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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)

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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 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

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)

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Mercury

The selenol group (-SeH) of selenocysteines is generally more reactive than thiols (-SH) towards mercury (Sugiura 1976, Khan, 2009). Methyl mercury (MeHg) can target both the GPx and TrxR proteins thereby causing induction of oxidative stress and neurotoxicity (Branco, 2017; Carvalho, 2008; Farina, 2011).

Table 2

KE_up Interference with SH/SeH	KE_down Oxidative stress induction	species; in vivo / in vitro	Stressor	Dose/ conc. + Duration of exp.	Protective/ aggravating evidence	Reference
Post-transcriptional effects on GPx1 and TrxR1 expression and activity. TrxR1 – 2-fold GPx1 – 0.6-fold	Disturbance of redox-response and induction of oxidative stress. SOD – 2-fold ROS – increased	Mouse myoblast C2C12,	MeHg	0.4 µM 9 h	Treatment with ebselen suppressed MeHg-induced oxidative stress	(Usuki, 2011)
Inhibition of TrxR and GSH activities. TrxR1&2 – 0.6-fold GSH – 0.7-fold	Oxidative stress shown by shift in GSSG/GSH ratio. GSSG/GSH – 1.5-fold	Human neuroblastoma cells (SH-SY5Y)	MeHg	1 µM	Se supplementation gave some extent of oxidative stress protection.	(Branco, 2017)
Decreased activity of TrxR and GPx. TrxR – 0.5-fold GPx – 0.5-fold	Oxidative stress. No fold reported.	Zebra fish brain	Hg²⁺, MeHg	1.8 molar (measured in brain tissue), 28 days		(Branco, 2012)
Inhibition of GPx activity. GPx – 0.4-fold	Increased ROS formation and lipid peroxidation ROS – 1.75-fold Total peroxidase – 4.5-fold Lipid perox. – 3-fold	Mouse brain	MeHg	40 mg/L in drinking water 21-days	Incubation of mitochondrial-enriched fractions with exogenous GPx completely blocked MeHg-induced mitochondrial lipid peroxidation.	(Franco, 2009)
Inhibition of GPx activity. GPx – 0.7-fold	Increased ROS formation and lipid peroxidation. Total H₂O₂ – 1.5-fold	Human neuro-blastoma SH-SY5Y cells.	MeHg	1 µM (nominal)	Inhibition of GPx substantially enhanced MeHg toxicity.	(Franco, 2009)
Decreased GPx1, activity in cerebral cortex and hippocampus. GPx1 – 0.5-fold	Induction of oxidative stress (oxidative damage product from the reaction of ROS and deoxy-thymidine in DNA) No fold-change reported.	Male C57BL/6NJcl mice	MeHg	1.5 mg kg⁻¹ day⁻¹ 6-weeks		(Fujimura, 2017)
Downregulation of antioxidant selenoprotein gene expression, and reduced GPx activity. Gpx1a – 0.2-fold Gpx4a – 0.2-fold TxnRd1 – 0.5-fold GPx – 0.2-fold	Indirect effects reported – larvae hypoactivity	Zebra fish	MeHg	0.05 mg/kg DM 20-days	0.7 mg/kg DM Se-supplementation partially restored GPx activity GPx activity upregulated from 0.2-fold to 0.7-fold.	(Penglase, 2014)
Depletion of GSH levels. GSH-activity: 10µM – 0.75-fold 30µM – 0.6-fold 100µM – 0,5-fold	Increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS). Mitochondrial viability: 10µM – 0.75-fold 30µM – 0.6-fold 100µM – 0,5-fold Total hydroperoxidases: 10µM – 1.0-fold 30µM – 1.2-fold 100µM – 1.75-fold	Mouse brain mito-chondrial-enriched fractions	MeHg	10, 30, and 100 μM 30 minutes	The co-incubation with diphenyl diselenide (100 μM) completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels. thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress	(Meinerz, 2011)
Depletion of mono- and disulfide glutathione in neuronal, glial and mixed cultures GSH activity – 0.83-fold	increased reactive oxygen species (ROS) formation measured by dichlorodihydro-fluorescein (DCF) fluorescence DCF – 1.2-1.5-fold	Mouse primary cortical cultures	MeHg	5 µM 24h	glutathione monoethyl ester (GSHME) (100 µM) supplementation protected against oxidative stress formation	(Rush, 2012)
Reduced glutathione (GSH) content decreased in liver, kidney and brain.	Increased lipid peroxidation and generation of reactive oxygen species	Adult male albino Sprague-Dawley rat	Dimethylmercury (DMM)	10 mg/kg bw 3-days	Supplementation with Se (2 mmol/kg and 0.5 mg/kg partially protected against DMM-induced tissue damage.	(Deepmala, 2013)
Reduced glutathione (GSH) level and acetyl cholinesterase activity, as well as reduced antioxidant enzyme glutathione peroxidase (GPx)	Increased lipid peroxidation level and DNA damage.	Adult male Sprague-Dawley rats	MeHg	1 mg kg−1 orally 6 months		(Joshi, 2014)
Depleted GSH levels.	Antioxidant imbalance and lipid peroxidation.	Adult male Wistar rats	mercuricchloride	30ppm in drinking water		(Agrawal, 2015)
GSH levels decreased in astrocytes.	Severe damage to the cell membranes, as well as to mitochondria.	Primary mouse neuron and astrocyte co-cultures	MeHg	10, 25, or 50 µM nominal 24h exposure		(Morken, 2005)
GPx1 significantly decreased prior to neurotoxic effects being visible. GPx1 – 0.7-fold	Increased lipid Peroxidation and later neuronal cell death. Lipid peroxidation - 1.75-fold	Primary cultured mouse cerebellar granule cells	MeHg	300nM nominal 24h	Overexpression of GPx-1 prevented MeHg-induced neuronal death	(Farina, 2009)
Reduction of GPx activity and increased glutathione reductase activity GPx – 0.7-fold	Increased oxidative stress – shown by increased TBA-RS and 8-OHdG content, as well as reduction of complexes I, II, and IV activities H2O2 – 1.6-fold		MeHg	3–5 µg/g brain tissue 21-days	Treatment with diphenyl diselenide (PhSe)₂ (5 µmol/kg) reversed MeHg’s inhibitory effect on mitochondrial activities, as well as the increased oxidative stress parameters.	(Glaser, 2013)
	Oxidative stress (increased H₂O₂ production)	Rat astro-glioma C6 cell line	MeHg	10 and 50 µM 1h	Cell viability protective effect of 1 µM of the organic selenium compound (PhSe)₂	(Glaser, 2013)
	Protein oxidation (increase of protein carbonyls)	Mouse primary cortical neurons, and cerebellar granule cells	MeHg	10-600 nM	All effects were prevented by co-treatment with the antioxidant probucol.	(Caballero, 2017)
Reduced glutathione peroxidase activity was found in the fetal side of human placental samples.		Human placenta tissue samples – INMA Valencia mother-infant cohort (Spain)	MeHg	20-40 µg/mL blood plasma		(Caballero, 2017)

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Acrylamide (acrylamide is a common food contaminant generated by heat processing)

No literature supporting the link “SH/she binding leads to oxidative stress” for acrylamide as stressor in brain/neural tissue can be found.

Acrolein

No literature supporting the link “SH/she binding leads to oxidative stress” for acrolein as stressor in brain/neural tissue can be found.

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).

References

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

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