Stressor: 303



Reactive oxygen species

Stressor Overview


AOPs Including This Stressor


Events Including This Stressor


Chemical Table


AOP Evidence


EGFR Activation Leading to Decreased Lung Function

Various sources of ROS, including glucose oxidase, xanthine/xanthine oxidase, acrolein, H2O2, cigarette smoke extract, phorbol 12-myristate 13-acetate (PMA), 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and supernatant from activated neutrophils or eosinophils cause a measurable, rapid increase in EGFR phosphorylation in human airway epithelial cells and the lungs of F344 rats (Ravid et al., 2002; Hewson et al., 2004; Casalino-Matsuda et al., 2006; Casalino-Matsuda et al., 2004; Deshmukh et al., 2008; Qi et al., 2010; Takeyama et al., 2001;Takeyama et al., 2000; Burgel et al. 2001; Kim et al. 2008; Yu et al. 2015; Yu et al., 2011; Lee et al.; 2011).

Peptide Oxidation Leading to Hypertension

Compounds or environmental conditions, which generate endothelium-localised ROS in vivo are the primary source of the MIE.  Notable examples include: 

ROS/ROS donors : (Song et al. 2008, van Gorp et al. 1999, van Gorp et al. 2002, Park et al. 2013, Montecinos et al. 2007, Schuppe et al. 1992, 

Hypoxia/ischaemia : Nozik-Grayck et al. 2014, Zhang et al. 2014, De Pascali et al. 2014, 

SIN-1 (CAS № 16142-27-1) :  Das et al. 2014  

Heavy Metals (Lead, Cadmium, Mercury) : Vaziri et al. 2001, Wolf et al. 2007

Carbonyls (including methylglyoxal, N,N′-bis(2-chloroethyl)-N-nitroso-urea), acrolein) : Morgan et al. 2014, Dhar et al. 2010, Su et al. 2013, Chen et al. 2010, Chen et al. 2011, Michaud et al. 2006, Qin et al. 2016, Zhang et al. 2011

Glucose : Zou et al. 2002, Song et al. 2007, Du et al. 2013, Du et al. 2001, Dhar et al. 2010, Su et al. 2008

Ultra-fine particulates : Du et al. 2013, Tseng et al. 2016

Cigarette smoke (known to contain carbonyls, metals and ROS) : Michaud et al. 2006, Zhang et al. 2006, Talukder et al. 2011

Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions

There is no evidence text for this AOP

Oxidative DNA damage leading to chromosomal aberrations and mutations

There is no evidence text for this AOP

Event Evidence


KE5 : Decrease, AKT/eNOS activity

There is no evidence text for this event.

Oxidation, Glutathione (To be considered with MIE)

There is no evidence text for this event.

KE1 : S-Glutathionylation, eNOS

There is no evidence text for this event.

KE3 : Decrease, Tetrahydrobiopterin

There is no evidence text for this event.

KE6 : Depletion, Nitric Oxide

There is no evidence text for this event.


There is no evidence text for this event.

Increase, Oxidative damage to DNA

There is no evidence text for this event.

Oxidation of membrane lipids

There is no evidence text for this event.

Oxidation/denatuation of membrane proteins

There is no evidence text for this event.

Inflamatory events in light-exposed tissues

There is no evidence text for this event.

Increased, DNA damage and mutation

There is no evidence text for this event.

Stressor Info


Chemical/Category Description


Characterization of Exposure




Chen CA, Wang TY, Varadharaj, S et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature (2010) 468: 1115–1118.

Chen CA, Lin CH, Druhan LJ et al. Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and coupling. J. Biol. Chem. (2011) 286 : 29098–29107.

Das A, Gopalakrishnan B, Druhan LJ et al. Reversal of SIN-1-induced eNOS dysfunction by the spin trap, DMPO, in bovine aortic endothelial cells via eNOS phosphorylation. (2014) Br. J. Pharmacol. 171: 2321–2334.

De Pascali F, Hemann C, Samons, K et al. Hypoxia and reoxygenation induce endothelial nitric oxide synthase uncoupling in endothelial cells through tetrahydrobiopterin depletion and S-glutathionylation. Biochemistry (2014). 53 : 3679–3688.

Dhar A, Dhar I, Desai KM et al.  Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. (2010) Br. J. Pharmacol. 161: 1843–1856.

Du J, Fan LM, Mai A et al. Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice. Br. J. Pharmacol. (2013) 170 : 1064–1077.

Du XL, Edelstein D, Dimmeler et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. (2001) 108 : 1341–1348.

Du Y, Navab M, Shen M, et al.  Ambient ultrafine particles reduce endothelial nitric oxide production via S-glutathionylation of eNOS. Biochem. Biophys. Res. Commun. (2013) 436 : 462–466.

Michaud SE, Dussault S, Groleau J et al. Cigarette smoke exposure impairs VEGF-induced endothelial cell migration: role of NO and reactive oxygen species. J. Mol. Cell. Cardiol. (2006) 41 : 275–284.

Montecinos V, Guzmán P, Barra V et al. Vitamin C is an essential antioxidant that enhances survival of oxidatively stressed human vascular endothelial cells in the presence of a vast molar excess of glutathione. (2007) J. Biol. Chem. 282: 15506–15515.

Morgan PE, Sheahan PJ, Davies MJ.  Perturbation of human coronary artery endothelial cell redox state and NADPH generation by methylglyoxal.  PLoS One. (2014) 21;9(1):e86564.

Nozik-Grayck E, Woods C, Taylor JM et al. Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension.  Am J Physiol Lung Cell Mol Physiol. (2014) 307(11):L868-76. 

Qin WS, Deng YH, Cui FC.  Sulforaphane protects against acrolein-induced oxidative stress and inflammatory responses: modulation of Nrf-2 and COX-2 expression.Arch Med Sci. 2016 Aug 1;12(4):871-80. 

Park WH. The effects of exogenous H2O2 on cell death, reactive oxygen species and glutathione levels in calf pulmonary artery and human umbilical vein endothelial cells. (2013) Int. J. Mol. Med. 31: 471–476.

Schuppe I, Moldéus P, and Cotgreave IA. Protein-specific S-thiolation in human endothelial cells during oxidative stress. (1992) Biochem. Pharmacol. 44: 1757–1764.

Song P, Wu Y, Xu J et al. Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation (2007) 116 :1585–1595.

Song P, Xie Z, Wu Y et al. Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. (2008) J. Biol. Chem. 283: 12446–12455.

Su Y, Liu XM, Sun YM et al. The relationship between endothelial dysfunction and oxidative stress in diabetes and prediabetes. (2008) Int. J. Clin. Pract. 62: 877–882.

Su Y, Qadri SM, Wu L et al. Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. (2013) Cardiovasc. Diabetol. 12, 134.

Talukder MA, Johnson WM, Varadharaj S et al.  Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice.  (2011) Am J Physiol Heart Circ Physiol. 300(1):H388-96.

Tseng, CY., Wang, JS. & Chao, MW. Causation by Diesel Exhaust Particles of Endothelial Dysfunctions in Cytotoxicity, Pro-inflammation, Permeability, and Apoptosis Induced by ROS Generation.  Cardiovasc Toxicol 1-9 (2016).

van Gorp RM, Broers JL, Reutelingsperger CP et al. Peroxide-induced membrane blebbing in endothelial cells associated with glutathione oxidation but not apoptosis. (1999) Am. J. Physiol. 277 : C20–C28.

van Gorp RM, Heeneman S, Broers JL et al. Glutathione oxidation in calcium- and p38 MAPK-dependent membrane blebbing of endothelial cells. (2002) Biochim. Biophys. Acta 1591: 129–138.

Vaziri ND, Ding Y.  Effect of lead on nitric oxide synthase expression in coronary endothelial cells: role of superoxide.  Hypertension. (2001) 37(2): 223-6.

Wolf MB, Baynes JW.  Cadmium and mercury cause an oxidative stress-induced endothelial dysfunction.  Biometals. 2007 Feb;20(1):73-81.

Zhang W, Han Y, Meng G et al. Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats. (2014) J. Am. Heart Assoc. 3(1): e000606.

Zhang WZ, Venardos K, Chin-Dusting J et al. Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress.  (2006)  Hypertension. 48(2):278-85

Zhang XW, Li WF, Li WW, Ren KH, Fan CM, Chen YY, Shen YL.  Protective effects of the aqueous extract of Scutellaria baicalensis against acrolein-induced oxidative stress in cultured human umbilical vein endothelial cells.  Pharm Biol. 2011 Mar;49(3):256-61.

Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. (2002) 109(6):817–26

Zou MH, Hou XY, Shi CM et al. Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. (2002) J. Biol. Chem. 277, 32552–32557.