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

115-09-3

BABMCXWQNSQAOC-UHFFFAOYSA-M

Methylmercuric(II) chloride

Methyl mercuric(II) chloride (Methyl mercuric chloride) (MeHg) Mercury, chloromethyl- Chlormethylquecksilber chloromethylmercure chloromethylmercury clorometilmercurio Mercury methyl chloride Methylmercuric chloride Methylmercury chloride Methylmercury monochloride METHYL-QUECKSILBER-CHLORID Monomethyl mercury chloride NSC 19998

DTXSID5020813

51312-24-4

Mercury chloride

DTXSID40858724

79-06-1

HRPVXLWXLXDGHG-UHFFFAOYSA-N

Acrylamide

2-Propenamide 2-Propene amide acrilamida Acrylamid Acrylamide monomer Acrylic acid amide Acrylic amide Bio-Acrylamide 50 Ethylenecarboxamide NSC 7785 Propenamide UN 2074 UN3426 Vinyl amide

DTXSID5020027

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

60-35-5

DLFVBJFMPXGRIB-UHFFFAOYSA-N

Acetamide

Acetamid acetamida Acetic acid amide Acetimidic acid Ethanamide Ethanimidic acid Methanecarboxamide NSC 25945

DTXSID7020005

103-90-2

RZVAJINKPMORJF-UHFFFAOYSA-N

Acetaminophen

4-Acetamidophenol APAP Paracetamol 4-hydroxyacetanilide Acetamide, N-(4-hydroxyphenyl)- 4-(Acetylamino)phenol 4-(N-Acetylamino)phenol 4-Acetaminophenol 4'-Hydroxyacetanilide Abensanil Acetagesic Acetalgin ACETAMIDE, N-(4-HYDROXYPHENYL) Acetaminofen Acetanilide, 4'-hydroxy- ACETANILIDE, 4-HYDROXY- Algotropyl Alvedon Anaflon Apamide Banesin Ben-u-ron Bickie-mol Biocetamol Cetadol Citramon P Claratal Clixodyne Dafalgan Daphalgan Dial-a-gesic Disprol Doliprane Dolprone Dymadon Efferalgan Endophy Febrilex Febrilix Febro-Gesic Febrolin Fepanil Finimal Gattaphen T Gelocatil Gutte Enteric Homoolan Jin Gang Lestemp Liquagesic Lonarid Lyteca Syrup Minoset Momentum N-(4-Hydroxyphenyl)acetamide N-Acetyl-4-aminophenol N-Acetyl-4-hydroxyaniline N-Acetyl-p-aminophenol Napafen Naprinol Nobedon NSC 109028 NSC 3991 Ortensan p-(Acetylamino)phenol p-Aceaminophenol Pacemol p-Acetamidophenol p-Acetoaminophen P-ACETYLAMINOPHENOL Paldesic panadeine Panadol Panadol Actifast Panadol Extend Panaleve Panasorb Panodil Paracetamol DC Paracetamole Parageniol Paramol Paraspen Parelan Pasolind N Perfalgan Phenaphen Phendon p-Hydroxyacetanilide Prodafalgan Puerxitong Pyrinazine Resfenol Resprin Rhodapop NCR Salzone Tabalgin Tachipirina Tempanal Tralgon Tylenol TylolHot Valadol Valgesic Vermidon Vick Pyrena

DTXSID2020006

968-81-0

VGZSUPCWNCWDAN-UHFFFAOYSA-N

Acetohexamide

Benzenesulfonamide, 4-acetyl-N-[(cyclohexylamino)carbonyl]- 1-(p-Acetylbenzenesulfonyl)-3-cyclohexylurea 1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea Acetohexamid acetohexamida Dimelin Dimelor Dymelor Gamadiabet Hypoglicil Metaglucina Minoral N-(p-Acetylphenylsulfonyl)-N'-cyclohexylurea Ordimel Tsiklamid Urea, 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexyl-

DTXSID7020007

67-66-3

HEDRZPFGACZZDS-UHFFFAOYSA-N

Chloroform

Trichloromethane Methane, trichloro- CARBON TRICHLORIDE Chloroforme cloroformo Formyl trichloride Methane trichloride Methane,trichloro- NSC 77361 Trichloroform UN 1888

DTXSID1020306

110-00-9

YLQBMQCUIZJEEH-UHFFFAOYSA-N

Furan

Divinylene oxide furanne Furfuran Oxacyclopentadiene Tetrole UN 2389

DTXSID6020646

7429-90-5

XAGFODPZIPBFFR-UHFFFAOYSA-N

AZDRQVAHHNSJOQ-UHFFFAOYSA-N

Aluminum

Aisin Metal Fiber Al 050P-H24 ALC Fine Alcan XI 1391 Almi-Paste SSP 303AR Aloxal 3010 Alpaste 00-0506 Alpaste 0100M Alpaste 0100MA Alpaste 0100M-C Alpaste 0200M Alpaste 0200T Alpaste 0230M Alpaste 0230T Alpaste 0241M Alpaste 0300M Alpaste 0500M Alpaste 0539X Alpaste 0620MS Alpaste 0625TS Alpaste 0638-70C Alpaste 0700M Alpaste 0780M Alpaste 0900M Alpaste 100M Alpaste 100MS Alpaste 100MSR Alpaste 1100M Alpaste 1100MA Alpaste 1100N Alpaste 1100NA Alpaste 1109MA Alpaste 1109MC Alpaste 1200M Alpaste 1200T Alpaste 1260MS Alpaste 1500MA Alpaste 1700NL Alpaste 1810YL Alpaste 1830YL Alpaste 1900M Alpaste 1900XS Alpaste 1950M Alpaste 1950N Alpaste 210N Alpaste 2172EA Alpaste 2173 Alpaste 240T Alpaste 241M Alpaste 417 Alpaste 46-046 Alpaste 4-621 Alpaste 4919 Alpaste 50-63 Alpaste 50-635 Alpaste 51-148B Alpaste 51-231 Alpaste 5205N Alpaste 5207N Alpaste 52-509 Alpaste 52-568 Alpaste 5301N Alpaste 5302N Alpaste 53-119 Alpaste 5422NS Alpaste 54-452 Alpaste 54-497 Alpaste 54-542 Alpaste 55-516 Alpaste 55-519 Alpaste 55-574 Alpaste 5620NS Alpaste 5630NS Alpaste 5640NS Alpaste 56-501 Alpaste 5650NS Alpaste 5653NS Alpaste 5654NS Alpaste 5680N Alpaste 5680NS Alpaste 60-600 Alpaste 60-760 Alpaste 60-768 Alpaste 62-356 Alpaste 6340NS Alpaste 6370NS Alpaste 6390NS Alpaste 640NS Alpaste 65-388 Alpaste 66NLB Alpaste 710N Alpaste 7130N Alpaste 7160N Alpaste 7160NS Alpaste 725N Alpaste 740NS Alpaste 7430NS Alpaste 7580NS Alpaste 7620NS Alpaste 7640NS Alpaste 7670M Alpaste 7670NS Alpaste 7675NS Alpaste 7679NS Alpaste 7680N Alpaste 7680NS Alpaste 76840NS Alpaste 7730N Alpaste 7770N Alpaste 7830N Alpaste 8004 Alpaste 8080N Alpaste 8260NAR Alpaste 891K Alpaste 91-0562 Alpaste 92-0592 Alpaste 93-0595 Alpaste 93-0647 Alpaste 94-2315 Alpaste 95-0570 Alpaste 96-0635 Alpaste 96-2104 Alpaste 97-0510 Alpaste 97-0534 Alpaste AW 520B Alpaste AW 612 Alpaste AW 9800 Alpaste F 795 Alpaste FM 7680K Alpaste FX 440 Alpaste FX 910 Alpaste FZ 0534 Alpaste FZU 40C Alpaste G Alpaste HR 8801 Alpaste HS 2 Alpaste J Alpaste K 9800 Alpaste MC 666 Alpaste MC 707 Alpaste MF 20 Alpaste MG 01 Alpaste MG 1000 Alpaste MG 1300 Alpaste MG 500 Alpaste MG 600 Alpaste MH 6601 Alpaste MH 8801 Alpaste MH 9901 Alpaste MR 7000 Alpaste MR 9000 Alpaste MS 630 Alpaste N 1700NL Alpaste NS 7670 Alpaste O 100N Alpaste O 2130 Alpaste O 300M Alpaste P 0100 Alpaste P 1950 Alpaste S Alpaste SAP 110 Alpaste SAP 414P Alpaste SAP 550N Alpaste SCR 5070 Alpaste TCR 2020 Alpaste TCR 2060 Alpaste TCR 2070 Alpaste TCR 3010 Alpaste TCR 3030 Alpaste TCR 3040 Alpaste TCR 3130 Alpaste TD 200T Alpaste UF 500 Alpaste WB 0230 Alpaste WD 500 Alpaste WJP-U 75C Alpaste WX 0630 Alpaste WX 7830 Alpaste WXA 7640 Alpaste WXM 0630 Alpaste WXM 0650 Alpaste WXM 0660 Alpaste WXM 1415 Alpaste WXM 1440 Alpaste WXM 5422 Alpaste WXM 760b Alpaste WXM 7640 Alpaste WXM 7675 Alpaste WXM-T 60B Alpaste WXM-U 75 Alpaste WXM-U 75C Altop X Aluchrome Ultrafin Super Alumat 1600 Alumet H 30 aluminio Aluminium Aluminium Flake Aluminum 27 Aluminum atom Aluminum element Aluminum Flake PCF 7620 Aluminum granules ALUMINUM METAL/GRANULE ALUMINUM PASTE ALUMINUM PIGMENT ALUMINUM TURNINGS Alumi-paste 640NS Alumipaste 91-0562 Alumipaste 98-1822T Alumipaste AW 620 Alumipaste CR 300 Alumipaste GX 180A Alumipaste GX 201A Alumipaste HR 7000 Alumipaste HR 850 Alumipaste MG 11 Alumipaste MH 8801 Aquamet NPW 2900 Aquapaste 205-5 Aquasilver LPW Astroflake 40 Astroflake Black N 020 Astroflake Black N 070 Astroflake LG 40 Astroflake LG 70 Astroflake Silver N 040 Astroshine NJ 1600 Astroshine T 8990 Atomizalumi VA 200 C.I. PIGMENT METAL 1 Chromal IV Chromal X Decomet 1001/10 Decomet 2018/10 Decomet High Gloss Al 1002/10 Ecka AS 081 Eckart 9155 Eterna Brite 301-1 Eterna Brite 601-1 Eterna Brite 651-1 Eterna Brite EBP 251PA Eterna Brite Primier 251PA Ferro FX 53-038 Friend Color F 500GR-W Friend Color F 500WT Friend Color F 700RE-W Friend Color F 701RE-W Hi Print 60T High Print 60T Hisparkle HS 2 Hydro Paste 8726 Hydrolac WHH 2153 Hydrolan 3560 Hydrolux Reflexal 100 Hydroshine WS 1001 JISA 51010P Kryal Z Lansford 243 LE Sheet 800 Leafing Alpaste LG-H Silver 25 Lunar Al-V 95 Metallux 161 Metallux 2154 Metallux 2192 Metalure Metalure 55350 Metalure L 55350 Metalure L 59510 Metalure W 2001 Metapor Metasheen 1800 Metasheen HR 0800 Metasheen KM 100 Metasheen KM 1000 Metasheen Slurry 1807 Metasheen Slurry 1811 Metasheen Slurry KM 100 Metax G Metax S Mirror Glow 1000 Mirror Glow 600 Mirrorsheen Noral Aluminium Noral Ink Grade Aluminium Obron 10890 Offset FM 4500 Puratronic Reflexal 145 Reynolds 400 Reynolds 4-301 Reynolds 4-591 Reynolds 667 SAP 260PW-HS SAP-FM 4010 SBC 516-20Z Scotchcal 7755SE Serumekku Setanium 50MIS-H8 Siberline ET 2025 Siberline ST 21030E1 Silvar A Silver VT 522 Silverline SSP 353 Silvex 793-20C Sparkle Silver 3141ST Sparkle Silver 3500 Sparkle Silver 3641 Sparkle Silver 5000AR Sparkle Silver 516AR Sparkle Silver 5242AR Sparkle Silver 5245AR Sparkle Silver 5271AR Sparkle Silver 5500 Sparkle Silver 5745 Sparkle Silver 7000AR Sparkle Silver 7005AR Sparkle Silver 7500 Sparkle Silver 960-25E1 Sparkle Silver E 1745AR Sparkle Silver L 1526AR Sparkle Silver Premier 751 Sparkle Silver SS 3130 Sparkle Silver SS 5242AR Sparkle Silver SS 5588 Sparkle Silver SSP 132AR Special PCR 507 Splendal 6001BG Spota Mobil 801 SSP 760-20C Stapa Aloxal PM 2010 Stapa Aloxal PM 3010 Stapa Aloxal PM 4010 Stapa Hydrolac BG 8n.1 Stapa Hydrolac BGH Chromal X Stapa Hydrolac PM Chromal VIII Stapa Hydrolac W 60NL Stapa Hydrolac WH 16 Stapa Hydrolac WH 66NL Stapa Hydrolux 2192 Stapa Hydrolux 8154 Stapa IL Hydrolan 2192-55900G Stapa Metallic R 607 Stapa Metallux 1050 Stapa Metallux 211 Stapa Metallux 212 Stapa Metallux 2196 Stapa Metallux 274 Stapa Mobilux 181 Stapa Offset 3000 Stapa PV 10 Stapa VP 46432G Starbrite 2100 Super Fine 18000 Super Fine 22000 Supramex 2022 Toyo Aluminum 02-0005 Toyo Aluminum 93-3040 Transmet K 102HE Tufflake 3645 Tufflake 5843 UN 1396 US Aluminum 809 Valimet H 2 Valimet H 3 White Silver 7080N White Silver 7130N

DTXSID3040273

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag Nanopaste NPS-J 90 Ag Sphere 2 Ag-C-GS Algaedyn Arctic Silver 3 Argentum Astroflake 5 Carey Lea silver Colloidal silver Dotite XA 208 Du Pont 4943 ECM 100AF4810 Enlight 600 Enlight silver plate 600 Epinall Finesphere SVND 102 Fordel DC FP 5369-502 Jelcon SH 1 Jungindai Takasago 300 KS (metal) LCP 1-19SFS Metz 3000-1 Nanomelt AGC-A Nanomelt Ag-XA 301 Nanomelt Ag-XF 301 Nanomelt Ag-XF 301H Nanopaste NPS-J 90 Perfect Silver Puff Silver X 1200 RT 1710S-C1 SD (metal) Shell Silver Silbest E 20 Silbest F 20 Silbest J 18 Silbest TC 12 Silbest TC 20E Silbest TC 25A Silbest TCG 1 Silbest TCG 7 Silcoat AgC 103 Silcoat AgC 2011 Silcoat AgC 209 Silcoat AgC 2190 Silcoat AgC 222 Silcoat AgC 2411 Silcoat AgC 74T Silcoat AgC-A Silcoat AgC-AO Silcoat AgC-B Silcoat AgC-BO Silcoat AgC-D Silcoat AgC-G Silcoat AgC-GS Silcoat AgC-L Silcoat AgC-O Silcoat GS Silcoat RF 200 Silflake 135 Silsphere 514 Silver atom Silver element Silver Flake 1 Silver Flake 25 Silver Flake 52 Silver Flake 7A SILVER FLAKES Silver metal Silvest TCG 11N Technic 299 Technic 450 Techno Alpha 175

DTXSID4024305

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

Colloidal manganese Cutaval Manganese element Manganese fulleride Manganese metal alloy Manganese-55 manganeso

DTXSID2024169

7440-02-0

PXHVJJICTQNCMI-UHFFFAOYSA-N

Nickel

Carbonyl 255 Carbonyl Ni 123 Carbonyl Ni 283 Carbonyl Nickel 123 Carbonyl Nickel 283 Carbonyl Nickel 287 Cerac N 2003 CNS 10 Micron Exmet 4 Ni X-4/0 Fibrex P Incofoam Nickel element NICKEL ROUND ANODES Nicrobraz LM:BNi 2 Ni-Flake 95 Novamet 123 Novamet 4SP Novamet 4SP10 Novamet 525 Novamet CNS 400 Novamet HCA 1 Novamet NI 255 Raney nickel Raney nickel 2800 UN 1325 UN 2881

DTXSID2020925

7440-66-6

HCHKCACWOHOZIP-UHFFFAOYSA-N

Zinc

Zn Asarco L 15 C.I. Pigment Black 16 Merrillite NC-Zinc Rheinzink Stapa TE Zinc AT UF (metal) UN 1436 Zinc dust Zinc Dust 3 Zinc Dust 500 mesh Zinc Dust LS 2 Zinc Dust MCS Zinc Flakes GTT ZINC METAL ZINC MOSSY ZINC STRIP ZINC, MOSSY Zincsalt GTT

DTXSID7035012

CHEBI:16856

CHEBI glutathione

GO:0005746

GO mitochondrial respiratory chain

GO:0016209

GO antioxidant activity

MP:0003674

MP oxidative stress

GO:0008219

GO cell death

GO:0001909

GO leukocyte mediated cytotoxicity

WIKI abnormal

WIKI increased

WIKI disrupted

Methylmercuric(II) chloride

2016-11-29T18:42:20

Mercury chloride

2018-10-08T04:33:29

Acrylamide

2017-11-08T11:15:19

Reactive oxygen species

2017-06-16T08:32:10

2017-08-15T10:43:27

Mercury

2016-11-29T18:42:19

Acetaminophen

2016-11-29T18:42:26

Chloroform

2016-11-29T18:42:27

furan

2020-05-01T14:35:22

Platinum

2022-02-04T14:36:54

Aluminum

2022-02-04T14:42:11

Cadmium

2017-10-25T08:33:12

Uranium

2021-08-05T14:28:50

Arsenic

2021-04-27T00:15:21

Silver

2022-02-03T11:20:11

Manganese

2022-02-04T14:47:23

Nickel

2022-02-04T14:47:59

Zinc

2022-02-04T15:05:00

nanoparticles

2016-12-21T09:40:06

10116

NCBI rat

10090

NCBI mouse

7955

NCBI zebra fish

WCS_9606

common toxicological species human

WCS_9031

common ecological species Gallus gallus

9606

NCBI Homo sapiens

WCS_9913

common ecological species Bos taurus

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

WikiUser_26

ApacheUser rodents

435435

NCBI Rattus sp. ABTC 42503

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

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

Molecular

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).

<ul> <li>Binding of Hg to thiol groups was analyzed by multiple collector inductively coupled plasma mass spectometry (Wiederhold et al., 2010).</li> <li>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).</li> <li>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).</li> <li style="text-align:justify">A photometric method to quantify GSH loss after reactio with organic electrophiles has also been reported (Böhme et al., 2009).</li> <li>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).</li> <li> 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.</li> <li>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)</li> <li>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.</li> </ul>

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).

UBERON:0000955

UBERON brain

High Female High Male

High

During brain development

Not Specified Not Specified Not Specified Not Specified Not Specified 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:// 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.   AOPWiki 2017-11-09T04:01:32

2022-07-15T09:18:22

Oxidation, Glutathione (To be considered with MIE)

Oxidation, Glutathione

Molecular

**NOTE** : This KE has been revised to be part of the MIE; Peptide Oxidation.   Glutathione (GSH) oxidation refers to the conversion of reduced glutathione to its oxidized form glutathione disulfide (GSSG) in the presence of oxidative species. GSH plays an important role as an anti-oxidant in regulating cellular redox homeostasis, and is mainly present in the cell as the reduced form (98%). Deficiency in GSH or a decrease in GSH/GSSG ratio results in decreased anti-oxidant function and increased susceptibility to oxidative stress, thus making it a marker of cellular redox status. An imbalance in GSH/GSSG ratio has been implicated in the onset and progression of human diseases, such as neurodegenerative diseases, cancers, pulmonary diseases and cardiovascular diseases (Ballatori et al., 2009; Kalinina et al., 2014).

GSH and GSSG levels can be determined by high-performance liquid chromatography HPLC, capillary electrophoresis, or biochemically in microplates. Several different assays have been designed to measure glutathione in samples. Enzyme recycling is a widely accepted method to determine total glutathione, in which GSH reacts with DTNB (Ellman's reagent) in the presence of glutathione reductase. Glutathione reductase reduces GSSG to GSH, which then reacts with DTNB to produce a yellow colored 5-thio-2-nitrobenzoic acid (TNB), which absorbs light at a wavelength of 412 nm (Tipple and Rogers, 2012). Another method uses HPLC separation and fluorometric detection, where iodoactetic acid is added as a thiol akylating agent followed by dansyl chloride derivatization for fluorometric detection. Similarly, monochlorobimane can be added to culture medium in order to form a fluorescent GSH-monochlorobimane adduct that can be measured fluorometrically (Kamencic et al., 2000).

The concentrations of GSH and GSSG have been shown in tissues of human and laboratory animals, including rats, mice and cows (Chen et al., 2010; Giustarini et al., 2013).

High Unspecific

High

All life stages

High High High High

Ballatori, N., Krance, S.M., Notenboom, S., Shi, S., Tieu, K., and Hammond, C.L. (2009). Glutathione dysregulation and the etiology and progression of human diseases. Biol. Chem. 390, 191–214. Chen, C.-A., Wang, T.-Y., Varadharaj, S., Reyes, L.A., Hemann, C., Talukder, M.A.H., Chen, Y.-R., Druhan, L.J., and Zweier, J.L. (2010). S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468, 1115–1118. Giustarini, D., Dalle-Donne, I., Milzani, A., Fanti, P., and Rossi, R. (2013). Analysis of GSH and GSSG after derivatization with N-ethylmaleimide. Nat. Protoc. 8, 1660–1669. Kalinina, E.V., Chernov, N.N., and Novichkova, M.D. (2014). Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochem. Biokhimii︠a︡ 79, 1562–1583. Kamencic, H., Lyon, A., Paterson, P.G., and Juurlink, B.H. (2000). Monochlorobimane fluorometric method to measure tissue glutathione. Anal. Biochem. 286, 35–37. Tipple, T.E., and Rogers, L.K. (2012). Methods for the Determination of Plasma or Tissue Glutathione Levels. Methods Mol. Biol. Clifton NJ 889, 315–324. AOPWiki 2016-11-29T18:41:27

2017-11-09T06:40:14

Decreased protection against oxidative stress

Protection against oxidative stress, decreased

Cellular

High levels reactive oxygen species (ROS) can be very damaging to cells and molecules within the cell.  As a result, the cell has important defense mechanisms to protect itself from ROS, such as glutathione and selenoenzymes.   Glutathione (GSH) is the most abundant low molecular mass thiol compound synthesized in cells, reaching intracellular concentrations of 1–10 mM, and is the major antioxidant and redox buffer in human cells. In fact, GSH serves as a reducing agent for ROS and other unstable molecules generated by catalytic systems, including glutathione peroxidase (GPx)(Forman, 2009).   Selenium plays a crucial role in antioxidant defense, as one Se atom is absolutely required at the active site of all selenoenzymes, such as GPx and thioredoxin reductase (TrxR), in the form of selenocystein (Rayman, 2000). GPx is an antioxidant enzyme that, in the presence of tripeptide GSH, adds two electrons to reduce H2O2 and lipid peroxides to water and lipid alcohols, respectively, while simultaneously oxidizing GSH to glutathione disulfide. The GPx/GSH system is thought to be a major defense in low-level oxidative stress, and decreased GPx activity or GSH levels may lead to the absence of adequate H2O2 and lipid peroxides detoxification, which may be converted to OH-radicals and lipid peroxyl radicals, respectively, by transition metals (Fe2+) (Brigelius-Flohe, 2013). Thioredoxin reductase (TrxR) is essential for maintaining intracellular redox status. The expression of this small (12 kDa) ubiquitous thiol-active protein is induced by ROS and an elevated serum level may indicate a state of oxidative stress. In this regard, TrxR, a NADPH-dependent lipid hydroperoxide reductase, uses NADPH to maintain the levels of reduced Trx via a mechanism similar to that used by GR to maintain GSH levels, contributing to the maintenance of thiol redox homeostasis in proteins. Importantly, the inhibition of TrxR impairs the cyclical regeneration of Trx activity, as Trx remains in the oxidized state (Bjornstedt, 1995, Zhong, 2002). Other, less studied selenoproteins, such as SelP, H, K, S, R, and W selenoproteins, play a role in antioxidant defense (Pisoschi, 2015, Reeves, 2009)

<ul> <li>Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html)</li> <li>Reduction of GPx activity. The activity of GPx can be measured by a colorimetric assay, using a commercially available kit (e.g., Abcam ab102530)</li> <li>Reduction of TrxR activity. The activity of TrxR can be measured by a colorimetric assay, using a commercially available kit (e.g., Abcam ab83463)</li> <li>Reduction of Selenoprotein R activity. The methionine sulfoxide reductase activity of SelR can be measured by HPLC (Chen, 2013)</li> <li>Selenoprotein P depletion. The depletion in SelP can be measured using an ELISA (e.g., MyBiosource #MBS9301054)</li> <li>Selenoprotein W depletion. The depletion in SelW can be measured using an ELISA (e.g., MyBiosource #MBS9312544)</li> <li>Selenoprotein S depletion. The depletion in SelS can be measured using an ELISA (e.g., MyBiosource #MBS9306607)</li> <li>Selenoprotein H and K depletion. The depletion in SelH and K can be measured by western blotting (Lee, 2015, Novoselov, 2007)</li> </ul>

Glutathione, GPx and TrxR are present in bacteria, archea, algae, and in the majority of animals, including humans.

UBERON:0000955

UBERON brain

Not Specified Male Not Specified Female

Not Specified

All life stages

Not Specified Not Specified Not Specified Bjornstedt, M., Hamberg, M., Kumar, S., Xue, J., Holmgre, A. (1995) Human thioredoxin reductase directly reduces lipid hydroperoxides by nadph and selenocysteine strongly stimulates the reaction via catalytically generated selenols. J Biol Chem 270, 11761-11764. Brigelius-Flohe, R., Maiorino, M. (2013) Glutathione peroxidases. Biochim Biophys Acta 1830, 3289-3303. Chen, P. et al. (2013) Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer's Disease. PLoS One 8, e66384. Forman, H.J., Zhang, H., Rinna, A. (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 30, 1-12. Lee, J.H. et al. (2015) Selenoprotein S-dependent Selenoprotein K Binding to p97(VCP) Protein Is Essential for Endoplasmic Reticulum-associated Degradation. J Biol Chem 290, 29941-29952. Novoselov, S.V. et al. (2007) Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern. J Biol Chem 282, 11960-11968. 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. Rayman, M.P. (2000) The importance of selenium to human health. Lancet 356, 233-241. Reeves, M.A., Hoffmann, P.R. (2009) The human selenoproteome: recent insights into functions and regulation. Cell Mol Life Sci 66, 2457-2478. Zhong, L., Holmgren, A. (2002) Mammalian thioredoxin reductases as hydroperoxide reductases. Methods Enzymol 347, 236-243. AOPWiki 2018-09-13T04:24:06

2022-07-15T09:28:06

Oxidative Stress

Molecular

Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell.  As a result, the cell has important defense mechanisms to protect itself from ROS. For example, Nrf2 is a transcription factor and master regulator of the oxidative stress response. During periods of oxidative stress, Nrf2-dependent changes in gene expression are important in regaining cellular homeostasis (Nguyen, et al. 2009) and can be used as indicators of the presence of oxidative stress in the cell. In addition to the directly damaging actions of ROS, cellular oxidative stress also changes cellular activities on a molecular level. Redox sensitive proteins have altered physiology in the presence and absence of ROS, which is caused by the oxidation of sulfhydryls to disulfides (2SH àSS) on neighboring amino acids (Antelmann and Helmann 2011). Importantly Keap1, the negative regulator of Nrf2, is regulated in this manner (Itoh, et al. 2010). ROS also undermine the mitochondrial defense system from oxidative damage. The antioxidant systems consist of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as α-tocopherol and ubiquinol, or antioxidant vitamins and minerals including vitamin E, C, carotene, lutein, zeaxanthin, selenium, and zinc (Fletcher, 2010). The enzymes, vitamins and minerals catalyze the conversion of ROS to non-toxic molecules such as water and O2. However, these antioxidant systems are not perfect and endogenous metabolic processes and/or exogenous oxidative influences can trigger cumulative oxidative injuries to the mitochondria, causing a decline in their functionality and efficiency, which further promotes cellular oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Guo et al., 2013; Karimi et al., 2017). However, an emerging viewpoint suggests that ROS-induced modifications may not be as detrimental as previously thought, but rather contribute to signaling processes (Foyer et al., 2017).  Protection against oxidative stress is relevant for all tissues and organs, although some tissues may be more susceptible. For example, the brain possesses several key physiological features, such as high O2 utilization, high polyunsaturated fatty acids content, presence of autooxidable neurotransmitters, and low antioxidant defenses as compared to other organs, that make it highly susceptible to oxidative stress (Halliwell, 2006; Emerit and al., 2004; Frauenberger et al., 2016). Sources of ROS Production Direct Sources: Direct sources involve the deposition of energy onto water molecules, breaking them into active radical species. When ionizing radiation hits water, it breaks it into hydrogen (H*) and hydroxyl (OH*) radicals by destroying its bonds. The hydrogen will create hydroxyperoxyl free radicals (HO2*) if oxygen is available, which can then react with another of itself to form hydrogen peroxide (H2O2) and more O2 (Elgazzar and Kazem, 2015). Antioxidant mechanisms are also affected by radiation, with catalase (CAT) and peroxidase (POD) levels rising as a result of exposure (Seen et al. 2018; Ahmad et al. 2021). Indirect Sources: An indirect source of ROS is the mitochondria, which is one of the primary producers in eukaryotic cells (Powers et al., 2008).  As much as 2% of the electrons that should be going through the electron transport chain in the mitochondria escape, allowing them an opportunity to interact with surrounding structures. Electron-oxygen reactions result in free radical production, including the formation of hydrogen peroxide (H2O2) (Zhao et al., 2019). The electron transport chain, which also creates ROS, is activated by free adenosine diphosphate (ADP), O2, and inorganic phosphate (Pi) (Hargreaves et al. 2020; Raimondi et al. 2020; Vargas-Mendoza et al. 2021). The first and third complexes of the transport chain are the most relevant to mammalian ROS production (Raimondi et al., 2020). The mitochondria have its own set of DNA and it is a prime target of oxidative damage (Guo et al., 2013). ROS are also produced through nicotinamide adenine dinucleotide phosphate oxidase (NOX) stimulation, an event commenced by angiotensin II, a product/effector of the renin-angiotensin system (Nguyen Dinh Cat et al. 2013; Forrester et al. 2018). Other ROS producers include xanthine oxidase, immune cells (macrophage, neutrophils, monocytes, and eosinophils), phospholipase A2 (PLA2), monoamine oxidase (MAO), and carbon-based nanomaterials (Powers et al. 2008; Jacobsen et al. 2008; Vargas-Mendoza et al. 2021).

Oxidative Stress. Direct measurement of ROS is difficult because ROS are unstable. The presence of ROS can be assayed indirectly by measurement of cellular antioxidants, or by ROS-dependent cellular damage. Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed <ul> <li>Detection of ROS by chemiluminescence (https://www.sciencedirect.com/science/article/abs/pii/S0165993606001683)</li> <li>Detection of ROS by chemiluminescence is also described in OECD TG 495 to assess phototoxic potential.</li> <li>Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html). </li> <li>TBARS. Oxidative damage to lipids can be measured by assaying for lipid peroxidation using TBARS (thiobarbituric acid reactive substances) using a commercially available kit. </li> <li>8-oxo-dG. Oxidative damage to nucleic acids can be assayed by measuring 8-oxo-dG adducts (for which there are a number of ELISA based commercially available kits),or  HPLC, described in Chepelev et al. (Chepelev, et al. 2015).</li> </ul> Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assay for Nrf2 activity include: <ul> <li>Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus</li> <li>Western blot for increased Nrf2 protein levels</li> <li>Western blot of cytoplasmic and nuclear fractions to observe translocation of Nrf2 protein from the cytoplasm to the nucleus</li> <li>qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)</li> <li>Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway (e.g., Jackson et al. 2014)</li> <li>OECD TG422D describes an ARE-Nrf2 Luciferase test method</li> <li>In general, there are a variety of commercially available colorimetric or fluorescent kits for detecting Nrf2 activation</li> </ul>   <table border="1" cellpadding="1" cellspacing="1"> <tbody> <tr> <td>Assay Type & Measured Content</td> <td>Description</td> <td>Dose Range Studied</td> <td> Assay Characteristics (Length / Ease of use/Accuracy) </td> </tr> <tr> <td> ROS Formation in the Mitochondria assay (Shaki et al., 2012) </td> <td>“The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 μM) in respiration buffer containing (0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 μM) to mitochondria and was then incubated for 10 min. Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.”</td> <td>0, 50, 100 and 200 μM of Uranyl Acetate</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td> Mitochondrial Antioxidant Content Assay Measuring GSH content (Shaki et al., 2012)</td> <td>“GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as μg/mg protein.”</td> <td> 0, 50, 100, or 200 μM Uranyl Acetate </td> <td> </td> </tr> <tr> <td> H2O2 Production Assay Measuring H2O2 Production in isolated mitochondria (Heyno et al., 2008)</td> <td>“Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.” (</td> <td> 0, 10, 30  μM Cd2+ 2  μM antimycin A</td> <td> </td> </tr> <tr> <td> Flow Cytometry ROS & Cell Viability (Kruiderig et al., 1997)</td> <td>“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”</td> <td> </td> <td> Strong/easy medium</td> </tr> <tr> <td> DCFH-DA Assay Detection of hydrogen peroxide production (Yuan et al., 2016) </td> <td> Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production.    </td> <td>0-400 µM</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td> H2-DCF-DA Assay Detection of superoxide production (Thiebault et al., 2007) </td> <td>This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.</td> <td>0–600 µM</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td>CM-H2DCFDA Assay</td> <td>**Come back and explain the flow cytometry determination of oxidative stress from Pan et al. (2009)**</td> <td> </td> <td> </td> </tr> </tbody> </table> Direct Methods of Measurement <table cellspacing="0" class="Table" style="border-collapse:collapse; width:623px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:141px"> Method of Measurement  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:151px"> References  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:255px"> Description  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:76px"> OECD-Approved Assay </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Chemiluminescence  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Lu, C. et al., 2006;  Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> ROS can induce electron transitions in molecules, leading to electronically excited products. When the electrons transition back to ground state, chemiluminescence is emitted and can be measured. Reagents such as uminol and lucigenin are commonly used to amplify the signal.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No   </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Spectrophotometry  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> NO has a short half-life. However, if it has been reduced to nitrite (NO2-), stable azocompounds can be formed via the Griess Reaction, and further measured by spectrophotometry.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Direct or Spin Trapping-Based Electron Paramagnetic Resonance (EPR) Spectroscopy  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The unpaired electrons (free radicals) found in ROS can be detected with EPR, and is known as electron paramagnetic resonance. A variety of spin traps can be used.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Nitroblue Tetrazolium Assay  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The Nitroblue Tetrazolium assay is used to measure O2•– levels. O2•– reduces nitroblue tetrazolium (a yellow dye) to formazan (a blue dye), and can be measured at 620 nm.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Fluorescence analysis of dihydroethidium (DHE) or Hydrocyans  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Fluorescence analysis of DHE is used to measure O2•– levels. O2•–  is reduced to O2 as DHE is oxidized to 2-hydroxyethidium, and this reaction can be measured by fluorescence. Similarly, hydrocyans can be oxidized by any ROS, and measured via fluorescence.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Amplex Red Assay  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Fluorescence analysis to measure extramitochondrial or extracellular H2O2 levels. In the presence of horseradish peroxidase and H2O2, Amplex Red is oxidized to resorufin, a fluorescent molecule measurable by plate reader.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Dichlorodihydrofluorescein Diacetate (DCFH-DA)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> An indirect fluorescence analysis to measure intracellular H2O2 levels. H2O2 interacts with peroxidase or heme proteins, which further react with DCFH, oxidizing it to dichlorofluorescein (DCF), a fluorescent product.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> HyPer Probe  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Fluorescent measurement of intracellular H2O2 levels. HyPer is a genetically encoded fluorescent sensor that can be used for in vivo and in situ imaging.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Cytochrome c Reduction Assay  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The cytochrome c reduction assay is used to measure O2•– levels. O2•–  is reduced to O2 as ferricytochrome c is oxidized to ferrocytochrome c, and this reaction can be measured by an absorbance increase at 550 nm.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Proton-electron double-resonance imagine (PEDRI) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> The redox state of tissue is detected through nuclear magnetic resonance/magnetic resonance imaging, with the use of a nitroxide spin probe or biradical molecule.  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Glutathione (GSH) depletion  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Biesemann, N. et al., 2018)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> A downstream target of the Nrf2 pathway is involved in GSH synthesis. As an indication of oxidation status, GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., <a href="http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html">http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html</a>).   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Thiobarbituric acid reactive substances (TBARS)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Griendling, K. K., et al., 2016) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Oxidative damage to lipids can be measured by assaying for lipid peroxidation with TBARS using a commercially available kit.   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"> Protein oxidation (carbonylation) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> (Azimzadeh et al., 2017; Azimzadeh etal., 2015; Ping et al., 2020) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"> Can be determined with enzyme-linked immunosorbent assay (ELISA) or a commercial assay kit. Protein oxidation can indicate the level of oxidative stress. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">Seahorse XFp Analyzer   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">Leung et al. 2018   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">The Seahorse XFp Analyzer provides information on mitochondrial function, oxidative stress, and metabolic dysfunction of viable cells by measuring respiration (oxygen consumption rate; OCR) and extracellular pH (extracellular acidification rate; ECAR).   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">No </td> </tr> </tbody> </table> Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assays for Nrf2 activity include:  <table cellspacing="0" class="Table" style="border-collapse:collapse; width:623px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:154px"> Method of Measurement  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:139px"> References  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:256px"> Description  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:75px"> OECD-Approved Assay </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:154px"> Immunohistochemistry  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> (Amsen, D., de Visser, K. E., and Town, T., 2009) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:256px"> Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:75px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:154px"> Quantitative polymerase chain reaction (qPCR)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px"> (Forlenza et al., 2012) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:256px"> qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:75px"> No </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:154px"> Whole transcriptome profiling via microarray or via RNA-seq followed by a pathway analysis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:139px"> (Jackson, A. F. et al., 2014) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:256px"> Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:75px"> No </td> </tr> </tbody> </table>

Taxonomic applicability: Occurrence of oxidative stress is not species specific.   Life stage applicability: Occurrence of oxidative stress is not life stage specific.  Sex applicability: Occurrence of oxidative stress is not sex specific.  Evidence for perturbation by prototypic stressor: There is evidence of the increase of oxidative stress following perturbation from a variety of stressors including exposure to ionizing radiation and altered gravity (Bai et al., 2020; Ungvari et al., 2013; Zhang et al., 2009).

High Mixed

High

All life stages

High High

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(2014), “Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan.”, Toxicology and Applied Pharmacology, Vol. 274/11, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.taap.2013.10.019" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.taap.2013.10.019</a> Jacobsen, N.R. et al. (2008), “Genotoxicity, cytotoxicity, and reactive oxygen species induced by single-walled carbon nanotubes and C60 fullerenes in the FE1-MutaTM Mouse lung epithelial cells”, Environmental and Molecular Mutagenesis, Vol. 49/6, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1002/em.20406" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1002/em.20406</a> Karimi, N. et al. (2017), “Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats”, International Journal of Pharmaceutical Investigation, Vol. 7/3, Phcog Net, Bengaluru, <a href="https://doi.org/10.4103/jphi.JPHI_60_17.%E2%80%AF" rel="noreferrer noopener" target="_blank">https://doi.org/10.4103/jphi.JPHI_60_17.</a> Leung, D.T.H., and Chu, S. (2018), “Measurement of Oxidative Stress: Mitochondrial Function Using the Seahorse System” In: Murthi, P., Vaillancourt, C. (eds) Preeclampsia. Methods in Molecular Biology, vol 1710. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7498-6_22  Lu, C., G. Song, and J. Lin (2006), “Reactive oxygen species and their chemiluminescence-detection methods”, TrAC Trends in Analytical Chemistry, Vol. 25/10, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.trac.2006.07.007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1016/j.trac.2006.07.007</a> Nguyen Dinh Cat, A. et al. (2013), “Angiotensin II, NADPH oxidase, and redox signaling in the vasculature”, Antioxidants & redox signaling, Vol. 19/10, Mary Ann Liebert, Larchmont, <a href="https://doi.org/10.1089/ars.2012.4641" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1089/ars.2012.4641</a> Ping, Z. et al. (2020), “Oxidative Stress in Radiation-Induced Cardiotoxicity”, Oxidative Medicine and Cellular Longevity, Vol. 2020, Hindawi, <a href="https://doi.org/10.1155/2020/3579143" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1155/2020/3579143</a> Powers, S.K. and M.J. Jackson. (2008), “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production”, Physiological Reviews, Vol. 88/4, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/physrev.00031.2007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1152/physrev.00031.2007</a> Raimondi, V., F. Ciccarese and V. Ciminale. (2020), “Oncogenic pathways and the electron transport chain: a dangeROS liason”, British Journal of Cancer, Vol. 122/2, Nature Portfolio, London, <a href="https://doi.org/10.1038/s41416-019-0651-y" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1038/s41416-019-0651-y</a> Seen, S. and L. Tong. (2018), “Dry eye disease and oxidative stress”, Acta Ophthalmologica, Vol. 96/4, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1111/aos.13526" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1111/aos.13526</a> Ungvari, Z. et al. (2013), “Ionizing Radiation Promotes the Acquisition of a Senescence-Associated Secretory Phenotype and Impairs Angiogenic Capacity in Cerebromicrovascular Endothelial Cells: Role of Increased DNA Damage and Decreased DNA Repair Capacity in Microvascular Radiosensitivity”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 68/12, Oxford University Press, Oxford, <a href="https://doi.org/10.1093/gerona/glt057." style="color:#0563c1; text-decoration:underline">https://doi.org/10.1093/gerona/glt057.</a>   Vargas-Mendoza, N. et al. (2021), “Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition”, Life, Vol. 11/11, Multidisciplinary Digital Publishing Institute, Basel, <a href="https://doi.org/10.3390/life11111269" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3390/life11111269</a> Wang, H. et al. (2019), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, <a href="https://doi.org/10.7150/ijbs.35460" style="color:#0563c1; text-decoration:underline">https://doi.org/10.7150/ijbs.35460</a> Zhang, R. et al. (2009), “Blockade of AT1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats”, Journal of applied physiology, Vol. 106/1, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/japplphysiol.01278.2007" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1152/japplphysiol.01278.2007</a>. Zhao, R. Z. et al. (2019), “Mitochondrial electron transport chain, ROS generation and uncoupling”, International journal of molecular medicine, Vol. 44/1, Spandidos Publishing Ltd., Athens, <a href="https://doi.org/10.3892/ijmm.2019.4188" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3892/ijmm.2019.4188</a> AOPWiki 2017-05-30T13:58:17

2023-03-21T15:16:10

Disruption, Mitochondrial electron transport chain

Cellular

CL:0000255

CL eukaryotic cell

AOPWiki 2016-11-29T18:41:23

2017-09-16T10:14:40

Increase, Cytotoxicity

Cellular

Reductions in cellular pH that exceed homeostatic controls leads to denatured/dysfunctional cellular apparatus (enzymes)<a href="#cite_note-1">[1]</a> and cell death<a href="#cite_note-2">[2]</a>.

Cytotoxicity is measured in vitro using one of many available standardized methods, including the release of the intracellular enzyme lactate dehydrogenase<a href="#cite_note-3">[3]</a>, alkaline phosphatase<a href="#cite_note-4">[4]</a> cell counts <a href="#cite_note-5">[5]</a>, mitochondrial function<a href="#cite_note-6">[6]</a> and dye exclusion assays<a href="#cite_note-7">[7]</a>. Cytotoxicity is measured in vivo by histopathological evaluation of tissue. The presence of dead cells and/or cellular debris is direct evidence of cytotoxicity at the time of tissue sampling. Histological evidence of previous cytotoxicity is reported as tissue degeneration and/or atrophy.

Cell death is the inevitable outcome of sufficient cellular disruption in any living cell. Cytotoxicity has been observed in the olfactory epithelium of rats and mice exposed by inhalation to one or more of the listed chemical initiators. Cytotoxicity is expected in humans based conserved properties of the of the olfactory epithelium across species.

CL:0000255

CL eukaryotic cell

High High Moderate

<ol class="references"> <li id="cite_note-1"><a href="#cite_ref-1">↑</a> Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326 </li> <li id="cite_note-2"><a href="#cite_ref-2">↑</a> Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Izumi, Torigoe, Ishiguchi, Uramoto, Yoshida, Tanabe, Ise, Murakami, Yoshida, Nomoto and Kohno (2003). Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 29: 541-549, Fais (2010). Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med. 267: 515-525 </li> <li id="cite_note-3"><a href="#cite_ref-3">↑</a> (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193 </li> <li id="cite_note-4"><a href="#cite_ref-4">↑</a> Kuykendall, Taylor and Bogdanffy (1993). Cytotoxicity and DNA-protein crosslink formation in rat nasal tissues exposed to vinyl acetate are carboxylesterase-mediated. Toxicol Appl Pharmacol. 123: 283-292 </li> <li id="cite_note-5"><a href="#cite_ref-5">↑</a> Theiszova, Jantova, Dragunova, Grznarova and Palou (2005). Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 149: 393-396, (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193 </li> <li id="cite_note-6"><a href="#cite_ref-6">↑</a> Theiszova, Jantova, Dragunova, Grznarova and Palou (2005). Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 149: 393-396, (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193 </li> <li id="cite_note-7"><a href="#cite_ref-7">↑</a> Weisenthal, Dill, Kurnick and Lippman (1983). Comparison of dye exclusion assays with a clonogenic assay in the determination of drug-induced cytotoxicity. Cancer Res. 43: 258-264, Elia, Storer, Harmon, Kraynak, McKelvey, Hertzog, Keenan, DeLuca and Nichols (1993). Cytotoxicity as measured by trypan blue as a potentially confounding variable in the in vitro alkaline elution/rat hepatocyte assay. Mutat Res. 291: 193-205 </li> </ol> AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:36

Chronic kidney disease

Organ

AOPWiki 2019-02-18T09:58:11

2019-02-18T09:58:11

Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress leads to chronic kidney disease

Oxidative stress in chronic kidney disease

Brendan Ferreri-Hanberry

Paul Jennings

BY-SA

2.0

This AOP links thiol oxidation to CKD via oxidative and mitochondrial stress. Within the nephron, the proximal tubule is especially susceptible to injury from oxidative chemicals, as they can cause mitochondrial damage, which in turn can result in impairment of active and secondary transport, as well as in cell death. CKD is characterized by a progressive loss of renal function, the onset of which is initiated and/or accelerated by other factors such as diabetes, high blood pressure or exposure to nephrotoxic chemicals. Given its high energy demand for active transport, the proximal tubule is especially susceptible to injury from oxidative chemicals and mitotoxins.

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 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).   <a href="https://aopwiki.org/system/dragonfly/production/2018/02/07/3zeb7785qn_Diapositive1.jpg"><img alt="" src="https://aopwiki.org/system/dragonfly/production/2018/02/07/3zeb7785qn_Diapositive1.jpg" style="height:540px; width:720px" /></a> 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. <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; width:554px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:23px; width:188px"> Functional Group </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:23px; width:246px"> Occurrence </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:23px; width:120px"> Formation constant </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:188px"> Thiol/thiolate (-SH/-S-) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:246px"> Cysteine, glutathione, proteins </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:120px"> ≈14-18 a,b </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:188px"> Selenol/selenolate (-SeH/Se-) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:246px"> Selenocysteinyl residues in selenoproteins </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:120px"> ≈ 16-18c </td> </tr> </tbody> </table> Table 2. Formation constants of Hg2+ with some representative nucleophilic centers from biomolecules. <table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <tbody> <tr> <td>Functional group</td> <td>Hg2+</td> </tr> <tr> <td>R-S-R</td> <td>≈ 6-12</td> </tr> <tr> <td>R-SH</td> <td>≈ 40-50</td> </tr> <tr> <td>R-SeH</td> <td>≈ 50-60</td> </tr> </tbody> </table> 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). <a href="https://aopwiki.org/system/dragonfly/production/2018/02/07/44zji8zmr8_Diapositive1.jpg"><img alt="" src="https://aopwiki.org/system/dragonfly/production/2018/02/07/44zji8zmr8_Diapositive1.jpg" style="height:540px; width:720px" /></a> 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 <table border="1" cellpadding="0" cellspacing="0" style="height:1399px; width:1217px"> <tbody> <tr> <td style="width:123px"> Protein activity inhibited by MeHg </td> <td style="width:94px"> Exposure </td> <td style="width:95px"> Functional group likely involved in the inhibition </td> <td style="width:142px"> Organism-preparation </td> <td style="width:142px">   </td> </tr> <tr> <td style="width:123px"> Glutathione peroxidase (total GPx) </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult mice </td> <td style="width:142px"> Glasser et al. 2013 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult mice </td> <td style="width:142px"> Glasser et al. 2010a </td> </tr> <tr> <td style="width:123px"> Mitochondrial total GPx </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult mice </td> <td style="width:142px"> Franco et al. 2009 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vitro </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> SH-SY5Y cells </td> <td style="width:142px"> Franco et al. 2009 </td> </tr> <tr> <td style="width:123px"> GPx1 and GPx4 </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult mice </td> <td style="width:142px"> Zemolin et al. 2012 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult male mice </td> <td style="width:142px"> Malagutti et al. 2009 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vitro </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> PC12 cells </td> <td style="width:142px"> Li et al. 2008 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Mice gestational exposure </td> <td style="width:142px"> Stringari et al. 2008 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult rats </td> <td style="width:142px"> Cheng et al. 2005 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vitro </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Fetal Telencepalic cells from rats </td> <td style="width:142px"> Sorg et al. 1998 </td> </tr> <tr> <td style="width:123px"> Total GPx </td> <td style="width:94px"> in vitro </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Mice neuroblastoma cells </td> <td style="width:142px"> Kromidas et al. 1990 </td> </tr> <tr> <td style="width:123px"> Thioredoxin Reductase (TrxR) </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH  and –SH </td> <td style="width:142px"> Adult mice </td> <td style="width:142px"> Zemolin et al. 2012 </td> </tr> <tr> <td style="width:123px"> TrxR </td> <td style="width:94px"> in vitro </td> <td style="width:95px"> -SeH  and –SH </td> <td style="width:142px"> Adult mice </td> <td style="width:142px"> Wagner et al. 2010 </td> </tr> <tr> <td style="width:123px"> TrxR </td> <td style="width:94px"> in vivo </td> <td style="width:95px"> -SeH-  and –SH </td> <td style="width:142px"> Adult rats </td> <td style="width:142px"> Dalla Corte et al. 2013 </td> </tr> <tr> <td style="width:123px"> Mitochondrial total Gpx </td> <td style="width:94px"> In vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult rat </td> <td style="width:142px"> Mori et al., 2007 </td> </tr> <tr> <td style="width:123px"> Mitochondrial total Gpx </td> <td style="width:94px"> In vivo </td> <td style="width:95px"> -SeH </td> <td style="width:142px"> Adult Swiss male mice brain </td> <td style="width:142px"> Franco et al., 2009 </td> </tr> <tr> <td style="width:123px"> </td> <td style="width:94px"> </td> <td style="width:95px"> </td> <td style="width:142px"> </td> <td style="width:142px"> </td> </tr> <tr> <td style="width:123px"> Total brain TrxR </td> <td style="width:94px"> In vivo </td> <td style="width:95px"> -SeH and -SH </td> <td style="width:142px"> Juvenile fish (zebra-seabreams) </td> <td style="width:142px"> Branco et al. 2011 Branco et al. 2012a,b </td> </tr> <tr> <td style="width:123px"> </td> <td style="width:94px"> </td> <td style="width:95px"> </td> <td style="width:142px"> </td> <td style="width:142px"> </td> </tr> <tr> <td style="width:123px"> Protein activity inhibited by Hg2+ </td> <td style="width:94px">   exposure </td> <td style="width:95px"> Functional group likely involved in the inhibition </td> <td style="width:142px">   organism-preparation </td> <td style="width:142px">   </td> </tr> <tr> <td style="width:123px"> Total brain TrxR </td> <td style="width:94px"> In vivo </td> <td style="width:95px"> -SeH and -SH </td> <td style="width:142px"> Juvenile fish (zebra-seabreams) </td> <td style="width:142px"> Branco et al. 2012a,b </td> </tr> </tbody> </table>   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).

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