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Relationship: 1689

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

Binding, SH/SeH proteins involved in protection against oxidative stress leads to Oxidative Stress

Upstream event

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

Binding, SH/SeH proteins involved in protection against oxidative stress

Downstream event

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

Oxidative Stress

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

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
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI
human	Homo sapiens	High	NCBI
zebra fish	Danio rerio	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
During brain development, adulthood and aging	High

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

Proteins with cysteine amino acid residues contain thiol (SH) groups, and proteins with selenocysteine amino acid residues contain selenol (SeH) are characterized as cysteine-/selenoprotein family. Thiol and selenol groups exhibit reactivity toward electrophiles and oxidants and have high binding affinities for metals (Higdon, 2012; Nagy, 2013; Winterbourn, 2008; Winther, 2014).

Figure 1. (Poole, 2015) Structures of cysteinyl and selenocysteinyl residues within proteins. The aminoacyl groups are shown to the left, with dotted lines representing peptide bonds to the next residue on either side. Both protonated (left) and deprotonated (right) forms of these amino acids are depicted with average pKa values.

The selenoprotein family composes of proteins with diverse functionality, however, several are classified as antioxidant enzymes (Reeves, 2009) and this function is of particular importance for this KER. Relevant for this KER there are two well-studied functional selenoprotein families which are described to be expressed in the brain; (i) the Glutathione Peroxidase (GPx) family, involved in detoxification of peroxidases; (ii) the Thioredoxin Reductase (TrxR) family, which is involved in the regeneration of reduced thioredoxin (Pillai, 2014). However, there is also a number of other selenoproteins with diverse functions, from selenium transport (SelP), to ER stress response (SelK, M, N, S, T and Sep15, as well as DIO2) (Pisoschi, 2015; Reeves, 2009). Due to their described functionalities (summarized in table below) an increased oxidative stress as a consequence of interference with selenoprotein function, through binding to active-site thiol-/selenol groups will primarily concern the interference with proteins of the GPx- and TrxR families, as well as SelH, K, S, R, W, and P selenoproteins.

Table1

Selenoprotein family	Protein name	Normal brain function	Disruption leading to oxidative stress	Reference
Glutathione	GSH	GSH is a major endogenous antioxidant functioning directly in neutralization of free radicals and reactive oxygen compounds. GSH is the reduced form of glutathione and its SH group of cysteine is able to reduce and/or maintain reduced form of other molecules.	Disruptions leads to increased oxidative stress and apoptosis.	(Dringen, 2000) (Hall, 1999)
Glutathione Peroxidase (GPx) Family	GPx1	Peroxide/ROS reduction (Promotes neuroprotection in response to oxidative challenge). Brain expression levels are highest in microglia and lower levels detected in neurons.	Brains of GPx1−/− mice are more vulnerable to mitochondrial toxin treatment, ischemia/ reperfusion, and cold-induced brain injury. Cultured neurons from GPx1−/− mice were reported to be more susceptible to Aβ-induced oxidative stress, and addition of ebselen reversed this.	(Lindenau, 1998) (Crack, 2001;Flentjar, 2002;Klivenyi, 2000) (Crack, 2006)
Glutathione Peroxidase (GPx) Family	GPx4	Reduction of phospholipid Hydroperoxides. Only in neurons during normal conditions.	Brains of GPx4+/− mice were shown to have increased lipid peroxidation (a sign of oxidative stress). Injury-induced GPx4 expression in astrocytes. In vivo over expression of GPx4 protects against oxidative stress-induced apoptosis.	(Chen, 2008) (Savaskan, 2007) and (Borchert, 2006) and (Ran, 2004)
Thioredoxin Reductase (TrxR) Family	TrxR1	Cytocsolic localization. Contributes to the reduction of hydrogen peroxide and oxidative stress, and regulates redox-sensitive transcription factors that control cellular transcription mechanisms. TrxR-1 regulates the induction of the antioxidant enzyme heme oxygenase 1 (HO-1).	Overexpression of human Trx1 and Trx2 protects retinal ganglion cells against oxidative stress-induced neurodegeneration.	(Pitts, 2014) (Zhong, 2000) (Burk, 2013) (Arbogast, 2010;Trigona, 2006) (Munemasa, 2008)
Thioredoxin Reductase (TrxR) Family	TrxR2	Mitochondrial localization. Contribute to the reduction of hydrogen peroxide and oxidative stress, and regulates redox sensitive transcription factors that control cellular transcription mechanisms.	Exogenously administered human rTrx ameliorates neuronal damage after transient middle cerebral artery occlusion in mice, reduces oxidative/nitrative stress and neuronal apoptosis after cerebral ischemia/reperfusion injury in mice	(Pitts, 2014) (Arbogast, 2010;Gladyshev, 1996;Papp, 2007) (Hattori, 2004)(Ma, 2012)
Other relevant seleno- proteins	SelH	Nuclear localization. Redox sensing.	Hypersensitivity of SelH shRNA HeLa cells to paraquat- and H2O2-induced oxidative stress.	(Panee, 2007)(Novoselov, 2007) (Wu, 2014)
	SelK	Transmembrane protein localized to the ER membrane. ER homeostasis and oxidative stress response.	Protects HepG2 cells from ER stress agent-induced apoptosis. Overexpression of SelK attenuated the intracellular reactive oxygen species level and protected cells from oxidative stress-induced toxicity in cardiomyocytes	(Shchedrina, 2011) (Du, 2010) (Lu, 2006)
	SelS	Transmembrane protein localized to the ER membrane. Catalyze the reduction of disulfide bonds and peroxides.	SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli, and suppression of SelS compromised astrocyte viability.	(Liu, 2013) (Fradejas, 2011) (Fradejas, 2008) (Gao, 2007)
	MSRB1, SelR, SelX	Function in reduction of oxidized methionine residues, and actin polymerization.	Induce expression of MSRB1 protects neurons from amyloid β-protein insults in vitro and in vivo.	(Lee, 2013) (Moskovitz, 2011)(Pillai, 2014)
	SelW	Expressed in synapses. Plays an antioxidant role in cells.	Rat in vivo overexpression of SelW was shown to protect glial cells against oxidative stress caused by heavy metals and 2,20-Azobis. Silencing of SelW made neurons more sensitive to oxidative stress.	(Reeves, 2009) (Sun, 2001) (Loflin, 2006) (Raman, 2013) (Chung, 2009)
	SelP	Is important for selenium transport, distribution and retention within the brain. Acts as a ROS-detoxifying enzyme. Protects human astrocytes from induced oxidative.	SelP-/- mice show neurological dysfunction and that Se content and GPx activity were reduced within brain, Se supplementation to diet attenuated. neurological dysfunctions. SelP-/- mice have reported deficits in PV-interneurons due to diminished antioxidant defense capabilities. Decreased neuronal selenoprotein synthesis may be a functional outcome of SelP Colocalization of Sel P with amyloid plaques SelP can function as an antioxidant enzyme against reactive lipid intermediates	(Steinbrenner, 2009)(Arbogast, 2010)(Zhang, 2008) (Hill, 2003;Hill, 2004) (Cabungcal, 2006) (Pitts, 2012) (Byrns, 2014) (Schomburg, 2003) (Rock, 2010)

https://aopwiki.org/system/dragonfly/production/2018/01/26/9o3c62z5ej_AOP17_KER1_Table1.pdf

Binding to thiol/sulfhydyryl groups of these proteins can firstly result in structural modifications of these proteins, which in turn negatively effects the catalytic capacity and thereby reducing or blocking the metabolic capacity to neutralize reactive oxygen species (Fernandes, 1996; Rajanna, 1995), secondly, SH/SeH binding would also the instrinsic primary antioxidant functionalities of selenoproteins (Kohen, 2002; Pisoschi, 2015).

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

Another important group of thiol-containing proteins are the metal-binging detoxifying metallothioneins. This protein family bind mercury and lead, and this binding thus serves as a protective mechanism and also protects against metal toxicity and oxidative stress (Aschner, 2006).

Lactational exposure to methylmercury (10 mg/L in drinking water) significantly increased cerebellar GSH level and GR activity. Possibly a compensatory response to mercury-induced oxidative stress (Franco et al., 2006)

Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation (Gatti et al., 2004).

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

cf Table 2

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

Mechanistic support for the link between interference of SH/SeH groups of proteins and induction of oxidative stress can be found in Zebrafish, rodents (mouse and rat) and to some extent in man (see Table 2).