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Event: 1487

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. 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. The short name should be less than 80 characters in length. More help
Binding, SH/SeH proteins involved in protection against oxidative stress

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Organ term
brain

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help
Process Object Action

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) Under development: Not open for comment. Do not cite EAGMST Under Review
Oxidative stress in chronic kidney disease MolecularInitiatingEvent Frederic Y. Bois (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
During brain development High

Sex Applicability

No help message More help
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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. 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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?
  • 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).
  • 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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  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).

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

Mercury (Methylmercury, mercury chloride)

 The binding of Methylmercury (MeHg) to redox sensitive thiol- or selenol-groups can disrupt the activity of enzymes or the biochemical role of non-enzymatic brain proteins. The stable or transitory interaction (binding) of MeHg with critical thiol and selenol groups in target enzymes can disrupt the biological function of different types of enzymes, particularly of the antioxidant selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase isoforms. The dysregulation of cerebral glutathione (GSH and GSSG) and thioredoxin [Trx or Trx(SH)2]  systems by MeHg (Farina et al. 2011; Branco et al. 2017) can impair the fine cellular redox balance via disruption of sensitive cysteinyl- or thiol-containing proteins (Go etal., 2013; Go et al. 2014; Jones 2015).

Figure 1 – Hypothetical Binding of MeHg to different types of target proteins. The binding of MeHg to proteins can cause either a transitory inhibition of the protein fucntion (first line, the yellow protein was reactivated by interacting with LMM-SH or R-SH). The pink protein is an example of protein that after the binding of MeHg suffered a change in the structure in such a way that it cannot be reactivated by LMM-SH or R-SH.  The third protein (blue) is an example of protein that was permanently denaturated after MeHg binding and even after the removal of MeHg the activity was not recovered. The same type of interactions can be applied to the selenol-containing proteins (i.e., the selenoproteins).

The affinity of Mercury chloride (Hg2+) for thiol and selenol groups is higher than that of MeHg (compare Table 2 with Table 1). The constants described in Table 1 and 2 indicate that MeHg and Hg2+ behave as  strong soft electrophiles, i.e., theyhave much higher affinity for the soft nucleophiles centers of thiol- and selenol-containing molecules (Rabenstein 1978a; Arnold et al. 1986; Sugiura et al., 1976).Furthermore, the rate constant for the reaction of MeHg with thiol/thiolate (R-SH/R-S-) has been estimated to be about 6 x 108 M-1.sec-1,  indicating that the reactions of electrophilic forms of Hg (EpHg; here MeHg and Hg2+) with thiolate and selenolate groups are diffusion controlled reactions (Rabenstein  and Fairhurst, 1975). The constant indicates that the binding of EpHg+ to thiolate (-S-) or selenolate (-Se-) groups will occurr almost instaneously, when an EpHg+ collides with –S- or -Se- groups.

 The studies of Rabenstein and others have also pointed out that the affinity of MeHg for –SeH groups is higher than for  –SH groups (Sugira et al. 1976; Arnold et al. 1986). Consequently, –SeH-containing molecules (i.e., selenoproteins) should be the preferential targets for MeHg (Farina et al. 2011). Accordingly, several studies have demonstrate that the selenoenzymes glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) were inhibited after in vitro and in vivo exposure to MeHg  or Hg2+ (Carvalho et al., 2008a; 2011, Farina et al.,  2009; Franco et al., 2009; Wagner et al., 2010; Branco et al., 2011; 2012; 2014, 2017; Dalla Corte et al., 2013; Meinerz et al., 2017).

As corollary, the occurrence of free MeHg and Hg2+ or bound to other ligands such as carboxylates, amines, chloride or hydroxyl anions in the physiological media of living cells is insignificant or nonexistent (George et al. 2008). The binding of MeHg to abundant low molecular mass thiols or LMM-SH (e.g., cysteine and reduced glutathione-GSH) and high molecular mass thiol-containing proteins or HMM-SH (e.g., albumin, hemoglobin, etc) is critical for the MeHg distribution from non-target to target organs and cells (Farina et al. 2017). The coordination of MeHg with one –S- group of a LMM-SH will determine MeHg distribution to its targets organs, including the brain. The coordination of Hg2+ with two –S- of LMM-SH molecules (particularly, cysteine or Cys) will determine the distribution of Hg2+ to kidney (which is its main target) and to non-classical targets organs, such as the brain (Oliveira et al. 2017). The entrance of Hg2+ into the brain is proportionally small, but recent literature data have indicated the neurotoxicity of very low and environmentally relevant doses of Hg2+ in rodents (Mello-Carpes et al. 2013 ), which confirms data obtained with toxic doses in rodents (Peixoto et al. 2007 ;  Franciscato et al. 2009 ; Chehimi et al. 2012).

Table 1 - Affinity constants of methylmercury for important chemical groups found in biomolecules (adapted from aRabestein, 1978a, bRabestein and Bravo, 1987, using different thiol-containing molecules with the arylmercurialpara-mercurybenzenosulfonate,  and from cArnold et al. 1986 taking into consideration that the calculated formation constant of –Se-MeHg conjugates was 0.1 to 1.2 order greater than that of –S-MeHg). The values represent the Log of the constants.

Functional Group Occurrence Formation constant
Thiol/thiolate (-SH/-S-) Cysteine, glutathione, proteins ≈14-18 a,b

Selenol/selenolate

(-SeH/Se-)
Selenocysteinyl residues in selenoproteins ≈ 16-18c

Table 2. Formation constants of Hg2+ with some representative nucleophilic centers from biomolecules.

Functional group Hg2+
R-S-R ≈ 6-12
R-SH ≈ 40-50
R-SeH ≈ 50-60

The approximate (≈) Log of the constants. The values were adapted  from Stricks and Kolthoff 1953; Mousavi 2011 and Liem-Nguyem et al. 2017.

We have to emphasize that what we call of binding to –SH or –SeH groups is, in fact, an exchange reaction of MeHg from MeHg-S conjugates (e.g., MeHg-cysteine or MeHg-Cys and MeHg-glutathione or MeHg-SG. conjugates) to  a free thiol/thiolate- or selenol/selenolate-group from non-target or target proteins. Thus, the interaction of MeHg with its target proteins in the brain usually involves the exchange of MeHg from low-molecular mass conjugates (LMM-S-conjugates) to a thiol or selenol group in different types of proteins (Rabenstein 1978b; Rabenstein and Fairhurst, 1975; Reid and Rabenstein et al.; 1982; Rabenstein and Reid, 1984; Arnold et al. 1986; Farina et al. 2011, 2017; Dórea et al. 2013).

Figure 2 – Binding of MeHg (CH3Hg+) to target thiol- (HMM-SH) or selenol-containing proteins (HMM-SeH). Note that, in fact, the binding of MeHg to their high molecular mass target proteins is mediated by exchange reactions of MeHg from low molecular mass thiol (LMM-SH) molecules to HMM-SH (represented by Prot-SH) or HMM-SeH (represented by Prot-SeH). The scheme also demonstrated that MeHg conjugated with one LMM-SH (here represented by either Cys1-SHgCH3 or G1SHgCH3) can exchange with others LMM-SH (here represented by Cys2-SH or G2SH). After one exchange reaction, the conjugated Cys1-SHgCH3 and G1SHgCH3 release the free LMM-SH molecules Cys1-SH or G1SH.

Table 3: References for the inhibition by MeHg and Hg2+ of SH-/seleno-proteins involved in protection against oxidative stress

Protein activity inhibited by MeHg

exposure

Functional group likely involved in the inhibition

organism-preparation

glutathione peroxidase (total GPx)

in vivo

-SeH

Adult mice

Glasser et al. 2013

Total GPx

in vivo

-SeH

Adult mice

Glasser et al. 2010a

Mitochondrial total GPx

in vivo

-SeH

Adult mice

Franco et al. 2009

Total GPx

in vitro

-SeH

SH-SY5Y cells

Franco et al. 2009

GPx1 and GPx4

in vivo

-SeH

Adult mice

Zemolin et al. 2012

Total GPx

in vivo

-SeH

Adult male mice

Malagutti et al. 2009

Total GPx

in vitro

-SeH

PC12 cells

Li et al. 2008

Total GPx

in vivo

-SeH

Mice gestational exposure

Stringari et al. 2008

Total GPx

in vivo

-SeH

Adult rats

Cheng et al. 2005

Total GPx

in vitro

-SeH

Fetal Telencepalic cells from rats

Sorg et al. 1998

Total GPx

in vitro

-SeH

Mice neuroblastoma cells

Kromidas et al. 1990

Thioredoxin Reductase (TrxR)

in vivo

-SeH  and –SH

Adult mice

Zemolin et al. 2012

TrxR

in vitro

-SeH  and –SH

Adult mice

Wagner et al. 2010

TrxR

in vivo

-SeH-  and –SH

Adult rats

Dalla Corte et al. 2013

Mitochondrial total Gpx

In vivo

-SeH

Adult rat

Mori et al., 2007

Mitochondrial total Gpx

In vivo

-SeH

Adult Swiss male mice brain

Franco et al., 2009

Total brain TrxR

In vivo

-SeH and -SH

Juvenile fish (zebra-seabreams)

Branco et al. 2011

Branco et al. 2012a,b

Protein activity inhibited by Hg2+

exposure

Functional group likely involved in the inhibition

organism-preparation

Total brain TrxR

In vivo

-SeH and -SH

Juvenile fish (zebra-seabreams)

Branco et al. 2012a,b

Acrylamide

            Acrylamide is an a,β-unsaturated (conjugated) reactive molecule, which can react with thiol (-SH) and amino (-NH2) groups in proteins  (LoPachin, 2004; LoPachin et al. 2007; 2009; 2011;  Friedman, 2003; Bent et al. 2016; Martyniuk et al.2011; LoPachin and Gavin, 2014 ). However, the rate constant for the reaction between acrylamide with thiol/thiolate groups is much lower than that for MeHg.  The rate of reaction of this compound with HMM-SH and LMM-SH is slow but can occur under physiological conditions (Tong et al. 2004; LoPachin, 2004). The inhibition of brain enzymes by acrylamide have been studied and the inhibition caused by acrylamide in some HMM-SH can be reversible  (Howland et al. 1980). Despite of this, we can infer that some targets of MeHg and acrylamide can overlap, in particular GSH,where the rate constant for MeHg and acrylamide are ≈6.0 x 108 M-1.sec-1 and ≈0.15-2.1 x 10-2 M-1.sec-1, respectively (Yousef and Demerdash, 2006; Lapadula et al. 1989; Kopańska et al. 2015). Acrylamide can also be metabolized to an epoxide intermediate (glycidamide), which can also form adducts with cysteinyl residues in HMM-SH target proteins (Bergmark et al. 1991).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). 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.

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:// doi.org/10.1016/j.bbr.2012.06.005

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. https://doi.org/10.1016/j. 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. 13-21.al. 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, C.et 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.