API

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Relationship: 353

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

BDNF, Reduced leads to Cell injury/death

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
BDNF, Reduced
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Cell injury/death

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
Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging adjacent Low Arthur Author (send email) Open for citation & comment WPHA/WNT Endorsed
Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities adjacent Low Agnes Aggy (send email) Open for citation & comment 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

Sex Applicability

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

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

BDNF influences the apoptosis occurring in developing neurons through two distinct mechanisms (Bernd, 2008). mBDNF can trigger prosurvival signaling after binding to TrkB receptor through inactivation of components of the cell death machinery and also through activation of the transcription factor cAMP-response element binding protein (CREB), which drives expression of the pro-survival gene Bcl-2 (West et al., 2001). On the other hand, proBDNF binds to the p75 neurotrophin receptor (p75NTR) and activates RhoA that regulates actin cytoskeleton polymerization resulting in apoptosis (Lee et al., 2001; Miller and Kaplan, 2001; Murray and Holmes, 2011). It is proved that reduced levels of BDNF can severely interfere with the survival of neurons in different brain regions, leading to cell death (Lee et al., 2001; Miller and Kaplan, 2001; Murray and Holmes, 2011).

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 Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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

Pb2+: A number of studies demonstrate that deletion of BDNF does not lead to significant apoptotic cell death of neurons in the developing CNS (reviewed in Dekkers et al., 2013). In an in vivo Pb2+ exposure study, where female rats received 1,500 ppm prior, during breeding and lactation shows no changes at mRNA levels of BDNF in different hippocampus section derived from their pups (Guilarte et al., 2003). Regarding Pb2+, the pre- and neonatal exposure of rats to Pb2+ (Pb2+ blood levels below 10 μg/dL) show a decreased number of hippocampus neurons but no morphological or molecular features of severe apoptosis or necrosis have been detected in tested brains (Baranowska-Bosiacka et al., 2013). In contrast to the lack of apoptotic signs, reduced levels of BDNF concentration (pg/mg protein) of BDNF in brain homogenates has been recorded in forebrain cortex (39%) and hippocampus (29%) (Baranowska-Bosiacka et al., 2013). Pregnant rats have been exposed to lead acetate (0.2% in the drinking water) after giving birth until PND 20. At PND 20, blood Pb2+ levels in pups reached at 80 μg/dl. In these animals, the gene expression in different brain regions has been assessed and demonstrated that hippocampus is most sensitive with alterations beginning at PND 12 when caspase 3 mRNA increases after Pb2+ exposure (Chao et al., 2007). However, bcl-x and BDNF mRNA in the hippocampus have been significantly increased after caspase 3 increase, suggesting that the apoptotic signal activates a compensatory response by increasing survival factors like BDNF and that the temporality suggested in this AOP may not be accurate (Chao et al., 2007).

Some of the reported “inconsistencies” may be due to the lack of sufficient details in the reporting since publications vary in what they measure. Some of the referenced studies look at BDNF transcripts, others look at BDNF protein. BDNF processing is highly complex and different mRNA transcripts are known to be implicated in different cellular function.

Several studies addressing apoptosis mainly in the developing cerebral cortex have shown that more mechanism besides neurotrophic factors may be involved. Cytokines, as well as neurotransmitters can potentially activate a number of intracellular proteins that execute cell death (Henderson, 1996; Kroemer et al., 2009), meaning that further branches to this AOP might be added in the future.

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

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

The survival and antiapoptotic role of BDNF has been investigated not only in rodents but also in developing chicken neurons (Hallbook et al., 1995; Frade et al., 1997; Reinprecht et al., 1998). In invertebrates, only recently a protein with possible neurotrophic role has been identified but its influence and function in neuronal cell death of developing neurons has not been investigated yet (Zhu et al., 2008).