Oxidative Stress

Oxidative stress is defined as excess production of reactive oxygen species (ROS) relative to antioxidant defense.

From: Encyclopedia of Toxicology (Third Edition), 2014

Hepatic Toxicology

J.R. Roede, ... D.R. Petersen, in Comprehensive Toxicology, 2010

9.26.4.1 Oxidative Stress

Oxidative stress is a widely used term, which, in essence, is defined as a disturbance in the pro-oxidant–antioxidant balance that leads to potential damage. Disease-associated oxidative stress may be due to a number of situations; however, in the case of aldehyde toxicity, oxidative stress is primarily due to the depletion of cellular GSH (Halliwell and Gutteridge 1999). GSH is a key component in the regulation of protein disulfide bonds and in the disposal and detoxification of oxidants and electrophiles. Depletion of GSH below a critical level would compromise adequate reduction of hydrogen peroxide by GSH peroxidases and conjugation of organic hydroperoxides and electrophiles such as acrolein or 4-HNE by GSTs. This depletion has the potential to sensitize cells to the toxicity of a given drug or toxicant (Fernandez-Checa and Kaplowitz 2005). For example, GSH depletion together with the capacity to regenerate GSH de novo are important determinants in the long-term toxicity of low concentrations of 4-HNE (Esterbauer et al. 1991).

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Abalone: Biology, Ecology, Aquaculture and Fisheries

Norman L.C. Ragg, in Developments in Aquaculture and Fisheries Science, 2023

Oxidative stress

Oxidative stress is frequently associated with a mismatch in cellular oxygen supply and demand (Vosloo et al., 2013); however, it is important to note that oxidative stress is deliberately employed as part of the principal pathogen elimination mechanism of the animals, which involves phagocytosis by hemocytes, followed by enzymatic digestion and reactive oxygen species (ROS) production (Cardinaud et al., 2015). Ironically the most significant cause of oxidative stress for abalone may be reoxygenation during the apparently beneficial return to normoxia. As antioxidant defense mechanisms are energetically costly to maintain (Gorr et al., 2010), the most effective hypoxia and oxidative stress-tolerant species are typically characterized by an ability to reactively elevate antioxidant enzyme and glutathione levels in anticipation of reoxygenation or in response to pervasive environmental stress (Hermes-Lima and Zenteno-Savín, 2002). In abalone, this response capacity seems to be highly context- and species-specific. For example, after one month adult H. midae antioxidant enzyme levels remained unaffected by acclimation to mild hypoxia or hyperoxia, with both environments subsequently causing some hemocyte DNA damage (Vosloo et al., 2013). In contrast, genes regulating production of the antioxidant enzymes Selenium-dependent glutathione peroxidase (SeGPOX) and catalase were upregulated within 2 h of exposure to self-induced hypoxia in H. discus discus (De Zoysa et al., 2009).

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Fly ash: Safety and health issues

S.S. Lahiri, in Handbook of Fly Ash, 2022

4.22.1 Inflammation

Inflammation is a pervasive phenomenon of the body resulting in an immediate response to environmental stress, such as tissue injury, or infection by pathogens or noxious chemicals (Ashley et al., 2012). It is characterized by its cardinal symptoms of rubor (redness), calor (heat), tumor (swelling), color (pain), and in severe case-loss of function. Exposure leads to the development of silicotic granuloma with reticulin and collagen fiber formation in lung.

4.22.1.1 Oxidative stress

Oxidative stress (Figs. 4.10–4.10.3) is caused by an imbalance between free radicals and antioxidants in the body. Free radicals are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules such as DNA, proteins, and lipids.

Glutathione, a major antioxidant in the cell, exists in reduced (GSH) and oxidized (GSSG) states. The ratio of reduced glutathione to the oxidized form within the cell is an indicator of cellular oxidative stress. In healthy cells, more than 90% (up to 98% of cellular GSH under normal conditions) of the glutathione pool remains in the reduced form (GSH) and the remainder in the disulfide form (GSSG). Intracellular GSSG accumulates, and the GSH/GSSG ratio decreases with increased levels of oxidative stress. The GSH:GSSG ratio and glutathione peroxidase (GPx) activity were significantly higher in girls than in boys (p < 0.001), in anemic than in non-anemic subjects (p < 0.001), and in overweight and obesity. Thus the GSH/GSSG ratio is a useful indicator of oxidative stress in cells and tissues. An increased GSSG-to-GSH ratio is indicative of oxidative stress.

The presence of high levels of free radicals in the body is associated with low levels of neutralizing antioxidants. When the amount of free radicals exceeds the amount of antioxidants available in the body, the surplus free radicals attack the protein, lipid, or DNA components causing oxidative stress and neuro-degenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD).

An imbalance in the generation of free radicals like ROS and reactive nitrogen species during cellular metabolism and their effective scavenging or removal by GSH, enzyme superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase, dietary antioxidants etc., lead to oxidative stress. The ROS begins with early uptake of oxygen, activation of the enzyme nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) is followed by the production of the superoxide anion (Nimse and Pal, 2015) radical (O2) which are described next.

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Arsenic-induced liver injury

Suman Santra, ... Amal Santra, in Handbook of Arsenic Toxicology (Second Edition), 2023

12.11.1 Arsenic causes oxidative stress in the liver

Oxidative stress has been implicated in the initiation of liver damage caused by various agents. Scanty information on the mechanism of hepatic damage in chronic inorganic arsenic exposure is available. Active oxygen species, such as superoxide (O2) and hydroxyl (OH) ions, are formed during arsenic metabolism through a chain of reactions. Moreover, metabolites of arsenic produce active oxygen species and peroxy radicals. The liver possesses an antioxidant defense system that removes free radicals, superoxides, and peroxides generated within the hepatocytes. GSH plays the most important role in detoxifying the reactive intermediate products of xenobiotics metabolism and prevents peroxidation of membrane lipids. GSH homeostasis is studied in chronic inorganic arsenic exposure in a murine model [79]. The antioxidant defense system in the liver of mice is activated after exposure of inorganic arsenic for short duration. Significant elevation of hepatic GSH content is observed. This elevation may reflect an attempt to counteract the oxidative stress induced by inorganic arsenic exposure and is probably mediated by elevation in the activities of glucose 6-phosphate dehydrogenase (G6PD) and glutathione reductase. However, after a certain period of inorganic arsenic exposure, a fall in GSH level is observed indicating failure of the antioxidant defense system. A fall in G6PD activity further supports this observation. Thus prolonged exposure to inorganic arsenic probably causes exhaustion of this defense system by over utilization, which might result in the initiation of biochemical injury to the liver [79].

One of the main features of inorganic arsenic-induced liver injury is the disruption of cellular integrity and function by the generation of oxidative stress. High intracellular GSH levels have been associated with cellular resistance to inorganic arsenic [80–82] while hepatocytes with low intracellular GSH level are susceptible to increase arsenic toxicity [81]. Arsenic methylation and transport are thought to be mediated by GSH [83,84] for efficient removal of inorganic arsenic from the body. Intrahepatic accumulation of arsenic is triggered by hepatic GSH depletion producing oxidative stress particularly at higher dose. No significant change in mitochondrial oxidative stress is observed at comparative low dose of inorganic arsenic exposure to evoke the normal cellular redox status [77]. The liver-arsenic content is found to be directly proportional to the elevated doses of inorganic arsenic exposure whereas on the other hand it is inversely proportional with hepatic GSH depletion. In response to high inorganic arsenic exposure, the accumulated oxidized glutathione (GSSG), a marker of oxidative stress in liver is found to be directly proportional with the liver arsenic content (Fig. 12.5).

Fig. 12.5

Fig. 12.5. Correlation between hepatic oxidative stress and arsenic content in liver. Hepatic oxidized glutathione (GSSG) serves as a marker of oxidative stress in the liver. Data showing a positive correlation between hepatic GSSG level and arsenic deposition in the liver in control and arsenic-exposed mice (r = 0.788; p &lt; 0.001).

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Arsenicals: toxicity, their use as chemical warfare agents, and possible remedial measures

Sakshi Srivastava, Swaran J.S. Flora, in Handbook of Toxicology of Chemical Warfare Agents (Third Edition), 2020

21.9.4 Mechanisms of toxicity

Arsenic in its free form generates free radicals resulting in lipid peroxidation, depletion of antioxidant enzymes, and DNA damage, thereby establishing oxidative stress as the major mechanism of As-induced toxicity and carcinogenicity (Sattar et al., 2016; Flora, 2011). Arsenite inhibits pyruvate dehydrogenase (PDH) activity, perhaps by binding to the lipoic acid moiety. Inhibition of PDH leads to decreased production of ATP. Inhibition of PDH may also explain in part the depletion of carbohydrates observed in rats administered arsenite. Methylated trivalent arsenicals such as MMAIII are potent inhibitors of GSH reductase and thioredoxin reductase. The inhibition may be due to the interaction of trivalent arsenic with critical thiol groups in these molecules. The reduction of arsenate to arsenite occurs in vivo. Another potential mechanism is the replacement of phosphate with arsenate. Oxidative injury causing damage to DNA molecules and various cell components, such as polyunsaturated fatty acid residues of phospholipids, amino acids, peptides, and proteins has been reported as one of the foremost consequences of arsenic exposure as they are susceptible targets of metal-induced ROS attack (Flora, 2011).

21.9.4.1 Oxidative stress

Oxidative stress has now been established as one of the major mechanisms involved in arsenic-induced carcinogenesis. A number of recent reports have provided direct evidence of inorganic arsenic-induced free radical formation or production of oxidative stress (Flora, 2011). Reactive oxygen species (ROS) that damage DNA in vitro are generated from iron released from ferritin. The results suggest that some clastogenic effects of arsenic are mediated via free radicals and could increase the production of ROS, activation of transcription factors (e.g., AP-1, c-fos, and NF-κB) and oversecretion of proinflammatory and growth-promoting cytokines, resulting in increased cell proliferation and finally carcinogenesis (Sattar et al., 2016). Increased ornithine decarboxylase activity is often interpreted as a biomarker for cell proliferation. Arsenite appears to have an effect on the cell cycle, which may alter cell proliferation. Amplification of the gene, which codes for the enzyme dihydrofolate reductase, is enhanced by arsenic.

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Advances in cutaneous toxicology of arsenic

Madison B. Lee, Mohammad Athar, in Handbook of Arsenic Toxicology (Second Edition), 2023

11.5.5 Mitochondrial dysfunction

Oxidative stress within mitochondria is a detrimental byproduct of arsenic-induced production of ROS. Mitochondria are particularly susceptible to damage from arsenic-induced ROS. In fact, oxidative stress inside the mitochondria directly leads to disturbed mitochondrial membrane potential, injurious damage to mitochondrial DNA, and uncoupling of the electron transport chain [51]. Recent research has delved further into the mitochondrial epigenetic alterations stimulated as a byproduct of arsenic exposure. Analyzing the mitochondrial genome of an arsenic-exposed population in West Bengal, India, revealed hypomethylation of D-loop and ND6, which results in both an elevation in D-loop's and ND6’s target gene expression as well as an increased mtDNA copy number [51].

Damage and mutation to the mitochondrial genome in arsenic-induced skin lesion appear to be a predictable result of oxidative stress and enhanced mitochondrial biogenesis [52]. A more recent case-control study performed among an arsenic-exposed population in West Bengal, India, confirmed arsenic's ability to augment mitochondrial biogenesis through epigenetically altering regulatory genes responsible for controlling mitochondrial biogenesis [53]. Moreover, increased mitochondrial biogenesis and elevated mtDNA copy number were observed in arsenic-induced skin cancer. This recent case study also highlighted the significance of mitochondria-nucleus crosstalk in the pathogenesis of arsenical skin cancer, and arsenic's ability to perturb mitochondrial fusion-fission dynamics [53]. Also, downregulation of MiR663 via a mitochondrial retrograde signal may promote arsenic-induced skin carcinogenesis by decreasing MiR663’s tumor suppressor function [53].

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Immune System Toxicology

S.B. Pruett, ... D. Liu, in Comprehensive Toxicology, 2010

5.16.2.3 Oxidative Stress Activates RAS that Leads to Disease Progression and Inflammation

Oxidative stress activates RAS in kidneys, and it plays a pivotal role in renal disease progression and inflammation (Figure 3). Renin, a proteolytic enzyme released by the kidneys, maintains sodium–potassium level in the blood and body fluids. Angiotensin is responsible for regulating blood pressure by constricting blood vessels and stimulating the release of aldosterone. Due to the presence of high oxidative stress in kidney cells, renin is released into the blood, and angiotensinogen, a circulating substrate in blood, undergoes proteolytic cleavage to form angiotensin I (Ang I). Angiotensin converting enzyme (ACE) released by vascular endothelium cleaves two amino acids from Ang I to form angiotensin II (Ang II). Hyperoxaluria-induced oxidative stress, inflammation, and kidney damage were significantly reduced by the administration of an ACE inhibitor and blockade of the AT1 receptor for angiotensin (Toblli et al. 2001, 2002). Experimental studies indicate a significant increase of renin in the kidneys of hyperoxaluric rats (Khan 2005). Increased production of Ang II induces tubulointerstitial injury in diabetes model (Zimpelmann et al. 2000). Collectively, these findings suggest a role for these hormones in CaOx-induced inflammation and kidney damage.

Figure 3. Mechanism of action of ethylene glycol and induction of renal injury and inflammation.

Both oxidative stress and Ang II play important roles in the induction of inflammation in response to CaOx. The increased expression of renin and Ang II in renal tissues results in the upregulation of transforming growth factor (TGF)-β (Gilbert et al. 1999). Ang II is also known to be a mediator of TGF-β in a variety of cell types including proximal tubular cells, interstitial fibroblast, mesangial cells, and muscle cells. OPN, another major component in renal inflammation in relation to hyperoxaluria, is upregulated by Ang II either directly or indirectly through TGF-β. It has also been shown to participate in ROS production through the activation of NADPH oxidase. One group (Diamond et al. 1998) found that Angn II stimulates OPN expression in renal tubules directly; however, another group (Malyankar et al. 1997) reported it happens only through the induction of TGF-β. Receptors of angiotensin (AT1) upregulate Ang II which in turn regulates OPN and MCP-1 synthesis in luminal cell surfaces of renal tubules. This chemokine is strongly proinflammatory and attracts monocytes to the site. Studies on hyperoxaluric rats have showed that blockade of AT1 receptors downregulated synthesis of OPN, which demonstrates the involvement of renin–angiotensin system in the upregulation of OPN in hyperoxaluric animals. Expression of OPN, macrophage infiltration, and tubulointerstitial injury can be induced by Ang II infusion (Giachelli et al. 1998).

Another significant role of OPN in oxalate crystal retention in kidneys is that it modulates the adhesion of calcium oxalate crystals in renal epithelial cells. Blockage of AT1 receptor reduces the synthesis of OPN in renal tubules, thereby inhibiting crystal adherence and deposition in kidneys (Umekawa et al. 2004). EG-mediated crystal retention by OPN in kidneys has been reported (Wesson et al. 2003). Although these studies are consistent with an important role for OPN in CaOx crystal formation and/or localization and in the induction of inflammation by crystals, recent studies with OPN knockout mice suggest a more complex situation in vivo in which lack of OPN affects inflammation differently in males and females (Vernon et al. 2005).

Crystal deposition in the kidney is associated with renal tubular atrophy, interstitial fibrosis, and the development of an inflammatory infiltrate. Development of nephropathy correlates with the kidney oxalate crystal accumulation has been reported in rats fed with EG in the diet (Cruzan et al. 2004). The presence of oxalate or calcium oxalate crystals in renal cells evokes inflammatory responses that lead to fibrosis, nephron loss, and ultimately chronic renal failure (Agarwal 2003; Nath 1992). Macrophages seem to be injurious to tubular epithelial cells. Injured epithelial cells provide cushion for the crystal adherence, because injuries to the renal epithelial cell surface cause an exposure of crystal-binding molecules like phosphatydyl serine, hyaluronan, and its ligands CD44 and OPN. Recent proteomic analysis of human kidney stones suggests that inflammation is involved in the formation of the stones. Proteins associated with inflammatory responses are found with the kidney stones (Canales et al. 2008). Thus, it seems that inflammation contributes to the formation of kidney stones as well as EG-induced crystals and that it also contributes to tissue damage that follows deposition of the stones (Bijarnia et al. 2008).

Studies on the molecular basis for activation of macrophages in the presence of CaOx indicate that ROS induced by CaOx activate signaling molecules such as protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK), and transcription factors such as nuclear factor (NF)-κB and activator protein-1 (AP-1) (Khan 2005). Activation of these molecules leads to the upregulation of genes and proteins such as MCP-1, OPN, and fibronectin. Locally produced MCP-1 seems to be involved in the initiation and progression of tubular interstitial damage. This chemokine is chemotactic for monocytes and other leukocyte subsets and elicits inflammatory and immune reactions. Experimental evidence shows that tubulointerstitial damage has been documented in transgenic mice with serum-induced nephritis compared with wild-type mice, and MCP-1 deficient mice exhibited less tubulointerstitial lesions. MCP-1 induces inflammatory activation of tubular epithelial cells and also leads to vascular damage in kidney cells (Viedt et al. 2002). It induces the synthesis of proinflammatory cytokines like IL-6 and intracellular adhesion molecule (ICAM)-1 via the Gi protein, PKC, and intracellular Ca2+ (Figure 2). I-κB kinase (IKK) is phosphorylated followed by the activation of PKC which in turn activates I-κBα (finally NF-κB is activated after degradation of its constitutive inhibitor, I-κBα, by proteosomes). MAPK from the cytoplasm phosphorylates components of AP-1, leading to the formation of a transcriptionally active dimmer which can stimulate production of IL-6. Distribution of IL-6 and renal tubular atrophy are correlated, which is consistent with a role for inflammation in tubular atrophy (Fukatsu et al. 1991).

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Developmental arsenic exposure impacts fetal programming of the nervous system

Fengyuan Piao, ... Huai Guan, in Handbook of Arsenic Toxicology (Second Edition), 2023

16.5.1 Induction of oxidative stress

Oxidative stress is defined as a disturbance in the balance between the production of reactive oxygen species (ROS) and antioxidant defenses. Several reports suggest that the developmental neurotoxicity of arsenic was related to the induction of oxidative stress [64–69]. Chandravanshi et al. exposed female rats to arsenic from GD6 to PD21 and found increased ROS in the frontal cortex, hippocampus, and corpus striatum of developing rats on PD22 [64]. Beeravolu et al. demonstrated that arsenic exposure up-regulated ROS levels in embryonic stem cells and inhibited cell growth in a concentration-dependent manner [65]. It was also found that arsenic exposure induced an increase in the production of ROS in human fetal brain explants [11]. These studies indicated that the increased ROS plays a crucial role in the arsenic-induced developmental neurotoxicity.

Arsenic may induce the production of ROS by impacting antioxidant enzymes. It was reported that arsenic exposure resulted in a significant decrease in the activity levels of antioxidant enzymes such as manganese-superoxide dismutase (Mn-SOD), Cu/Zn superoxide dismutase (Cu/Zn-SOD), catalase (CAT), and glutathione peroxidase (GPx), while malondialdehyde (MDA) levels were significantly increased in the cerebral cortex, hippocampus, and cerebellum of developing rats [70]. Kadeyala et al. demonstrated that arsenic exposure significantly decreased the activities of SOD isoforms, CAT, GPx, and glutathione reductase (GR) with an increase in glutathione-S-transferase (GST), while lipid peroxidation (LPx) and arsenic levels were significantly increased in different brain regions. The induced alterations in these parameters were more pronounced in the cerebral cortex [71]. Developmental subchronic exposure to diphenylarsinic acid also induced reduction in the concentration of cerebellar GSH, which might be a primary cause of oxidative stress [62]. Comprehensive gene expression analyses in primary cultured rat cerebellar cells exposed to arsenic revealed significant alterations in the mRNA expression of genes encoding antioxidative stress proteins (heme oxygenase 1 and heat shock protein 72) [58]. Knockdown of oxidative stress adaptor protein p66shc improves the developmental competence of As-exposed embryos in vitro by increasing the resistance to oxidative stress. It is suggested that the disturbance of p66Shc-linked redox contributes to As-induced developmental retardation in mouse preimplantation embryos [72]. Zhang et al. showed that p66Shc-linked redox imbalance and metabolic abnormality of amino acids promote developmental delay in arsenite-exposed mouse preimplantation embryo [13]. An antioxidant, N-acetyl-l-cysteine, improves the development of arsenite-exposed embryos by reducing intracellular ROS and adjusting amino acid metabolism. These results support further that redox imbalance is involved in arsenite-induced embryonic toxicity.

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Radioisotopes and their impact on plants

K.F. Abdelmotelb, ... Sahil Mehta, in Plants and Their Interaction to Environmental Pollution, 2023

5.6 Cell death

Oxidative stress destroys biomolecules such as proteins and lipids and induces mitochondrial depolarization, resulting in an imbalance in the redox state of cells. This triggers a chain of events that results in cell death (Pardo et al., 2019). Through the channels of proapoptotic proteins such BAX and BAK, mitochondrial depolarization releases cytochrome C into the cytoplasm (Düssmann et al., 2017).

Further, cytochrome C binds to the APAF-1 proteins to form an apoptosome complex that starts the caspase cascade (Rahmanian et al., 2016). When the caspase pathway is activated, DNAse breaks the DNA and cleaves cytosolic and nuclear proteins, resulting in cell death. Another apoptosis mechanism is triggered by radiation-induced cellular damage or extreme oxidative stress, and it is regulated by the p53 protein (Kulaberoglu et al., 2016; Sueiro-Benavides et al., 2021). BAX in the cytosol is activated by further modulation of pro-apoptotic proteins such as PUMA (p53 upregulated modulator of apoptosis). The membrane-bound form of activated BAX opens the voltage-dependent anion channel in mitochondria, allowing cytochrome C to be released. As previously explained, the release of cytochrome C triggers a cascade of proteins that results in cell death.

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Neurotoxicology

H.A.N. El-Fawal, in Encyclopedia of Environmental Health, 2011

Oxidative Stress

Oxidative stress refers to the imbalance between cellular antioxidant cascade and processes that generate reactive oxygen species (ROS), such as superoxide (O2radical dot), hydrogen peroxide (H2O2), and hydroxyl anion (OH) (Figure 2). Saturation or compromise of these antioxidant processes results in accumulation of ROS and damage to macromolecules (proteins, lipids, and nucleotides), failure in cell function and death. The CNS is particularly vulnerable to oxidative stress because of (1) its high utilization of oxygen, (2) relatively lower antioxidant activity, and (3) the relatively high content of polyunsaturated lipids. Regional concentrations of redoxtransitional metals that can catalyze ROS generation may also increase the likelihood of ROS generation. In addition to ROS generation, there is a large body of evidence implicating the generation of nitric oxide (NO) from neurons and glia during neuroinflammatory and neurodegenerative processes. Accumulation of NO, together with O2radical dot, results in generation of toxic peroxynitrites (ONOO) (Figure 2). Ironically, it is during the neuroinflammatory process that gene transcription factors like nuclear factor κB (NFκB) are activated to induce further NO and ROS production through induction of gene transcription for such enzymes as inducible nitric oxide synthase (iNOS).

Figure 2. A major site of reactive oxygen species (ROS) and nitrogen species in the mitochondria. Partly reduced species may also be produced by cytochrome c and enzymes of the respiratory chain (e.g., complexes I and III). This includes superoxide (O2) that can be converted to hydrogen peroxide (H2O2) and then water or toxic hydroxyl (OH). Nitric oxide (NO) is generated from arginine by nitric oxide synthase (NOS) activity. Reaction between ROS and NO produces reactive nitrogen species, including toxic peroxynitrite (ONOO). More radicals are produced under conditions of inefficient electron transfer, and oxidative and nitrative damage of mitochondrial proteins exacerbates radical production. Radical production contributes to excitotoxicity, calpain activation, and promotion of proapoptotic cascade activation (see text for details).

Heavy metals have been shown to compromise antioxidant activity. Lead forms a complex with glutathione, inhibits glutathione peroxidase, and interferes with oxidative phosphorylation. Similarly, contributing to MeHg's neurotoxicity is the increased production of ROS demonstrated in the cerebellum and striatal synaptosomes. MeHg also selectively interferes with the transport of cysteine and cystine and reduces glutathione content in astrocytes. Increased hippocampal ROS production and interference with mitochondrial function has also been demonstrated for trimethyltin exposure. Furthermore, trimethyltin decreases glutathione and antioxidant activity. It has been shown that, depending on dose, trimethyltin-induced ROS production may result in either apoptosis or necrosis. Similarly, low-dose organophosphate exposure may contribute to oxidative stress directly or via excitotoxic processes.

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