatory Response to Excitotoxic Brain Damage." J. Neurosc. 20 RC87: 1-5.

Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM (1994) Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure. ToxicolApplPharmacol 129: 196-206

Chiang, C.-S., A. Stalder, et al. (1994). "Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice." Dev.Neurosci. 16: 212-221.

Cicchetti F, Lapointe N, Roberge-Tremblay A, Saint-Pierre M, Jimenez L, Ficke BW, Gross RE (2005) Systemic exposure to paraquat and maneb models early Parkinson's disease in young adult rats. Neurobiol Dis 20: 360-371

Davis LE, Kornfeld M, Mooney HS, Fiedler KJ, Haaland KY, Orrison WW, Cernichiari E, Clarkson TW (1994) Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family. Ann Neurol 35: 680-688

Figiel I, Dzwonek K (2007) TNFalpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res 1131: 17-28

Finsen, B. R., M. B. Jorgensen, et al. (1993). "Microglial MHC antigen expression after ischemic and kainic acid lesions of the adult rat hippocampus." Glia 7: 41-49.

Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP (2012) Trimethyltin-induced neurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis. Neurotoxicol Teratol 34: 72-82

Liu MC, Liu XQ, Wang W, Shen XF, Che HL, Guo YY, Zhao MG, Chen JY, Luo WJ (2012) Involvement of microglia activation in the lead induced long-term potentiation impairment. PLoS One 7: e43924

Mangano EN, Peters S, Litteljohn D, So R, Bethune C, Bobyn J, Clarke M, Hayley S (2011) Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease. Neurobiol Dis 43: 99-112

Marin-Teva, J. L., M. A. Cuadros, et al. (2011). "Microglia and neuronal cell death." Neuron Glia Biol 7(1): 25-40.

Monnet-Tschudi F, Zurich MG, Pithon E, van Melle G, Honegger P (1995a) Microglial responsiveness as a sensitive marker for trimethyltin (TMT) neurotoxicity. Brain Res 690: 8-14

Monnet-Tschudi F, Zurich MG, Honegger P (1996) Comparison of the developmental effects of two mercury compounds on glial cells and neurons in aggregate cultures of rat telencephalon. Brain Res 741: 52-59

Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314-1318

O'Callaghan, J. P. (1988). "Neurotypic and gliotypic proteins as biochemical markers of neurotoxicity." Neurotoxicol.Teratol. 10: 445-452.

Pitter, K. L., I. Tamagno, et al. (2014). "The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions." Glia 62(10): 1595-1607.

Sandstrom von Tobel, J., D. Zoia, et al. (2014). "Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures." Toxicol Lett. 10.1016/j.toxlet.2014.02.001

Selvin-Testa A, Loidl CF, Lopez-Costa JJ, Lopez EM, Pecci-Saavedra J (1994) Chronic lead exposure induces astrogliosis in hippocampus and cerebellum. NeuroToxicology 15: 389-402

Streit, W. J., J. Conde, et al. (2001). "Chemokines and Alzheimer's disease." Neurobiol. Aging 22: 909-913.

Taetzsch T, Block ML (2013) Pesticides, microglial NOX2, and Parkinson's disease. J Biochem Mol Toxicol 27: 137-149

von Tobel, J. S., P. Antinori, et al. (2014). "Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype." Neurotoxicology 44C: 61-70.

Zurich M-G, Eskes C, Honegger P, Bérode M, Monnet-Tschudi F (2002) Maturation-dependent neurotoxicity of lead aceate in vitro: Implication of glial reactions. J Neurosc Res 70: 108-116