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Relationship: 1689

Title

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

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

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
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

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
Sex Evidence
Unspecific High

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
Term Evidence
During brain development, adulthood and aging High

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

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)

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)

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 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

Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors (Pisosci and Pop 2015).

 

Thiol- and selenol containing proteins have a high affinity for binding soft metals which contributes to the target site – brain – distribution of such toxicants (Farina, 2011).

 

GPx family

GPxs are tetrameric enzymes where their thiol groups can either act directly act as a reductant, or they catalyze reduction of hydrogen peroxide and/or phospholipid hydroperoxides through glutathione co-factors (Hanschmann, 2013; Labunskyy, 2014)

 

TrxR family

The thioredoxin reductase (TxRs) family of selenoproteins are homodimeric flavoenzymes, which mediate the reduction of oxidized Txn at the expense of NADPH (Birben et al., 2012). Inhibition of TrxR enzymes have been shown to lead to oxidative stress (Carvalho, 2008).

 

SelP

Downregulation of intracellular SelP by use of small interfering RNA (siRNA) impaired the viability of human astrocytes and made them more susceptible to hydroperoxide-induced oxidative stress, pointing to a direct contribution of SeP to ROS clearance (Steinbrenner, 2006)

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

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).

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
Time-scale
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

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).

References

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

Agrawal, S., P. Bhatnagar and S. J. Flora (2015). "Changes in tissue oxidative stress, brain biogenic amines and acetylcholinesterase following co-exposure to lead, arsenic and mercury in rats." Food Chem Toxicol 86: 208-216.

Arbogast, S. and A. Ferreiro (2010). "Selenoproteins and protection against oxidative stress: selenoprotein N as a novel player at the crossroads of redox signaling and calcium homeostasis." Antioxid Redox Signal 12(7): 893-904.

Arbogast, S., M. Beuvin, B. Fraysse, H. Zhou, F. Muntoni and A. Ferreiro (2009). "Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment." Ann Neurol 65(6): 677-686.

Aschner, M., T. Syversen, D. O. Souza and J. B. Rocha (2006). "Metallothioneins: mercury species-specific induction and their potential role in attenuating neurotoxicity." Exp Biol Med (Maywood) 231(9): 1468-1473.

Borchert, A., C. C. Wang, C. Ufer, H. Schiebel, N. E. Savaskan and H. Kuhn (2006). "The role of phospholipid hydroperoxide glutathione peroxidase isoforms in murine embryogenesis." J Biol Chem 281(28): 19655-19664.

Branco, V., J. Canario, J. Lu, A. Holmgren and C. Carvalho (2012). "Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase." Free Radic Biol Med 52(4): 781-793.

Branco, V., J. Canario, J. Lu, A. Holmgren and C. Carvalho (2012). "Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase." Free Radic Biol Med 52(4): 781-793.

Branco, V., L. Coppo, S. Sola, J. Lu, C. M. P. Rodrigues, A. Holmgren and C. Carvalho (2017). "Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury." Redox Biol 13: 278-287.

Burk, R. F., G. E. Olson, K. E. Hill, V. P. Winfrey, A. K. Motley and S. Kurokawa (2013). "Maternal-fetal transfer of selenium in the mouse." FASEB J 27(8): 3249-3256.

Byrns, C. N., M. W. Pitts, C. A. Gilman, A. C. Hashimoto and M. J. Berry (2014). "Mice lacking selenoprotein P and selenocysteine lyase exhibit severe neurological dysfunction, neurodegeneration, and audiogenic seizures." J Biol Chem 289(14): 9662-9674.

Caballero, B., N. Olguin, F. Campos, M. Farina, F. Ballester, M. J. Lopez-Espinosa, S. Llop, E. Rodriguez-Farre and C. Sunol (2017). "Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies." Neurotoxicology 59: 197-209.

Cabungcal, J. H., D. Nicolas, R. Kraftsik, M. Cuenod, K. Q. Do and J. P. Hornung (2006). "Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia." Neurobiol Dis 22(3): 624-637.

Carvalho, C. M., E. H. Chew, S. I. Hashemy, J. Lu and A. Holmgren (2008). "Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity." J Biol Chem 283(18): 11913-11923.

Chen, L., R. Na, M. Gu, A. Richardson and Q. Ran (2008). "Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease." J Neurochem 107(1): 197-207.

Crack, P. J., J. M. Taylor, N. J. Flentjar, J. de Haan, P. Hertzog, R. C. Iannello and I. Kola (2001). "Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury." J Neurochem 78(6): 1389-1399.

Crack, P. J., K. Cimdins, U. Ali, P. J. Hertzog and R. C. Iannello (2006). "Lack of glutathione peroxidase-1 exacerbates Abeta-mediated neurotoxicity in cortical neurons." J Neural Transm (Vienna) 113(5): 645-657.

Deepmala, J., M. Deepak, S. Srivastav, S. Sangeeta, S. A. Kumar and S. S. Kumar (2013). "Protective effect of combined therapy with dithiothreitol, zinc and selenium protects acute mercury induced oxidative injury in rats." J Trace Elem Med Biol 27(3): 249-256.

Dringen, R. (2000). "Metabolism and functions of glutathione in brain." Prog Neurobiol 62(6): 649-671.

Du, S., J. Zhou, Y. Jia and K. Huang (2010). "SelK is a novel ER stress-regulated protein and protects HepG2 cells from ER stress agent-induced apoptosis." Arch Biochem Biophys 502(2): 137-143.

Farina, M., F. Campos, I. Vendrell, J. Berenguer, M. Barzi, S. Pons and C. Sunol (2009). "Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells." Toxicol Sci 112(2): 416-426.

Farina, M., M. Aschner and J. B. Rocha (2011). "Oxidative stress in MeHg-induced neurotoxicity." Toxicol Appl Pharmacol 256(3): 405-417.

Fernandes, A. C., P. M. Filipe, J. P. Freitas and C. F. Manso (1996). "Different effects of thiol and nonthiol ace inhibitors on copper-induced lipid and protein oxidative modification." Free Radic Biol Med 20(4): 507-514.

Ferreiro, A., S. Quijano-Roy, C. Pichereau, B. Moghadaszadeh, N. Goemans, C. Bonnemann, H. Jungbluth, V. Straub, M. Villanova, J. P. Leroy, N. B. Romero, J. J. Martin, F. Muntoni, T. Voit, B. Estournet, P. Richard, M. Fardeau and P. Guicheney (2002). "Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies." Am J Hum Genet 71(4): 739-749.

Flentjar, N. J., P. J. Crack, R. Boyd, M. Malin, J. B. de Haan, P. Hertzog, I. Kola and R. Iannello (2002). "Mice lacking glutathione peroxidase-1 activity show increased TUNEL staining and an accelerated inflammatory response in brain following a cold-induced injury." Exp Neurol 177(1): 9-20.

Fradejas, N., C. Serrano-Perez Mdel, P. Tranque and S. Calvo (2011). "Selenoprotein S expression in reactive astrocytes following brain injury." Glia 59(6): 959-972.

Fradejas, N., M. D. Pastor, S. Mora-Lee, P. Tranque and S. Calvo (2008). "SEPS1 gene is activated during astrocyte ischemia and shows prominent antiapoptotic effects." J Mol Neurosci 35(3): 259-265.

Franco JL, Teixeira A, Meotti FC, Ribas CM, Stringari J, Garcia Pomblum SC, Moro AM, Bohrer D, Bairros AV, Dafre AL, et al: Cerebellar thiol status and motor deficit after lactational exposure to methylmercury. Environ Res 2006, 102:22-28.

Franco, J. L., T. Posser, P. R. Dunkley, P. W. Dickson, J. J. Mattos, R. Martins, A. C. Bainy, M. R. Marques, A. L. Dafre and M. Farina (2009). "Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase." Free Radic Biol Med 47(4): 449-457.

Fujimura, M. and F. Usuki (2017). "In situ different antioxidative systems contribute to the site-specific methylmercury neurotoxicity in mice." Toxicology 392: 55-63.

Gao, Y., J. Pagnon, H. C. Feng, N. Konstantopolous, J. B. Jowett, K. Walder and G. R. Collier (2007). "Secretion of the glucose-regulated selenoprotein SEPS1 from hepatoma cells." Biochem Biophys Res Commun 356(3): 636-641.

Gatti, R., Belletti, S., Uggeri, J., Vettori, M.V., Mutti, A., Scandroglio, R., Orlandini, G. Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation (2004) Toxicology, 204 (2-3), pp. 175-185.

Gladyshev, V. N., K. T. Jeang and T. C. Stadtman (1996). "Selenocysteine, identified as the penultimate C-terminal residue in human T-cell thioredoxin reductase, corresponds to TGA in the human placental gene." Proc Natl Acad Sci U S A 93(12): 6146-6151.

Glaser, V., B. Moritz, A. Schmitz, A. L. Dafre, E. M. Nazari, Y. M. Rauh Muller, L. Feksa, M. R. Straliottoa, A. F. de Bem, M. Farina, J. B. da Rocha and A. Latini (2013). "Protective effects of diphenyl diselenide in a mouse model of brain toxicity." Chem Biol Interact 206(1): 18-26.

Hall, A. G. (1999). "Review: The role of glutathione in the regulation of apoptosis." Eur J Clin Invest 29(3): 238-245.

Hanschmann, E. M., J. R. Godoy, C. Berndt, C. Hudemann and C. H. Lillig (2013). "Thioredoxins, glutaredoxins, and peroxiredoxins--molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling." Antioxid Redox Signal 19(13): 1539-1605.

Hattori, I., Y. Takagi, H. Nakamura, K. Nozaki, J. Bai, N. Kondo, T. Sugino, M. Nishimura, N. Hashimoto and J. Yodoi (2004). "Intravenous administration of thioredoxin decreases brain damage following transient focal cerebral ischemia in mice." Antioxid Redox Signal 6(1): 81-87.

Higdon, A., A. R. Diers, J. Y. Oh, A. Landar and V. M. Darley-Usmar (2012). "Cell signalling by reactive lipid species: new concepts and molecular mechanisms." Biochem J 442(3): 453-464.

Hill, K. E., J. Zhou, W. J. McMahan, A. K. Motley and R. F. Burk (2004). "Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene." J Nutr 134(1): 157-161.

Hill, K. E., J. Zhou, W. J. McMahan, A. K. Motley, J. F. Atkins, R. F. Gesteland and R. F. Burk (2003). "Deletion of selenoprotein P alters distribution of selenium in the mouse." J Biol Chem 278(16): 13640-13646.

Joshi, D., M. D. Kumar, S. A. Kumar and S. Sangeeta (2014). "Reversal of methylmercury-induced oxidative stress, lipid peroxidation, and DNA damage by the treatment of N-acetyl cysteine: a protective approach." J Environ Pathol Toxicol Oncol 33(2): 167-182.

Khan, M. A. and F. Wang (2009). "Mercury-selenium compounds and their toxicological significance: toward a molecular understanding of the mercury-selenium antagonism." Environ Toxicol Chem 28(8): 1567-1577.

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