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Event: 1487

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Binding, Thiol/seleno-proteins involved in protection against oxidative stress

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Binding, SH/SeH proteins involved in protection against oxidative stress
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Biological Context

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Level of Biological Organization

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Oxidative stress and Developmental impairment in learning and memory MolecularInitiatingEvent Marie-Gabrielle Zurich (send email) Open for citation & comment WPHA/WNT Endorsed
Oxidative stress in chronic kidney disease MolecularInitiatingEvent Frederic Y. Bois (send email) Under development: Not open for comment. Do not cite

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI
zebra fish Danio rerio NCBI
human Homo sapiens NCBI
Gallus gallus Gallus gallus NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During brain development High

Sex Applicability

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Term Evidence
Female High
Male High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

In the brain, thiol (SH)- and seleno-containing proteins involved in protection against oxidative stress are mainly located in mitochondria and in the cytoplasm of the different neural cell types (Comini, 2016; Hoppe et al. 2008; Barbosa et al. 2017; Zhu et al. 2017). The main SH-containing peptide involved in protection against oxidative stress is Glutathione (GSH), a tripeptide acting as a cofactor for the enzyme peroxidase and thus serving as an indirect antioxidant donating the electrons necessary for its decomposition of H2O2. The seleno-containing proteins of interest are: (i) the Glutathione Peroxidase (GPx) family, involved in detoxification of hydroperoxides; (ii) the Thioredoxin Reductase (TrxR) family, involved in the regeneration of reduced thioredoxin (Pillai et al., 2014; ), and the less studied SelH, K, S, R, W, and P selenoproteins (Pisoschi and Pop, 2015, Reeves and Hoffmann, 2009). Binding of chemicals to these proteins induces either their inactivation or favor their degradation (Farina et al. 2009; Zemolin et al. 2012). Of particular importance, the GSH/GPx and thioredoxin (Trx)/TrxR systems are the two main redox regulators of mammalian cells and the disruption of their activities can compromise cell viability (Ren et al. 2016).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  • Binding of Hg to thiol groups was analyzed by multiple collector inductively coupled plasma mass spectometry (Wiederhold et al., 2010).
  • The binding affinity of methylmercury by various selenium-containing lingands was investigated by proton magnetic resonance spectometry (Sugiura et al., 1978; Arnold et al., 1986).
  • A methylene blue-mediated enzyme biosensor was developed for the detection of mercury-glutathione complex. The biosensor was the enzyme horseradish peroxidase. The binding site of HgCl2 with the enzyme was a cysteine residue-SH (Han et al., 2001).
  • A photometric method to quantify GSH loss after reactio with organic electrophiles has also been reported (Böhme et al., 2009).
  • Binding of mercuric chloride to GSH was measured by high performance liquid chromatography (HPLC)-ultraviolet (UV) detection, HPLC-inductively coupled mass spectometry and HPLC-electrospray ionization mass spectometry (Qiao et al., 2017).
  •  Carvalho et al. (2011) determined the binding of MeHg or Hg2+ with purified Thioredoxin Reductase using mass spectrometry. The liquid chromatography was not applied because they have used a pure chemical system, i.e, without living cells.
  • Mass spectra analysis allowed to measure the binding of mercury chloride and methylmercury to proteins of the mamallian thioredixin system, thioredoxin reductase (Trx) and thioredoxin (Trx), and of the glutaredoxin system, glutathione reductase (GR) and glutaredoxin (Grx) (Carvahlo et al., 2008)
  • The methodology to detect acrylamide-cysteine adducts has been performed by liquid chromatography coupled to tandem mass spectrometry  (Martyniuk et al. 2013). In this paper the authors dected by using  a shotgun proteomic approach a total of 15,243 peptides in ACR-exposed N27 cells. And from those 15,243 peptides, 103 peptides (from 100 different proteins) contained acrylamide-cysteine adducts.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Due to the ubiquitous distribution of the SH-/ and seleno-proteins involved in protection against oxidative stress and inview of the strong affinity of MeHg and Hg2+ for thiolate and selenolate groups the binding of MeHg and Hg2+ to thiol and selenol groups is expected to occur in the living cells of all taxonomic groups found in the biosphere.The conservation of these effects across different vertebrate species indicates that thiol- and selenol-containing proteins (particularly, TrxR and GPx) can also be important targets of electrophilic forms of Hg(EpHg+ or MeHg and Hg2+) toxicity in fish and birds (Heinz, 1979; Carvalho et al. 2008b; Heinz et al. 2009; Xu et al.2012, 2016). The disruption of the Trx and GSH systems by MeHg and Hg2+have been demonstrated in zebra-sea breams  (Branco et al. 2011; 2012a,b) and salmon (Salmo salar, Bernstssen et al. 2003).  MeHg can also interfere with the Trx and GSH systems in zebrafish (Yang et al. 2007; Cambier et al. 2012).


List of the literature that was cited for this KE description. More help

Arnold, A.P.,K.-S. Tan, D.L. Rabenstein (1986), Nuclear Magnetic Resonance Studies of the Solution Chemistry of Metal Complexes. 23. Complexation of Methylmercury by Selenohydryl-Containing Amino Acids and Related Molecules. Inorganic Chemistry, 25 (14), pp. 2433-2437.

Barbosa, N.V., et al. (2017), Organoselenium compounds as mimics of selenoproteins and thiol modifier agents (2017) Metallomics, 9 (12), pp. 1703-1734.

Boehme, A. et al. (2009), Kinetic gluthathione chemoassay to quantify thiol reactivity of organic electrophiles – Application to a, b-unsaturated ketones, acrylates, and propiolates. Chem. Res. Toxicol. 22(4): 742-50. doi: 10.1021/tx800492x.

Berntssen, M.H, A. Aatland, R.D. Handy (2003), Chronic dietary mercury exposure causes oxidative stress, brain lesions, and altered behaviour in Atlantic salmon (Salmo salar) parr. Aquatic Toxicology. 65, pp.55-72.

Branco V. et al. (2011), Inhibition of the thioredoxin system in the brain and liver of zebra-seabreams exposed to waterborne methylmercury. Toxicology and applied pharmacology. 251(2), pp. 95-103.

Branco, V. et al. (2012a), Mercury and selenium interaction in vivo: on thioredoxin reductase and glutathione peroxidase.Free Radical in  Biology and  Medicine, 52(4): 781-793.

Branco, V., et al. (2012b), Biomarkers of adverse response to mercury: histopathology versus thioredoxin reductase activity. Journal of Biomedicine and Biotechnology, 2012:359879. doi: 10.1155/2012/359879.

Branco, V, (2014), Mitochondrial thioredoxin reductase inhibition, selenium status, and Nrf-2 activation are determinant factors modulating the toxicity of mercury compounds. Free Radical Biology and Medicine 73: 95-105.

Branco, V. et al. (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.

Carvalho, C.M. et al. (2008a) Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity. J Biol Chem 283, 11913-11923.

Carvalho, M.C. et al. (2008b); Behavioral, morphological, and biochemical changes after in ovo exposure to methylmercury in chicks. Toxicological sciences, 106(1), pp.180-185.

Carvalho, C.M.L. et al. (2011), Effects of selenite and chelating agents on mammalian thioredoxin reductase inhibited by mercury: Implications for treatment of mercury poisoning . FASEB Journal, 25 (1), pp. 370-381.

Cambier S., et al. (2012), Effects of dietary methylmercury on the zebrafish brain: histological, mitochondrial, and gene transcription analyses. Biometals. 25(1):165-180.

Chehimi L, et al. (2012), Chronic exposure to mercuric chloride during gestation affects sensorimotor development and later behaviour in rats. Behav. Brain Res. 234:43–50. https://

Cheng JP, Yang YC, Hu WX, Yang L, Wang WH, Jia JP, Lin XY(2005) Effect of methylmercury on some neurotransmitters and oxidative damage of rats. J Environ  Sci (China) 17:469-473.

Comini, M.A., (2016), Measurement and meaning of cellular thiol: disufhide redox status. Free Radical Research, 50(2):246-271.

Dalla Corte CL, Wagner C, Sudati JH, Comparsi B, Leite GO, Busanello A, Soares FAA, Aschner M, Rocha JBT.(2013) Effects of diphenyl diselenide on methylmercury toxicity in rats. BioMed Res Int 983821, doi: 10.1155/2013/983821.

Dórea JG, Farina M, Rocha JBT. Toxicity of ethylmercury (and Thimerosal): A comparison with methylmercury. J Appl Toxicol 33:700-711, 2013.

Farina, M. et al. (2009) Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells. Toxicological Sciences 112, 416-426.

Farina, M. et al. (2011) Oxidative stress in MeHg-induced neurotoxicity. Toxicol Appl Pharmacol 256, 405-417.

Farina M. , Aschner M., Rocha J.B. (2017),The catecholaminergic neurotransmitter system in methylmercury-Induced neurotoxicity. In Advances in Neurotoxicology (Vol. 1, pp. 47-81). Academic Press.

Flohé, L., W.A. Günzler (1984),   Assays of Glutathione Peroxidase.  Methods in Enzymology, 105 : 114-120.

Franciscato, C., (2009), ZnCl2 exposure protects against behavioral and acetylcholinesterase changes induced by HgCl2. Int. J. Dev. Neurosci. 27:459–468. ijdevneu.2009.05.002

Franco, J.L., (2009), Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase.Free Radical Biology and Medicine, 47 (4), pp. 449-457.

George, G.N., et al. (2008) Chemical forms of mercury and selenium in fish following digestion with simulated gastric fluid. Chemical Research in Toxicology, 21 (11), pp. 2106-2110.

Glaser V, Leipnitz G, Straliotto MR, Oliveira J, dos Santos VV, Wannmacher CMD, de Bem AF, Rocha JBT, Farina M, Latini A. Oxidative stress-mediated inhibition of brain creatine kinase activity by methylmercury. NeuroToxicology 31:454-460, 2010b.

Glaser V, Moritz B, Schmitz A, Dafré AL, Nazari EM, Müller YM, Feksa L, Straliottoa MR, de Bem AF, Farina M, Rocha JBT. Protective effects of diphenyl diselenide in a mouse model of brain toxicity. Chem-Biol Interac 206:18-26, 2013.

Go, Y.M., D.P. Jones (2014), Redox biology: interface of the exposome with the proteome, epigenome and genome. Redox Biology, 2:358-60.

Go, Y.M., et al. (2013). Selective targeting of the cysteine proteome by thioredoxin and glutathione redox systems. Molecular Cell Proteomics. 12(11): 3285-3296.

Han S, Zhu M, Yuan Z, Li X (2001) A methylene blue-mediated enzyme electrode for the determination of trace mercury (II), mercury (I), methylmercury, and mercury-glutathione complex. Biosensors & Bioelectronics. 16 : 9-16.

Holmgren, A., M. Björnstedt (1995), Thioredoxin and thioredoxin reductase. Methods in Enzymolozy, 252: 199-208.

 Heinz, G.H., (2009),  Species differences in the sensitivity of avian embryos to methylmercury. Archives of Environmental Contamination and Toxicology, 56(1) :  pp.129-138.

Heinz, G.H., (1979), Methylmercury: reproductive and behavioral effects on three generations of mallard ducks. The Journal of Wildlife Management, pp.394-401.

Hoppe, B., et al (2008), Biochemical analysis of selenoprotein expression in brain cell lines and in distinct brain regions. Cell and Tissue Research, 332 (3), pp. 403-414.

Jones, D.P. (2015), Redox theory of aging. Redox Biology, 5: 71-79. Liem-Nguyen V, (2017), Thermodynamic stability of mercury(II) complexes formed with environmentally relevant low-molecular-mass thiols studied by competing ligand exchange and density functional theory. Environ. Chem.14:243-253, 2017.

Li, Y., Shi, W., Li, Y., Zhou, Y., Hu, X., Song, C., Ma, H., Wang, C., Li, Y. Neuroprotective effects of chlorogenic acid against apoptosis of PC12 cells induced by methylmercury (2008) Environmental Toxicology and Pharmacology, 26 (1), pp. 1990 neuroblastoma gpx

Liem-Nguyen V, Skyllberg U, Nam K, Björn E. Thermodynamic stability of mercury(II) complexes formed with environmentally relevant low-molecular-mass thiols studied by competing ligand exchange and density functional theory. Environ Chem 14:243-253, 2017.

Malagutti, K.S., da Silva, A.P., Braga, H.C., Mitozo, P.A., Soares dos Santos, A.R., Dafre, A.L., de Bem, A.F., Farina, M. 17β-estradiol decreases methylmercury-induced neurotoxicity in male mice (2009) Environmental Toxicology and Pharmacology, 27 (2), pp. 293-297.

Martyniuk, C. J., Feswick, A., Fang, B., Koomen, J. M., Barber, D. S., Gavin, T., & LoPachin, R. M. (2013). Protein targets of acrylamide adduct formation in cultured rat dopaminergic cells. Toxicology letters, 219(3), 279-287.

Meinerz, DF,  et al.  (2017) . Diphenyl diselenide  protects against methylmercury-induced inhibition of thioredoxin reductase and glutathione peroxidase in human neuroblastoma cells: a comparison with ebselen. Journal of Applied Toxicology 37(9):1073-1081. doi: 10.1002/jat.3458.

Mello-Carpes, P.B. et al.  (2013), Chronic exposure to low mercury chloride concentration induces object recognition and aversive memories deficits in rats. Int J Dev Neurosci 31:468–472.

Mori N, Yasutake A, Hirayama K. Comparative study of activities in reactive oxygen species production/defense system in mitochondria of rat brain and liver, and their susceptibility to methylmercury toxicity. Archives of toxicology. 2007 Nov 1;81(11):769-76.

Mousavi A. (2011), Predicting mercury(II) binding by organic ligands: A chemical model of therapeutic and environmental interests. Environ Forensics 12:327–332.

Oliveira CS., et al. (2017)Chemical Speciation of Selenium  and Mercury as Determinant of Their Neurotoxicity. Advances in  Neurobiology 18:53-83. doi: 10.1007/978-3-319-60189-2_4. 

Pillai, R., J.H.Uyehara-Lock, F.P. Bellinger (2014), Selenium and selenoprotein function in brain disorders. IUBMB Life, 66(4): 229-39. doi: 10.1002/iub.1262.

Pisoschi, A.M., Pop, A. (2015) The role of antioxidants in the chemistry of oxidative stress: A review. Eur J Med. Chem.  97, 55-74.

Peixoto, N.C.,  et al.  (2007), Behavioral alterations induced by HgCl2 depend on the postnatal period of exposure. Int. J. Dev. Neurosc.i 25:39–46

Qiao Y, Huang X, Chen B, He M, Hu B 2017. In vitro study on antagonism mechanism of glutathione, sodium selenite and mercuric chloride. Talanta 171 : 262-269.

Rabenstein, D.L. (1978a), The chemistry of methylmercury toxicology. Journal of Chemical Education 54: 292-296.

Rabenstein, D.L. (1978b), The Aqueous Solution Chemistry of Methylmercury and Its Complexes.Accounts of Chemical Research, 11 (3), pp. 100-107.

Rabenstein, D.L., A.P. Arnold, R.D. Guy, (1986), 1H-NMR study of the removal of methylmercury from intact erythrocytes by sulfhydryl compounds.Journal of Inorganic Biochemistry, 28 (2-3), pp. 279-287.

Rabenstein, D.L., J. Bravo (1987), Nuclear Magnetic Resonance Studies of the Solution Chemistry of Metal Complexes: 24: Arylmercury(II) Complexes of Sulfhydryl-Containing Ligands.Inorganic Chemistry, 26 (17), pp. 2784-2787.

Rabenstein, D.L., M.T. Fairhurst (1975), Nuclear Magnetic Resonance Studies of the Solution Chemistry of Metal Complexes. XI. Binding of Methylmercury by Sulfhydryl-Containing Amino Acids and by Glutathione.Journal of the American Chemical Society, 97 (8), pp. 2086-2092.

Rabenstein, D.L., R.S. Reid (1984), Nuclear Magnetic Resonance Studies of the Solution Chemistry of Metal Complexes. 20. Ligand-Exchange Kinetics of Methylmercury(II)-Thiol Complexes.Inorganic Chemistry, 23 (9), pp. 1246-1250.

Rabenstein, D.L., R.S. Reid, A.A. Isab (1983) 1H nmr study of the effectiveness of various thiols for removal of methylmercury from hemolyzed erythrocytes.Journal of Inorganic Biochemistry, 18 (3), pp. 241-251.

Reid, R.S., D.L. Rabenstein (1982), Nuclear Magnetic Resonance Studies of the Solution Chemistry of Metal Complexes. 19. Formation Constants for the Complexation of Methylmercury by Glutathione, Ergothioneine, and Hemoglobin. Journal of the American Chemical Society, 104 (24), pp. 6733-6737.

Reeves, M.A., Hoffmann, P.R. (2009) The human selenoproteome: recent insights into functions and regulation. Cell Mol Life Sci 66, 2457-2478.

Ren X, Zou L, Zhang X, Branco V, Wang J, Carvalho C, Holmgren A, Lu J. Redox Signaling Mediated by Thioredoxin and Glutathione Systems in the Central Nervous System. Antioxid Redox Signal. 2017 Nov 1;27(13):989-1010. doi: 10.1089/ars.2016.6925.

Ruszkiewicz, J.A.  et al. (2016), Sex-and structure-specific differences in antioxidant responses to methylmercury during early development. Neurotoxicology, 56, pp.118-126.

Sorg, O., (1998), Increased vulnerability of neurones and glial cells to low concentrations of methylmercury in a prooxidant situation. Acta Neuropathologica, 96 (6), pp. 621-627.

Stricks, W., I.M. Kolthoff (1953), Reactions between mercuric mercury and cysteine and glutathione. Apparent dissociation constants, heats and entropies of formation of various forms of mercuric mercaptocysteine and -glutathione. J Am Chem Soc 75:5673-5681, 1953.

Stringari, J. (2008), Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain.Toxicology and Applied Pharmacology, 227 (1), pp. 147-154.

Sugiura, Y., et al.(1976), Selenium protection against mercury toxicity. Binding of methylmercury by the selenohydryl-containing ligand. Journal of the American Chemical Society,  98:2339–2341.

Sugiura Y, Tamai Y, Tanaka H. (1978) Selenium protection against mercury toxicity : high binding affinity of methylmercury by selenium-containing ligands in comparison with sulfur-containing ligands. Bioinorg. Chem. 9 :167-180.

Wagner, al. (2010), In vivo and in vitro inhibition of mice thioredoxin reductase by methylmercury . BioMetals, 23 (6), pp. 1171-1177.

Wiederhold JG, Cramer CJ, Daniel K, Infante I, Bourdon B, Kretzschmar R. (2010) Equilibrium mercury isotope fractionation between dissolved Hg(II) species and thiol-bound Hg. Environ Sci Technol. 44 :4191-7. Doi : 10.1021/es100205t.

Yang, L. (2007), Transcriptional profiling reveals barcode-like toxicogenomic responses in the zebrafish embryo. Genome biology. 8(10):R227.

Xu, X., (2012), Developmental methylmercury exposure affects avoidance learning outcomes in adult zebrafish. Journal of Toxicology and Environmental Health Sciences,  4, no. 5 (2012): 85-91.

Xu X, et al (2016),  Trans-generational transmission of neurobehavioral impairments produced by developmental methylmercury exposure in zebrafish (Danio rerio). Neurotoxicology and Teratology, 53:19-23.

Zemolin, A.P.P.,et al. (2012),  Evidences for a role of glutathione peroxidase 4 (GPx4) in Methylmercury induced neurotoxicity in vivo. Toxicology, 302 (1), pp. 60-67.

Zhu, S.-Y., et al. (2017), Biochemical characterization of the selenoproteome in Gallus gallus via bioinformatics analysis: structure-function relationships and interactions of binding molecules.Metallomics, 9 (2), pp. 124-131.