Please cite this paper as:

     Ghosh, P., Dey, T., Chattopadhyay, A. and Bandyopadhyay, D. 2021. An insight into the ameliorative effects of melatonin against chromium induced oxidative stress and DNA damage: a review. Melatonin Research. 4, 3 (Sept. 2021), 377-407. DOI:https://doi.org/https://doi.org/10.32794/mr112500101.

Review

An insight into the ameliorative effects of melatonin against chromium induced oxidative stress and DNA damage: a review

Priyanka Ghosh^1#, Tiyasa Dey^1#, Aindrila Chattopadhyay², Debasish Bandyopadhyay^1*

¹Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata-700009, India.

²Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata 700 006, India.

*Correspondence: debasish63@gmail.com, Tel: +91 9433072066

^#The authors have equal contribution.

Running title: Melatonin attenuates chromium-induced oxidative damage

Received: November 16, 2020; Accepted: July 22, 2021

ABSTRACT

     Chromium (Cr), a ubiquitous metal, has become a potent pollutant due to global industrialization, leading to pollution of air, water, and food that impacts human health. The most stable forms of Cr are Cr(III) and Cr(VI) (the major product of industrial activities). Cr(III) is a micronutrient essential for maintaining normal blood glucose and lipid profiles in our body but it can also form Cr (III)-DNA adducts. In addition, it directly produces reactive oxygen species (ROS) via Fenton and Haber-Weiss reactions; leading to tissue injuries. Cr (VI) has the capacity to generate Cr(V), Cr (IV), and Cr(III), respectively under suitable conditions. These intermediates also damage to biological macromolecules by interactions with several enzymatic and non-enzymatic antioxidants. For example, Cr(III) can make double DNA strands breaking to inhibit DNA replication, induce DNA oxidation, and DNA adducts formation. All of these lead to the development of malignancy. Melatonin, a potent radical scavenger as well as a metal chelator, effectively chelates Cr(VI) and prevents DNA oxidative damage. Melatonin can upregulate the gene expression of several antioxidant enzymes, and thereby, maintains cellular integrity from the oxidative stress. Thus, melatonin can be a prime molecule to protect against Cr(VI) induced cytotoxicity and genotoxicity. This review aims to highlight the potential benefits of melatonin on Cr(VI) induced oxidative stress and DNA damage.

Key words: Chromium, oxidative stress, reactive oxygen species (ROS), DNA damage, DNA adduct, cytotoxicity, genotoxicity, antioxidant, melatonin.

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INTRODUCTION

      For decades, huge quantities of pollutants have been emitted into the environments due to substantially global industrialization. Unlike most organic contaminants, metals bring more severe biohazards to organisms since they are non-biodegradable and can accumulate in the tissues of organisms via the food chain (1, 2).  There are various heavy metals present in nature, among them  Cr has a very narrow concentration margin between its beneficial and toxic effects for organisms (3). It is an essential nutrient but it also acts as a potential carcinogen (4). Thus, Cr is referred as an “essential metal with potential for toxicity” (5). 

     Cr is the 21^st most abundant element found in the earth’s crust usually as chromite (FeCr₂O₄) (a relatively insoluble soil mineral), at about 100 ppm (6, 7). Cr was first discovered by Vaquelin in 1797 from crocoite (PbCrO₄). It has an atomic number of 24 and a high atomic weight of 52. It exists in several oxidation states ranging from -2 to +6. The trivalent (Cr-III), and hexavalent (Cr-VI) states are the stable forms of Cr (8). Cr(III) is an essential micronutrient; widely used as a dietary supplement. It is the most stable and biologically active form of chromium. Cr(III) not only potentiates the action of insulin but also improves glucose tolerance (9–12), by facilitating the binding of insulin with the receptor in the cell surface (13). Studies also reveal that the supplementation of Cr(III) to patients with heart diseases increases HDL but decreases the VLDL cholesterol levels(14–16). Thus, it is essential for carbohydrate and lipid metabolism(17, 18).

     Cr(VI) is a highly toxic compound and is mostly used for industrial purposes including in metallurgy (67%), refractories (18%), and chemicals (15%) (19). [Cr(III) is also used for chemical manufacturing but in a lesser extent, compared to Cr(VI) (20)]. Cr(VI) is also naturally obtained from the chromite ore in the form of sodium chromate (Na₂CrO₄), sodium dichromate (Na₂Cr₂O₇), and chromium oxide (CrO₃). Other oxidized forms of Cr are also present in nature such as potassium chromate (K₂CrO₄), potassium dichromate (K₂Cr₂O₇), chromic acid, etc. (21). The most common routes of Cr(VI) exposure include occupational as well as non-occupational exposure with ingestion of contaminated water and food (22). Environmental Cr contamination is the consequence of various anthropogenic processes; one of the major causes is the discharge of effluents from the tanneries and industries into water (23). The United States Environmental Protection Agency (USEPA) has identified Cr(VI) as one of 17 chemicals and one of the top 20 contaminants that need to be treated since it possesses a great threat to human health (24). It is well known that transition metals cause oxidative tissue damage (25). Cr is also a transition metal. Cr(VI) can deplete glutathione and protein-bound sulfhydryl groups (26) and generate a large number of reactive oxygen species (ROS) including hydroxyl radical (HO^.), superoxide anion radical (O₂^.-), or hydrogen peroxide (H₂O₂) through various mechanisms (Fenton and Haber–Weiss type reactions) (25, 27–29) and cause oxidative damage in cardiac (30), hepatic (31–33), renal tissues (32,34) as well as cause toxic hepatitis (35), immunotoxicity (36, 37), and genotoxicity (38–40).

     Cr(VI) is also toxic to the plants. It stalls the various physiological processes in plants such as germination, photosynthesis, and water balance (41–43). It accumulates in various parts of plants (42, 44, 45) thereby, reducing the biomass, chlorophyll content, and relative water content of the plants and impedes the growth of roots, stems, and leaves (41). Cr(VI) causes overproduction of H₂O₂, and malondialdehyde (46, 47) and aggravates electrolytes leakage and mutagenesis in plants (42).

     It appears that suitable antioxidants are essential to detoxify the Cr-induced oxidative damages in organisms. Among various potent antioxidants, melatonin seems the best choice for this purpose (48, 49). Melatonin (N-acetyl-5-methoxytryptamine) is primarily secreted from the pineal gland of vertebrates at night, also known as a sleep promoter (50–52). Recently, high levels of melatonin have been identified in the extrapineal tissues (Table 1). For example, the gastrointestinal tract generates 400 times higher concentrations of melatonin than that in the pineal gland (53, 54). The locally generated melatonin exerts its potential beneficial effects on those organs and tissues (Table 2). It is of notice that the metabolites of melatonin, N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK) and N¹-acetyl-5 methoxykynuramine (AMK), also exhibit the antioxidant capacity (55–57) to further intensify the melatonin’s activity as a potent antioxidant. In addition, melatonin can effectively chelate metal (58, 59) with high efficiency (60). At the level of molecular mechanisms, melatonin possesses antiapoptotic activity (61, 62), modulates the activity of mitochondrial permeability transition pores and reduces mitochondrial depolarization (63), downregulates gene expressions of cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS),  and inhibits the production of nitric oxide, prostanoids, leukotrienes (64, 65) with potent anti-inflammatory activity.

     As to the plants, Cr(VI) can cause adverse effects on their growth (66–68) which can be prevented by melatonin to minimize the Cr(VI) uptake in all parts of the plant (roots, leaves, shoots) (69). Ayyaz et al.(70) have also reported that melatonin mitigates the toxic effects of Cr(VI) on the growth of canola by harmonizing photosynthesis and regulate electron transport flux to protect against oxidative damage.

     Based on the evidence, we hypothesize that melatonin may protect against chromium-induced oxidative stress and toxicity in organisms.

                                                                          Table 1. List of extrapineal melatonin sources.

                                                                                                                                                                    Table 2. Functions of extrapineal melatonin.

2. ROLE OF Cr IN PATHOGENESIS OF OXIDATIVE STRESS

     To know the biological effects of Cr, it is important to distinguish its valence states. Cr(III) is 10-100 times less toxic than that of Cr(VI) for organisms (4) because Cr(III) is less soluble and poorly absorbed by the gastrointestinal tract (GI tract) (13, 76). However, long-term exposure to Cr(III) can cause genotoxicity (77–80). The reason is that when Cr(III) enters into the nucleus it can react with DNA to produce mutagenic or clastogenic effects (81, 82). In contrast, Cr(VI) is highly soluble and a powerful oxidizing agent (83). The cytotoxic effect of Cr(VI) is related to its carrier-mediated transport across the plasma membrane, followed by its intracellular reduction to Cr(III) (84), and this nature of Cr(VI) makes it very toxic for organisms in comparison to other species of Cr. According to the International Agency for Research on Cancer (IARC), Cr(VI) is a Group I carcinogen that triggers cancer by multiple complex mechanisms (85).

2.1. Permeability of Cr(VI) into the cell membrane.

     In the presence of O₂, Cr(VI) can form two predominant species: 1. Chromate (CrO₄^2-) (in the basic condition) and 2. Dichromate (Cr₂O₇^2-) (in the acidic condition). Cr(VI) in the form of tetrahedral divalent (CrO₄^2-) (anion, can cross the plasma membrane easily through chloride phosphate (86) and sulfate anionic carrier (87, 88), against the concentration gradient of the divalent anion^(2-). These processes do not involve in active transports. After absorption through the GI tract, Cr(VI) is uptake by cells in different tissues and organs (89). Then the Cr(VI) can be reduced to its most stable intermediate intracellularly. The extracellular reduction of Cr(VI) is also present primarily in saliva, followed by gastric juice of the stomach (90) and in the intestine by bacteria (82). Once Cr(VI) is reduced to its stable state of Cr (III), it is generally retained in the place where it is produced, as it is impermeable to the membrane (79, 90). However, a small amount of extracellular Cr(III) can enter cell majorly by phagocytosis. The maximum toxic effect of Cr(III) usually occurs at the nuclei or mitochondria (91).

2.2. Intracellular/extracellular reduction of Cr(VI).

     Cr(VI) can be reduced by the intracellular antioxidants (92). The reduction of Cr(VI) by enzymatic and non-enzymatic antioxidants lowers the intracellular Cr(VI) level and this leads to constant entry of the extracellular Cr(VI) into the cell to maintain its balance (93). Several antioxidants involve in Cr(VI) reduction. These include glutathione (GSH), ascorbate (Asc), thioredoxin (94, 95), cysteine (96, 97), etc., whereas, some enzymes also involve its reduction, such as mitochondrial electron transport complexes, microsomal cytochrome P450/NADPH-cytochrome P450 reductase (98, 99), glutathione reductase (GR), ferredoxin, NADP+ oxidoreductase (100, 101), etc. All of these can reduce chromate effectively at pH 7.4 (90). Both mitochondria and microsomes have the capacity to reduce Cr(VI). NADPH-dependent flavoenzymes possess chromate-reductase activity. On contrary, enzymes that do not contain flavoproteins cannot efficiently react with chromates, such as isocitrate dehydrogenase (ICDH), malate dehydrogenase (MDH), and glutamate dehydrogenase (GDH) (99). As a transition metal, chromium (i) can generate ROS by indirectly oxidizing flavin cofactors to adopt a semiquinone radical (UQ·^_) state, and (ii)  interacts either with oxygen (under the action of cytochrome P450) or with peroxides (under the actions of myoglobin, hemoglobin, cyclooxygenase, peroxidase, catalase) or (iii)  transfers an oxen from the oxygen or peroxide to the metal ion (102). Considering the role of GSH and Asc as the classic antioxidants, it is not yet clear whether they exhibit protective effects against Cr(VI) induced oxidative stress since they reduce it to potentiate the oxidative stress. Thus, it is important to understand the actions of antioxidants on Cr(VI) induced pathology.

2.3. Role of Cr(VI) on the aggravation of oxidative stress.

     Similar to iron (Fe) and copper (Cu), Cr is also a redox-active metal. Thus, it can undergo redox cycling to produce a large amount of ROS in cells (25, 26, 29). Each step of Cr(VI) reduction involves the use of H₂O₂ to generates HO^. via Fenton-like reactions (eq.1-3) (90, 100, 103–107). In the presence of Cr(VI), endogenous O₂^.-anions and H₂O₂ also lead to the generation of HO^. radical via Haber-Weiss reactions (eq.4) (90).

Cr(VI) + H₂O₂ → HO· + Cr (V) + OH^-          (1)

Cr(V) + H₂O₂ → HO· + Cr (IV) + OH^-          (2)

Cr(IV) + H₂O₂ → HO· + Cr(III) + OH^-          (3)

  O₂^.-+ H₂O₂ → O₂ + HO· + HO^-                         (4)

     Superoxide anion  (most importantly generated in mitochondria)  is also harmful as it reacts with nitric oxide (NO) to produce peroxynitrite (ONOO¯), a potent reactive nitrogen species (RNS) (108).

2.4. Mechanisms of Cr(VI) mediated oxidative damage.

     Several mechanisms are responsible for lipid and protein oxidation in Cr(VI) induced oxidative damages.

(i) The H₂O₂ and HO^. produced by Cr(VI)  during Fenton and Haber-Weiss reactions attack membrane lipids causing peroxidation and membrane injury (102, 109–111).

(ii) The reduced intermediates of Cr(VI) bind to proteins, peptides, and amino acids to form protein carbonyls under the presence of  H₂O₂ (112).

(iii) Cr(VI) causes both structural and functional alterations on the plasma membrane by altering the proportion of cholesterol and phospholipid by depletion of  GSH (113).

(iv) Accumulation of Cr(III) intracellularly and extracellularly induces morphological alterations in the cell surface resulting in the disruption of lipid-protein structures of the plasma membranes that eventually cause loss of cellular integrity (91).

     Studies have shown that Cr(VI) exposure to human erythrocytes causes an increment in plasma lipid peroxidation (114–116), protein oxidation, and the decrease in total sulfhydryl content, the activities of superoxide dismutase (SOD), glutathione S-transferase (GST), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TR) (117, 118). In a cell line study, GPX/GR activity shows a biphasic characteristic, that is, it increases at a later stage followed by an initial decrease as a consequence of de novo synthesis or reactivation of enzymes (119) after exposed to Cr(VI). Cr(VI) induced oxidative stress also exhibit organ-specific response on different antioxidant enzymes, which also depends on some factors such as chemical composition, days, and routes of treatment. But the increase in lipid peroxidation, glutathione depletion, and nuclear DNA damage are common in all tissues (120–125).

2.5. Effects of Cr(VI) on Sirt-1, Pgc-1α, Nrf-2, HO-1, and NQO1 pathway.

     The Sirt-1, Pgc-1α, Nrf-2, HO-1, and NQO1 molecules play an important role in oxidative stress-related signal transductions. Distortion of signals after Cr(VI) exposure causes oxidative damages (126). Silent information regulator 1 (Sirt-1), a NAD⁺-dependent deacetylase, which locates in the nucleus and cytoplasm, regulates the gene expression, energy metabolism, and oxidative stress response and also participates in the anti-inflammatory and antiapoptotic processes by deacetylase protein substrate in various signal transduction pathways (127–129). However, peroxisome proliferation-activated receptor-g coactivator 1α (Pgc-1α) is a transcription factor coactivator that controls several cellular metabolic pathways. It improves ROS defense system (130), fatty acid metabolism, and master regulator of mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) (131), by interacting with specific transcription factors (132,133). Sirt-1 increases the activity of cellular antioxidants by inducing expressions of SOD and GPx in cells via activating transcription of Pgc-1α (134, 135). Cr(VI) inhibits  Sirt-1 and Pgc-1α, and thus, it reduces the antioxidant capacity, causes disorder of mitochondrial dynamics and oxidative stress (126, 136). On the other hand, nuclear erythroid 2-related factor-2 (Nrf-2) is a transcriptional regulator that induces the gene expression of the component of cellular antioxidants (glutathione and thioredoxin system) as well as helps in phase I and phase II cellular detoxification of substances (137, 138). Hence, it plays a crucial role against xenobiotics and oxidative stress (137). Nrf-2 also regulates the expression of two antioxidant proteins (139). First one is NADPH dehydrogenase quinone-1 (NQO1), which plays multiple roles in adapting cellular stress (140, 141) and another is heme oxygenase-1 (HO-1), that stimulates cell proliferation/growth, and helps to maintain cellular homeostasis as well as upregulate the expression of antioxidant and antiapoptotic pathways (142–145). The deficiency of HO-1 in the cell causes DNA damage and carcinogenesis (146). Cr(VI) exposure suppresses Nrf-2, HO-1, and NQO1 expressions and leads the tissues vulnerable to oxidative damage.

3. ROLE OF Cr(VI) ON DNA DAMAGE

3.1. Cr(VI) induced DNA damage.

     Cr(VI) is an inducer of DNA-crosslinks and  DNA strand breaks at pH-7.4 with genotoxicity and carcinogenicity (147).  The majority of these alterations are made by its reduced metabolite Cr (III). Cr(III) causes (i) oxidative DNA lesions such as strand breaks, (ii) formation of Cr-DNA adducts, (iii) DNA-DNA interstrand cross-links, and (iv) DNA-protein cross-links (148). These Cr-DNA adducts are considered as the principal genetic lesions for replication inhibition, mutagenesis, and finally cell death (149). In this respect, we need to discuss the potential roles of antioxidants played in this process.

3.2. Non-enzymatic antioxidants.

3.2.1. Association of Cr(VI) related DNA damage with GSH.

     GSH  is the most important antioxidant and also a prime metal chelator as its thiol (-SH) group has a high affinity to metals (150). The metal chelation activity of GSH seems diminished in the case of Cr(III). GSH can directly reduce Cr(VI) to form Cr (V), Cr (IV), and Cr(III) step by step by donating one electron at a time (95, 101). Cr(V) and Cr(III) are known to activate DNA damaging signals and break DNA double-strands (86). Initially, Cr(VI) reacts with glutathione to form Cr (V)-glutathione complex and glutathione thiyl radical (GS^.) (eq.5) (105–107, 151, 152). The Cr(V)-glutathione complex reacts with H₂O₂ to produce HO^.  through a Fenton-type reaction, leading to DNA damage (105).

Cr(VI) + GSH → Cr(V)-GSH complex + GS^.           (5)

GS^. further reacts with one molecule of GSH and produces di-sulfide radical (eq.6) (153) that  reacts with molecular oxygen to generate(eq.7) (154).

GS^. + GSH → GSSG^.¯+ H⁺                (6)

                                                                                         GSSG^.¯ + O₂ → GSSG + O₂^.-                         (7)

     The decomposition of Cr(V)-glutathione complex leads to the formation of Cr (IV) and thiyl radical (GS^.), both of which continue to produce HO^. and Cr(III) (Fenton type reaction). The interaction between DNA and Cr compounds is responsible for strand break (101, 155, 156), along with the catalytical production of HO^. which has sufficient potential to cleave DNA (48, 59, 83, 114). Guanine residues of DNA can react with HO^. producing radical adducts such as 8-hydroxy-deoxyguanosine (8-OH-dG), a conspicuous marker for oxidative damage in cancer (158, 159), which is significantly increased in the urine of chrome plating workers (160–164). The glutathione-Cr(III)-DNA cross-links are known to be the most abundant lesion, resulting in ternary Cr-DNA adducts (coordination of Cr(III) with DNA phosphates (phosphotriester-type adduct)), accounting for about 80% in cultured cells which have proved as mutagenic in the human cells during replication (149, 165). The cellular concentration of GSH in the presence of Cr(VI) becomes very low due to the inhibitory effect of Cr(VI)  on GR (166, 167) or the consumption of GSH during Cr(VI) reduction. Wiegand et al.(168) have suggested that generally 3 molecules of GSH are needed to reduce 1 molecule of Cr(VI) and this process is accelerated in the presence of excessive GSH. This GSH  may be synthesized through the g-glutamyl cysteine pathway by breaking down the protein for the availability of its precursor amino acid cysteine (169). This is supported by the observation that Cr(VI) exposure increases GSH level up to ~120% in rat liver (170) and kidney tissues following an initial decrease by accelerating protein breakdown for GSH biosynthesis (171). A dramatic increase in Cr(VI) induced DNA strand breaks is associated with an increase in GSH level in cells (172, 173) as GSH is responsible for the reduction of  Cr(VI) (174). Further studies show that GSH not only acts as a reductant of Cr(VI) but it also enhances the formation of Cr-DNA interstrand crosslink, which is the principal polymerase arresting lesion responsible for blocking DNA replication (94). Cr-DNA adducts formation simply depends on the production of Cr(VI) intermediates. On the other hand, DNA strand breakage is associated with the production of HO^.; thus, the nature of DNA damage solely relates to the formation of reactive intermediates in the presence of GSH (107).

3.2.2. Association of Cr(VI) mediated  DNA damage with Asc. 

     Asc is also an important Cr(VI) reductant that has been extensively studied. Suzuki and Fukuda (175) have shown that Asc is even more reactive with Cr(VI) than GSH. This is confirmed by Standeven and Watterhahn (173). They claim that Asc is the principal non-enzymatic reductant of Cr(VI) in rat liver and kidney. Asc-dependent metabolism of Cr(VI)  injuries nuclear DNA while sulfhydryls and NADPH-dependent Cr(VI)  metabolism has limited effect on DNA damage (176). Electronic paramagnetic resonance (EPR) study shows that the reaction of Asc with Cr(VI) produces ascorbate radical, carbon-di-oxide anion radical and other carbon-based radicals as produced by GSH (eq.8-10) (177–179) and also facilitates the binding of Cr(III) with un-cleaved DNA (180).

                                                                                                                              Cr(VI) + Asc^H- → Cr (V) + Asc^.-                   (8)

                                                                                    Cr (V) + Asc^H- → Cr (IV) + Asc^.-           (9)

                                                                                    Cr (IV) + Asc^H- → Cr(III) + Asc^.-                   (10)

According to Bielski, those Asc^.-  radicals react with each other to form a dimer that further reacts with H⁺ and converts again to ascorbate and dehydroascorbate (DHA) (Eq.11) (181) that then,  enters into the Cr(VI) reduction cycle again.

Asc^H- + H⁺ → Asc + DHA                 (11)

     EPR study also shows that Asc enhances Cr(III) complex by reduction of the long-lived intermediate Cr (V) complex. This indicates that Asc can reduce Cr(VI) directly to Cr(III) and increases DNA-protein crosslinks and produces cytotoxicity (182, 183). Actually, Cr(VI) and Asc can form Cr–DNA adducts by multi-coordinated binding of Cr(III) to DNA which is more resistant to dissociation by chelators (184, 185) resulting in the crosslinking of DNA-Cr-DNA by arresting the guanine specific area in mammalian DNA polymerases (94, 186).

3.3. Antioxidant enzymes.

3.3.1. Association of Cr(VI) mediated DNA damage with NADPH/NADH linked enzymes.

     The main mechanisms of microsomal and cytosolic reductions of Cr(VI) associated with antioxidant enzymes (81) are exclusively NADPH-dependent along with the involvement of DT-diaphorase (87, 88, 187). DT-diaphorase (quinone oxidoreductase) can donate two electrons directly to form Cr(III) from Cr(VI) to avoid the formation of Cr (IV) and Cr (V) intermediates (81, 98). In the presence of NADPH, cytosolic Cr(VI) reduction involves a one-electron transfer process that produces Cr(V) to form Cr(V)-NADPH complex using flavoenzyme GR (88, 103, 104). Cr(V) is responsible for DNA single-strand break and inhibition of GR activity while Cr(III) is responsible for DNA-protein crosslinks (182, 188). Inhibition of the activity of GR may be due to the loss of cytosolic NADPH (166). Reduction of Cr(VI) to Cr(III) requires the presence of both microsomal proteins as well as NADPH cofactor since Cr(VI) reduction was not observed at the presence of this cofactor with heat-denatured microsomal protein (99). So, in the absence of these cofactors, chromate reduction does not occur, leading to no oxidation of other components of the microsomal system (88). The cytochrome P-450 electron-transport chain appears to be responsible for the microsomal Cr(VI)-reduction in the presence of NADPH (172). In the presence of NADPH, Cr(VI) can form stable Cr(V)-NADPH complexes such as glucose-6-phosphate (G6P)-Cr (V) complex (98). Incubation of Cr(VI) with microsomes and NADPH results in both single-stranded and double-stranded DNA binding; caused by the interaction between enzymatically generated Cr intermediates and DNA to produce polyoxyriboadenylic acid, polyribocytidylic acid, polyriboguanylic acid, and polyribouridylic acid (189). In the intracellular environment both Cr(VI) as well as Cr (V) complexes can interact with adenine and guanine of  DNA, resulting in oxidative damage which is ultimately transfigured to stable Cr(III)-deoxyadenosine (dA)-DNA and Cr(III)–deoxyguanosine (dG)-DNA adducts in human cells to produce bulky DNA, i.e. less repairable and consequently induces mutations (190).

3.3.2. Cr(VI) and Mitochondrial electron transport chain (ETC) enzymes on DNA damage.

     Cr(VI) can be reduced by the enzymes of the mitochondrial ETC complex in the inner mitochondrial membrane (191) due to the fact that ETC complex I can donate two electrons to Cr(VI) (192). In the isolated submitochondrial particles (SMPs) of rat liver, under anaerobic condition, the Complex I and IV dependent-Cr(VI) reduction causes the formation of Cr(V) intermediate detectable by EPR spectroscopy and higher rate of oxygen depletion, whereas, complex II has less effect (191). A specific study on complex II of the respiratory chain indicates both succinate and glutamate serve as electron donors in this complex. Succinate in the presence of uncoupler (such as ADP) facilitates Cr(VI) reduction while glutamate-mediated reduction occurs only in the presence of respiratory-chain inhibitors thus, they exhibit different mechanisms on  Cr(VI) reductions for NAD-linked or FAD-linked substrates (193). Cr(VI) can also inhibit mitochondrial ETC complexes I and II by reaction with the thioredoxin system[thioredoxin (Trx)/peroxiredoxin (Prx)] to damage mitochondrial proteins. The excessive Trx/Prx oxidation and thioredoxin reductase (TrxR) inhibition result in loss of mitochondrial membrane potential(192,194). Reduction of Trx’s by Cr(VI) may be due to the inhibition of TrxR that keeps the Trx’s in the reduced state, and the activity of TrxR cannot be reversed by the removal of residual Cr(VI) or by the addition of NADPH (electron donor for TrxR) (195). Thus, most of the endogenous antioxidant defense systems are suppressed or damaged after exposure to Cr(VI) accordingly in both time as well as dose-dependent manner.

4. ADVERSE EFFECTS OF Cr IN HUMANS

 Generally, human exposure to Cr(VI) is mainly via oral routes (drinking water and foods), inhalation (welding fumes), and dermal contacts (using products such as leather bags, shoes, stainless steel containers, cement, etc.). Bhattacharya et al. have reported that a saturated level of Cr(VI) is present in groundwater (in the form of CrO₄^2-) and soil at the unregulated disposal site of pre-tanning industrial waste and chromite ore processing residue (COPR) (196). 1-3% of the general population is allergic to Cr compounds which are also known as a “contact allergen”. Cr-induced allergic dermatitis (such as hand eczema (197), foot dermatitis (198), hand dermatitis (199) result from direct contact with leather goods (200–202), cement (203), etc. Allergic reactions are triggered by Cr(VI) as well as Cr(III) at a very low concentration (204, 205). Groundwater contamination with Cr(VI) from tanneries causes dermatological, digestive, hematological abnormalities along with GI distress found in community areas (206). Singhal et al. have reported that 69.69% of workers in the sodium dichromate manufacturing industry and 56.22%  of workers in the chrome plating industry had a disorder of nasal mucous membrane and skin ulcer (207). Exposure to Cr can also cause kidney damage and produce low molecular weight (LMW) proteinuria and acute tubular necrosis (ATN) among the chrome platers and welders (208).

5. MELATONIN: A POTENTIAL THERAPEUTIC MOLECULE FOR Cr EXPOSURE IN ORGANISMS

     As mentioned above, Cr(VI) causes oxidative damages; however, the classic antioxidants including glutathione and vitamin C exhibit little protective effects while in most cases they may make the damage worse. It is challenging to find the unique antioxidants that can protect against Cr(VI) induced oxidative stress. Melatonin seems to be one of these unique antioxidants. Its unique properties to protect against Cr(VI) toxicities will be discussed below.

5.1. Direct effects of melatonin on Cr(VI) induced oxidative stress.

     Melatonin is a phylogenetically conserved molecule present in almost all organisms. Its primary function serves as a first line antioxidant (209–212). The antioxidant capacity of melatonin is more potent than that of classic antioxidants vitamin C, E, and GSH, etc. (209, 213), and it minimizes both oxidative and nitrosative stress efficiently (214–216). Melatonin can directly scavenge the ROS or upregulate the expression of antioxidant enzymes via its membrane receptors or even its nuclear receptor activation (217). Several physiochemical mechanisms contribute to its high efficiency to interact with ROS (eq.12-14) (218):

                                                                                Radical adduct formation: Melatonin + R^· → melatonin-R^·                              (12)

                                                                                Hydrogen atom transfer: Melatonin + R^· → melatonin (-H)^· + HR              (13)

                                                                                Single-electron transfer: Melatonin + R^·→ melatonin^·++ R^--                          (14)

     Different from the classic antioxidants, melatonin does not participate in the redox recycle reaction and, thus, is devoid of pro-oxidant activity (219). It can interact with a variety of ROS including singlet oxygen (¹O₂) (220–223), peroxyl radical (ROO·) (224–226), hypochlorous acid (HOCl) (227), HO· (51, 223, 228–230), H₂O₂, O₂·- (223). Due to its amphiphilic nature, it can protect the membrane against lipophilic-oxy radicals, and also the hydrophilic radicals originated from the aqueous environment by locating between the polar head group of membrane phospholipid (231). Melatonin attenuates the chain reaction of lipid peroxidation (227, 232–235) to prevent the rigidity of phospholipid bilayer and acts as a mask against radical attack by blocking the site of membrane lipids (236, 237). It reduces the lipoperoxyl radical (LOO·) formation and stabilizes the cell membrane structure by directly neutralizing it (238) or by inhibiting the gene expression of lipoxygenase (239). It also reduces protein oxidation (224, 240) and protects the structure of the cell membrane damage caused by Cr(VI).

     Apart from the radical scavenging activity, melatonin also upregulates the gene expression of several antioxidant enzymes such as GPx, GR, SOD, CAT, etc. (239, 241–243). Melatonin and its metabolite AMK also decrease the expression of nitric oxide synthases such as iNOS and mtNOS, thus reducing the level of NO and ONOO¯(244–248). In addition, melatonin is also a metal chelating agent (59). It can form di-, tri-, and tetradentate ligands with transition metal (59) to exert its metal detoxification activity. Due to this characteristic, melatonin can chelate up to 95% of metal ions (60). As a result, melatonin treatment relates to Cr and reduces the metal load on hepatic tissues (125).

 5.2. Receptor mediated effects of melatonin on Cr(VI) induced oxidative stress.

     Some antioxidant activities of melatonin are mediated by its membrane receptors (MT1 and MT2). For example, binding to MT2, melatonin enhances the pathway of Sirt-1 and Pgc-1α, and partially activates signaling to mitochondria for their biogenesis (249). Sirt-1/Pgc-1α signaling pathway is important for maintaining the cellular antioxidant defense system (250), which upregulates the cellular and subcellular levels of antioxidant enzymes including SOD, GPx, CAT (251). In addition, melatonin induces the translocation of the Nrf2 transcription factor from the cytosol into the nucleus, therefore, it enhances gene expression of phase-2 antioxidative enzymes including c-glutamylcysteine synthetase (c-GCS), heme oxygenase-1 (HO-1), and NADPH: quinone dehydrogenase-1 (NQO1) (252) and suppresses the expression of proinflammatory NF-kB/COX-2 pathway (253). Thus, the decreased levels of Sirt-1, Pgc-1α, Nrf-2, HO-1, and NQO1 proteins caused by Cr(VI) exposure can be attenuated by melatonin treatment (126).

5.3. Mechanisms of melatonin on classic antioxidants potentiated Cr(VI) induced DNA damage.

     The in-vitro study has shown that GSH can enhance metal-induced oxidative stress while melatonin administration reduces the damage with increased GSH level. The recovered GSH level is assumed by melatonin thermodynamically binding with GSH and making GSH be unavailable for metal chelation (254). Moreover, melatonin can increase the activity of rate-limiting enzyme g-glutamylcysteine synthase in the GSH synthesis pathway (239,255).

     Asc, a well-known antioxidant, but in the presence of transition metals, it promotes peroxidation for the bio-molecules including  DNA (256). Thus, it is referred as a true paradoxical compound (257) and often used to potentiate oxidative stress in iron or copper system. Melatonin has been successfully used to protect against oxidative stress induced by both Fe²⁺/asc (258, 259) and Cu²⁺/asc (260, 261) systems. Thus, it can be assumed that melatonin can also protect the cells from Cr(VI), although it requires intense study. Melatonin not only detoxifies oxygen-derived species but also scavenges other types of species including carbon-centered free radicals (234) produced as reaction intermediate during Cr(VI) reduction by Asc. Melatonin present in the nucleus not only protects forming  Cr(III)-DNA adduct but also reduces other DNA  oxidative damage (262, 263). For example, melatonin can reduce Cr(VI) induced DNA single-strand break up to 60-80% (264).

5.4. Mechanisms of melatonin on antioxidative enzyme potentiated Cr(VI) induced DNA damage.

     The concentrations of melatonin vary in subcellular compartments including cytosol, mitochondria, and nucleus (265–267). The highest melatonin level is detected in the mitochondria. Thus, melatonin effectively protects the mitochondrial membranes as well as mitochondrial DNA from ROS-mediated oxidative damage (268). Mitochondria are the powerhouse of ATP production. In the presence of Cr(VI), mitochondrial function is jeopardized with reduced activity of complex I and IV and ATP production. Mitochondrial dysfunction can cause an apoptotic signaling cascade which can be effectively shielded by melatonin (269). Melatonin increases ATP production by increasing the activity of ETC (265, 269, 270), restricting the mitochondrial membrane permeability pores to increase mitochondrial membrane potential. Castroviejo et al. have reported that melatonin as well as AMK increases the activities of Complex I and IV and preserves their normal conditions under oxidative stress (244,  270). As a result, it may also protect against Cr(VI) induced damages to the mitochondria(271).

6. EFFECTIVE CONCENTRATIONS OF MELATONIN USED FOR TOXIC METALS.

      Melatonin has been widely used to detoxify the variable toxic metals including Cr. For comparable purposes, its effective concentrations on different metals have been summarized in Table 3.

7. CONCLUSION

     Being a transition metal, Cr particularly Cr(VI) induces oxidative stress and DNA damage by producing HO^. or by formatting Cr-DNA adducts and DNA strands breaking (single and double-strand breaking). Cr(VI) is classified as a carcinogen due to its ability of causing gene mutations and tumors. Melatonin, a low molecular weight molecule synthesized by mitochondria, is a potent antioxidant. It is an environment friendly molecule with no obvious toxicity to organisms. It is also available from foodstuff with the reported high levels in cereals (rice, wheat), green vegetables, fruits, and beverages (wine, beer, orange juice) that humans consume almost regularly. Melatonin exerts its protective effects on Cr(VI) induced oxidative stress and DNA damage via multiple mechanisms: (i) it chelates Cr(VI) and Cr (III), (ii) it scavenges free radicals, (iii) it reduces the Cr(VI) induced protein breakdown and generates GSH by increasing g-glutamylcysteinesynthase (γ-GCS) activity, and (iv) it increases the mitochondrial ETC activity thereby protecting against the Cr(VI) induced mitochondrial damage. The protective mechanisms of melatonin against Cr(VI) induced oxidative stress have been summarized in figure 1. Thus, we speculate that melatonin can serve as an important future therapeutic molecule or as an important nutraceutical in the amelioration of Cr(VI) induced oxidative damage in organisms. 

                                                    Table 3. The effective doses of melatonin on metal-induced oxidative damage.

                                      i.p: Intraperitoneal injection, s.c: Subcutaneous injection. 

Fig.1. Protective mechanism of melatonin against Cr(VI) induced oxidative stress- and DNA damage.

     (SSR)- Single-Strand Breaks, (DSR)- Double-Strand Breaks, (Cr)- Chromium, (GSH)- reduced glutathione, (GS^.)- glutathione thiyl radical, (Asc)- ascorbate,(Asc^._)- ascorbate radical, CO₂^.- -carbon radical, (8-OH-dG)- 8-hydroxy-deoxyguanosine, (HO^.)- hydroxyl radical, O₂^.- - superoxide radical, (GR)- glutathione reductase, (GPx)- glutathione peroxidase, (GST)- glutathione-S- transferase, (SOD)- superoxide dismutase, (CAT)- catalase.

ACKNOWLEDGEMENTS

     Priyanka Ghosh gratefully acknowledges the receipt of the UGC Junior Research Fellowship (ref no.1571/PWD (NET-NOV2017), Govt. of India. Tiyasa Dey thankfully acknowledges the receipt of UGC Senior Research Fellowship (ref no.1418/ (NET-JUNE 2015), Govt. of India. AC is supported from a research project awarded to her by the Department of Science and Technology, Govt. of West Bengal, India. DB is also supported from departmental BI grant of University of Calcutta. DB also gratefully acknowledges the support he received from DST-PURSE Program awarded to the University of Calcutta. The authors remain grateful to Dr. DunXian Tan, Editor-in-Chief of Melatonin Research for his critical reading and thoughtful editing of the manuscript which the authors believe has definitely increased the scientific and readership quality of the manuscript.

AUTHORS CONTRIBUTION

     Dr. DB and Dr. AC contributed to conception and critical revision of the manuscript and approved it. PG and TD prepared figures, drafted the manuscript, and edited it.

CONFLICT OF INTEREST

     Authors declare no conflict of interest.

REFERENCES

1. Barrera-Díaz CE, Lugo-Lugo V, Bilyeu B (2012) A review of chemical, electrochemical and biological methods for aqueous Cr(VI) reduction. J. Hazard. Mater. 223–224: 1–12. DOI: 10.1016/j.jhazmat.2012.04.054.

2. Rita Evelyne J, Ravisankar V (2014) Bioremediation of chromium contamination- a review. Int. J. Res. Earth Environ. Sci. 1 (6): 20–26.

3. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ (2012) Heavy metal toxicity and the environment. Mol. Clin. Environ. Toxicol. 101: 133–164. DOI: 10.1007/978-3-7643-8340-4.

4. Katz SA, Salem H (1993) The toxicology of chromium with respect to its chemical speciation: A review. J. Appl. Toxicol. 13 (3): 217–224. DOI: 10.1002/jat.2550130314.

5.  Goyer RA, Clarkson TW 2001. (2001) Toxic effects of metals. In: Klaassen CD (ed) Cassarett and Doull’s toxicology: the basic science of poisons McGraw-Hill, New York. 2001. p. 811–867.

6. Duffus JH (2002) “Heavy metals” a meaningless term? (IUPAC Technical Report). Pure Appl. Chem. 74 (5): 793–807. DOI: 10.1351/pac200274050793.

7. Schmidt RL (1984) Thermodynamic properties and environmental chemistry of chromium. Richland, WA; 1984.

8. Barnhart J (1997) Occurrences, uses, and properties of chromium. Regul. Toxicol. Pharmacol. 26 (1): S3–S7. DOI: 10.1006/rtph.1997.1132.

9. Mertz W (1969) Chromium occurrence and function in biological systems. Physiol. Rev. 49 (2): 163–239. DOI: 10.1152/physrev.1969.49.2.163.

10. Anderson RA, Polansky MM, Bryden NA, Roginski EE, Mertz W, Glinsmann W (1983) Chromium supplementation of human subjects: Effects on glucose, insulin, and lipid variables. Metabolism 32 (9): 894–899. DOI: 10.1016/0026-0495(83)90203-2.

11. Anderson RA, Polansky MM, Bryden NA, Canary JJ (1991) Supplemental-chromium effects on glucose, insulin, glucagon, and urinary chromium losses in subjects consuming controlled low-chromium diets. Am. J. Clin. Nutr. 54 (5): 909–916.

12. Mertz W (1993) Chromium in human nutrition: A review. J. Nutr. 123 (4): 626–633. DOI: 10.1093/jn/123.4.626.

13. Pechova A, Pavlata L (2007) Chromium as an essential nutrient: a review. Vet. Med. (Praha). 52 (1): 1–18. DOI: 10.17221/2010-VETMED.

14. Abraham SA, Baruch AB EU (1991) Chromium and cholesterol-induced atherosclerosis in rabbits. Ann. Nutr. Metab. 35: 203–207. DOI: Doi: 10.1159/000177646.

15. Abraham AS, Brooks BA, Eylath U (1992) The effects of chromium supplementation on serum glucose and lipids in patients with and without non-insulin-dependent diabetes. Metabolism 41 (7): 768–771. DOI: 10.1016/0026-0495(92)90318-5.

16.  Balk E, Tatsioni A, Lichtenstein A, Lau J, Pittas A (2007) Effect of chromium supplementation on glucose metabolism and lipids. Diabetes Care 30 (8): 2154–2163. DOI: Doi: 10.2337/dc06-0996.

17. Davis CM, Vincent JB (1997) Chromium in carbohydrate and lipid metabolism. J. Biol. Inorg. Chem. 2 (6): 675–679.

18. Anderson RA (1998) Chromium, glucose intolerance and diabetes. J. Am. Coll. Nutr. 17 (6): 548–555. DOI: 10.1080/07315724.1998.10718802.

19. Saha R, Nandi R, Saha B (2011) Sources and toxicity of hexavalent chromium. J. Coord. Chem. 64 (10): 1782–1806. DOI: 10.1080/00958972.2011.583646.

20. Kimbrough DE, Cohen Y, Winer AM, Creelman L, Kimbrough DE (1999) A critical assessment of chromium in the environment. Crit. Rev. Environ. Sci. Technol. 29 (1): 1–46. DOI: 10.1080/10643389991259164.

21. Mishra S, Bharagava RN (2016) Toxic and genotoxic effects of hexavalent chromium in environment and its bioremediation strategies. J. Environ. Sci. Heal. - Part C Environ. Carcinog. Ecotoxicol. Rev. 34 (1): 1–32. DOI: 10.1080/10590501.2015.1096883.

22. Shrivastava R, Upreti RK, Chaturvedi UC (2003) Various cells of the immune system and intestine differ in their capacity to reduce hexavalent chromium. FEMS Immunol. Med. Microbiol. 38 (1): 65–70. DOI: 10.1016/S0928-8244(03)00107-X.

23. Chuan MC, Liu JC (1996) Release behavior of chromium from tannery sludge. Water Res. 30 (4): 932–938. DOI: 10.1016/0043-1354(95)00227-8.

24.  ATSDR (2012) Public health statement: Chromium. Public Heal. Serv. (September): 1–9.

25. Ercal N, Gurer-Orhan H, Aykin-Burns N (2001) Toxic metals and oxidative stress part i: mechanisms involved in metal induced oxidative damage. Curr. Top. Med. Chem. 1 (6): 529–539. DOI: 10.2174/1568026013394831.

26. Stohs SJ, Bagchi D (1995) Oxidative mechanisms in the toxicity of metal ions. Free Radic. Biol. Med. 18 (2): 321–336. DOI: 10.1016/0891-5849(94)00159-H.

27. Sharma B, Singh S, Siddiqi NJ (2014) Biomedical implications of heavy metals induced imbalances in redox systems. Biomed Res. Int. : 1–26. DOI: 10.1155/2014/640754.

28. Leonard SS, Harris GK, Shi X (2004) Metal-induced oxidative stress and signal transduction. Free Radic. Biol. Med. 37 (12): 1921–1942. DOI: Doi:10.1016/j.freeradbiomed.2004.09.010.

29. Valko M, Morris H  and CM (2005) Metals, toxicity and oxidative stress. Curr. Med. Chem. 12 : 1161–1208. DOI: Doi: 10.2174/0929867053764635.

30. Soudani N, Troudi A, Bouaziz H, Ben Amara I, Boudawara T, Zeghal N (2011) Cardioprotective effects of selenium on chromium (VI)-induced toxicity in female rats. Ecotoxicol. Environ. Saf. 74 (3): 513–520. DOI: 10.1016/j.ecoenv.2010.06.009.

31. Soudani N, Ben Amara I, Sefi M, Boudawara T, Zeghal N (2011) Effects of selenium on chromium (VI)-induced hepatotoxicity in adult rats. Exp. Toxicol. Pathol. 63 (6): 541–548. DOI: 10.1016/j.etp.2010.04.005.

32. Balakrishnan R, Satish Kumar CSV, Rani MU, Srikanth MK, Boobalan G, Reddy AG (2013) An evaluation of the protective role of α-tocopherol on free radical induced hepatotoxicity and nephrotoxicity due to chromium in rats. Indian J. Pharmacol. 45 (5): 490–495. DOI: 10.4103/0253-7613.117778.

33. Saidi M, Aouacheri O, Saka S (2019) Protective effect of curcuma against chromium hepatotoxicity in rats. Phytothérapie 18 (3–4): 148–155. DOI: 10.3166/phyto-2019-0114.

34. Soudani N, Sefi M, Ben Amara I, Boudawara T, Zeghal N (2010) Protective effects of selenium (Se) on chromium (VI) induced nephrotoxicity in adult rats. Ecotoxicol. Environ. Saf. 73 (4): 671–678. DOI: 10.1016/j.ecoenv.2009.10.002.

35.  Lanca S, Alves A, Vieira AI, Barata J, Freitas JD  and CA (2002) Chromium-induced toxic hepatitis. Eur. J. Intern. Med. 13 : 518–520. DOI: Https://doi.org/10.1016/S0953-6205(02)00164-4.

36. Shrivastava R, Upreti RK, Seth PK, Chaturvedi UC (2002) Effects of chromium on the immune system. FEMS Immunol. Med. Microbiol. 34 (1): 1–7. DOI: 10.1016/S0928-8244(02)00345-0.

37. Burastero SE, Paolucci C, Breda D, Pontp J MB and SE (2006) Chromium (VI)-induced immunotoxicity and intracellular accumulation in human primary dendritic cells. Int. J. Immunopathol. Pharmacol. 19 (3): 581–591.

38.  Nickens KP, Patierno SR, Ceryak S (2010) Chromium genotoxicity: A double-edged sword. Chem. Biol. Interact. 188 (2): 276–288. DOI: 10.1016/j.cbi.2010.04.018.

39. Blasiak J, Kowalik J (2000) A comparison of the in vitro genotoxicity of tri- and hexavalent chromium. Mutat. Res. - Genet. Toxicol. Environ. Mutagen. 469 (1): 135–145. DOI: 10.1016/S1383-5718(00)00065-6.

40. Bianchi V, Levis AG (1984) Mechanisms of chromium genotoxicity. Toxicol. Environ. Chem. 9 (1): 1–25. DOI: 10.1080/02772248409357064.

41. Shanker AK, Cervantes C, Loza-Tavera H, Avudainayagam S (2005) Chromium toxicity in plants. Environ. Int. 31 (5): 739–753.

42. Oliveira H (2012) Chromium as an environmental pollutant: Insights on induced plant toxicity. J. Bot. 2012 : 1–8.

43. Sharma A, Kapoor D, Wang J, Shahzad B, Kumar V, Bali AS, Jasrotia S, Zheng B, Yuan H, Yan D (2020) Chromium bioaccumulation and its impacts on plants: An overview. Plants. 9 (1): 1–17.

44. Kundu D, Dey S Raychaudhuri SS (2018) Chromium (VI) - induced stress response in the plant Plantago ovata Forsk in vitro. Genes Environ. 40 (1): 1–13.

45. Stambulska UY, Bayliak MM, Lushchak VI (2018) Chromium(VI) toxicity in legume plants: Modulation effects of rhizobial symbiosis. Biomed. Res. Int. 2018: 8031213. doi: 10.1155/2018/8031213.

46. Seleiman MF, Ali S, Refay Y, Rizwan M, Alhammad BA, El-Hendawy SE (2020) Chromium resistant microbes and melatonin reduced Cr uptake and toxicity, improved physio-biochemical traits and yield of wheat in contaminated soil. Chemosphere 250:126239. DOI: 10.1016/j.chemosphere.2020.126239.

47. Shahid M, Shamshad S, Rafiq M, Khalid S, Bibi I, Niazi NK, Dumat C, Rashid MI (2017) Chromium speciation, bioavailability, uptake, toxicity and detoxification in soil-plant system: A review. Chemosphere 178 : 513–533.

48. Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ (2003) Melatonin: A hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J. Pineal Res. 34 (1): 75–78. DOI: 10.1034/j.1600-079X.2003.02111.x.

49. Reiter RJ (2000) Melatonin: Lowering the high price of free radicals. News Physiol. Sci. 15 (5): 246–250. DOI: 10.1152/physiologyonline.2000.15.5.246.

50. Reiter RJ (2003) Melatonin: clinical relevance. Best Pract. Res. Clin. Endocrinol. Metab. 17 (2): 273–285. DOI: 10.1053/ybeem.2003.249.

51. Poeggeler B RR, Tan DX, Chen LD  and ML (1993) Melatonin, hydroxyl radical-mediated oxidative damage , and aging : A hypothesis. J. Pineal Res. 14 : 151–168. DOI: DOI: 10.1111/j.1600-079x.1993.tb00498.x.

52. Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2011) Melatonin and its analogs in insomnia and depression. J. Pineal Res. 52 (4): 1–11. DOI: 10.1111/j.1600-079X.2011.00962.x.

53. Chen CQ, Fichna J, Bashashati M, Li YY, Storr M (2011) Distribution, function and physiological role of melatonin in the lower gut. World J. Gastroenterol. 17 (34): 3888–3898.

54. Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC, Rosales-Corral S, Tan DX, Reiter RJ (2014) Extrapineal melatonin: Sources, regulation, and potential functions. Cell. Mol. Life Sci. 71 (16): 2997–3025.

55. Galano A, Tan DX, Reiter RJ (2012) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J. Pineal Res. 54 (3): 245–257. DOI: 10.1111/jpi.12010.

56. Hardeland R (2005) Antioxidative protection by melatonin: Multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 27 (2): 119–130. DOI: 10.1385/ENDO:27:2:119.

57. Hardeland R, Reiter RJ, Poeggeler B, Tan DX (1993) The significance of the metabolism of the neurohormone melatonin: Antioxidative protection and formation of bioactive substances. Neurosci. Biobehav. Rev. 17 (3): 347–357. DOI: 10.1016/S0149-7634(05)80016-8.

58. Romero A, Ramos E, De Los Ríos C, Egea J, Del Pino J, Reiter RJ (2014) A review of metal-catalyzed molecular damage: Protection by melatonin. J. Pineal Res. 56 (4): 343–370. DOI: 10.1111/jpi.12132.

59. Rana SVS (2018) Protection of metal toxicity by melatonin - recent advances. EC Pharmacol. Toxicol. 9: 851–864.

60. Gulcin I, Buyukokuroglu ME, Kufrevioglu OI (2003) Metal chelating and hydrogen peroxide scavenging effects of melatonin. J. Pineal Res. 34: 278–281. DOI: 10.1034/j.1600-079X.2003.00042.x.

61. Sun FY, Lin X, Mao LZ, Ge WH, Zhang LM, Huang YL, Gu J (2002) Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. J. Pineal Res. 33 (1): 48–56.

62. Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, Pinton P (2019) Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 10 (4): 317 DOI: 10.1038/s41419-019-1556-7.

63. Waseem M, Tabassum H, Parvez S (2016) Melatonin modulates permeability transition pore and 5-hydroxydecanoate induced KATP channel inhibition in isolated brain mitochondria. Mitochondrion 31: 1–8. DOI: 10.1016/j.mito.2016.08.005.

64. Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J (2013) A review of the molecular aspects of melatonin’s anti-inflammatory actions: Recent insights and new perspectives. J. Pineal Res. 54 (1): 1–14.

65. Cao Z, Fang Y, Lu Y, Tan DX, Du C, Li Y, Ma Q, Yu J, Chen M, Zhou C, Pei L, Zhang L, Ran H, He M, Yu Z ZZ (2017) Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome. J. Pineal Res. 62 (3): doi: 10.1111/jpi.12389.

66. Gill RA, Zang L, Ali B, Farooq MA, Cui P, Yang S, Ali S, Zhou W (2015) Chromium-induced physio-chemical and ultrastructural changes in four cultivars of Brassica napus L. Chemosphere 120: 154–164. DOI: 10.1016/j.chemosphere.2014.06.029.

67. Ali S, Chaudhary A, Rizwan M, Anwar HT, Adrees M, Farid M, Irshad MK, Hayat T, Anjum SA (2015) Alleviation of chromium toxicity by glycinebetaine is related to elevated antioxidant enzymes and suppressed chromium uptake and oxidative stress in wheat (Triticum aestivum L.). Environ. Sci. Pollut. Res. 22 (14): 10669–10678.

68. Ali S, Bharwana SA, Rizwan M, Farid M, Kanwal S, Ali Q, Ibrahim M, Gill RA, Khan MD (2015) Fulvic acid mediates chromium (Cr) tolerance in wheat (Triticum aestivum L.) through lowering of Cr uptake and improved antioxidant defense system. Environ. Sci. Pollut. Res. 22 (14): 10601–10609.

69. Tan DX, Hardeland R, Manchester LC, Korkmaz A, Ma S, Rosales-Corral S, Reiter RJ (2012) Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. J. Exp. Bot. 2012: 577–597. DOI: 10.1093/jxb/err256.

70. Ayyaz A, Amir M, Umer S, Iqbal M, Bano H, Gul HS, Noor Y, kanwal A, khalid A, Javed M, Athar HR, Zafar ZU, Farooq MA (2020) Melatonin induced changes in photosynthetic efficiency as probed by OJIP associated with improved chromium stress tolerance in canola (Brassica napus L.). Heliyon 6 (7): e04364.

71. Marchiafava PL, Longoni B (1999) Melatonin as an antioxidant in retinal photoreceptors. J. Pineal Res. 26 (3): 184–189.

72. Bubenik GA, Pang SF (1994) The role of serotonin and melatonin in gastrointestinal physiology: Ontogeny, regulation of food intake, and mutual serotonin‐melatonin feedback. J. Pineal Res. 16 (2): 91–99.

73. Lee PPN, Shiu SYW, Chowb PH PS (1996) Regional and diurnal studies of melatonin and melatonin binding sites in the duck gastro-lntestinal tract. Biol. Signals. 4: 212–224.

74. Mojaverrostami S, Asghari N, Sc M, Khamisabadi M, Khoei HH, Abbas A (2019) The role of melatonin in polycystic ovary syndrome: A review. Int. J. Reprod. Biomed. 17 (12): 865–882.

75. Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee F, Tamura I, Maekawa R, Aasada H YY and SN (2012) The role of melatonin as an antioxidant in the follicle. J. Ovarian Res. 5 (5): 1–9.

76. Mertz W (1992) Chromium - History and nutritional importance. Biol. Trace Elem. Res. 32 (1–3): 3–8. DOI: 10.1007/BF02784581.

77. Vincent JB (2001) The bioinorganic chemistry of chromium(III). Polyhedron 20 : 1–26. DOI: 10.1016/S0277-5387(00)00624-0.

78. Vincent JB (2003) The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent. Sport. Med. 33 (3): 213–230. DOI: 10.2165/00007256-200333030-00004.

79. Stearns DM, Joseph BJ, Wetterhahn EK (1995) A prediction humans of chromium ( III ) from accumulation dietary supplements in chromium. FASEB J. 9 (15): 1650–1657. DOI: Doi: 10.1096/fasebj.9.15.8529846.

80. Eastmond DA, MacGregor JT, Slesinski RS (2008) Trivalent chromium: Assessing the genotoxic risk of an essential trace element and widely used human and animal nutritional supplement. Crit. Rev. Toxicol. 38 (3): 173–190. DOI: 10.1080/10408440701845401.

81. Petrilli FL and Flora SD (1988) Metabolic reduction of chromium as a threshold mechanism limiting its in vivo activity. Sci. Total Environ. 71:357–364. DOI: 10.1016/0048-9697(88)90208-2.

82. Maret W (2019) Chromium supplementation in human health, metabolic syndrome, and diabetes. Met. Ions Life Sci. 19:231–251. DOI: 10.1515/9783110527872-015.

83.  Katz SA (1991) The analytical biochemistry of chromium. Environ. Health Perspect. 92:13–16. DOI: 10.1289/ehp.919213.

84. Debetto P and Luciani S (1988) Toxic effect of chromium on cellular metabolism. Sci. Total Environ. 71:365–377. DOI: 10.1016/0048-9697(88)90209-4.

85. Chromium (VI) compounds. Vol. 100 C, IARC Monographs on the evaluation of carcinogenic risks to humans. 2011. p. 147–167.

86. Chiu A, Shi XL, Lee WKP, Hill R, Wakeman TP, Katz A, Xu B, Dalal NS, Robertson JD, Chen C, Chiu N, Donehower L (2010) Review of chromium (VI) apoptosis, cell-cycle-arrest, and carcinogenesis. J. Environ. Sci. Heal. - Part C Environ. Carcinog. Ecotoxicol. Rev. 28 (3): 188–230. DOI: 10.1080/10590501.2010.504980.

87. De Flora S, Serra D, Camoirano A, Zanacchi P (1989) Metabolic reduction of chromium, as related to its carcinogenic properties. Biol. Trace Elem. Res. 21 (1): 179–187. DOI: 10.1007/BF02917250.

88. Jennette KW (1979) Chromate metabolism in liver microsomes. Biol. Trace Elem. Res. 1 (1): 55–62. DOI: 10.1016/0006-291x(78)90931-2.

89. Costa M (1997) Toxicity and carcinogenicity of Cr(VI) in animal models and humans. Crit. Rev. Toxicol. 27 (5): 431–442. DOI: 10.3109/10408449709078442.

90. Sun H, Brocato J, Costa M (2015) Oral chromium exposure and toxicity. Curr. Env. Heal. Rep. 2 (3): 295–303. DOI: 10.1007/s40572-015-0054-z.

91. Wang Y, Su H, Gu Y, Song X, Zhao J (2017) Carcinogenicity of chromium and chemoprevention: A brief update. Onco. Targets Ther. 10: 4065–4079. DOI: 10.2147/OTT.S139262.

92. De Flora S (2000) Threshold mechanisms and site specificity in chromium(VI) carcinogenesis. Carcinogenesis 21 (4): 533–541. DOI: 10.1093/carcin/21.4.533.

93. Arslan P, Beltrame M, Tomasi A (1987) Intracellular chromium reduction. Biochim. Biophys. Acta - Mol. Cell Res. 931 (1): 10–15. DOI: 10.1016/0167-4889(87)90044-9.

94. O’Brien T, Xu J, Patierno SR (2001) Effects of glutathione on chromium-induced DNA crosslinking and DNA polymerase arrest. Mol. Cell. Biochem. 222 (1–2): 173–182. DOI: 10.1023/A:1017918330073.

95. Chen QY, Murphy A, Sun H CM (2019) Molecular and epigenetic mechanisms of Cr(VI)-induced carcinogenesis. Toxicol. Appl. Pharmacol. 377: DOI: 10.1016/j.taap.2019.114636.

96. Kitagawa S, Seki H, Kametani F, Sakurai H (1988) EPR study on the interaction of hexavalent chromium with glutathione or cysteine: Production of pentavalent chromium and its stability. Inorganica Chim. Acta. 152: 251–255. DOI: 10.1016/S0020-1693(00)91477-4.

97. Zhitkovich A, Quievryn G, Messer J, Motylevich Z (2002) Reductive activation with cysteine represents a chromium(III)-dependent pathway in the induction of genotoxicity by carcinogenic chromium(VI). Environ. Health Perspect. 110 (5): 729–731. DOI: 10.1289/ehp.02110s5729.

98. Aiyar J, De Flora S, Wetterhahn KE (1992) Reduction of chromium(vi) to chromium(v) by rat liver cytosolic and microsomal fractions: Is dt-diaphorase involved? Carcinogenesis 13 (7): 1159–1166. DOI: 10.1093/carcin/13.7.1159.

99. Connett PH, Wetterhahn KE (1983) Metabolism of the carcinogen chromate by cellular constituents. Inorg. Elem. Biochem. DOI: 10.1007/bfb0111319.

100. Shi X, Chiu A, Chen CT, Halliwell B, Castranova V, Vallyathan V (1999) Reduction of chromium (vi) and its relationship to carcinogenesis. J. Toxicol. Environ. Heal. - Part B Crit. Rev. 2 (1): 87–104. DOI: 10.1080/109374099281241.

101. Wise JTF, Wang L, Xu J, Zhang Z, Shi X (2019) Oxidative stress of Cr(III) and carcinogenesis. In: The Nutritional Biochemistry of Chromium (III). Elsevier B.V.; 2019. p. 323–340. DOI: 10.1016/b978-0-444-64121-2.00010-6.

102. Kanner J, German JB, Kinsella JE (1987) Initiation of lipid peroxidation in biological systems. CRC Crit. Rev. Food Sci. Nutr. 25 (4): 317–364. DOI: 10.1080/10408398709527457.

103. Shi X, Dalal NS (1989) Chromium (V) and hydroxyl radical formation during the glutathione reductase-catalyzed reduction of chromium (VI). Biochem. Biophys. Res. Commun. 163 (1): 627–634. DOI: 10.1016/0006-291X(89)92183-9.

104. Ye J, Zhang X, Young HA, Mao Y, Shi X (1995) Chromium(VI)-induced nuclear factor-kB activation in intact cells via free radical reactions. Carcinogenesis 16 (10): 2401–2405. DOI: 10.1093/carcin/16.10.2401.

105. Aiyar J, Berkovits HJ, Floyd RA, Wetterhahn KE (1990) Reaction of chromium(VI) with hydrogen peroxide in the presence of glutathione: reactive intermediates and resulting DNA damage. Chem. Res. Toxicol. 3 (6): 595–603. DOI: 10.1021/tx00018a016.

106. Aiyar J, Borges KM, Floyd RA, Wetterhahn KE (1989) Role of chromium(V), glutathione thiyl radical and hydroxyl radical intermediates in chromium(VI)-induced DNA damage. Toxicol. Environ. Chem. 22 (1–4): 135–148. DOI: 10.1289/ehp.919253.

107. Aiyar J, Berkovits HJ, Floyd RA, Wetterhahn KE (1991) Reaction of chromium(VI) with glutathione or with hydrogen peroxide: identification of reactive intermediates and their role in chromium(VI)-lnduced DNA damage. Environ. Health Perspect. 92: 53–62. DOI: DOI: 10.1289/ehp.919253.

108. Blanchard-Fillion B, Servy C, Ducrocq C (2001) 1-nitrosomelatonin is a spontaneous NO-releasing compound. Free Radic. Res. 35 (6): 857–866. DOI: 10.1080/10715760100301351.

109. Gutteridge JMC HB (1990) The measurement and mechanism of lipid peroxidation in biological systems. Science 15 (4): 129–135. DOI: 10.1016/0968-0004(90)90206-q.

110. Halliwell B, Chirico S (1993) Lipid peroxidation: its mechanism, measurement, and significance. Am. J. Clin. Nutr. 57 (5): 715–725. DOI: 10.1093/ajcn/57.5.715S.

111. Upadhyay RK, Panda SK (2010) Influence of chromium salts on increased lipid peroxidation and differential pattern in antioxidant metabolism in Pistia stratiotes L. Brazilian Arch. Biol. Technol. 53 (5): 1137–1144. DOI: 10.1590/S1516-89132010000500008.

112. Mattagajasingh SN MB and MH (2008) Carcinogenic chromium(VI)-induced protein oxidation and lipid peroxidation: implications in DNA–protein crosslinking. J. Appl. Toxicol. 28: 987–997. DOI: 10.1002/jat.1364.

113. Dey SK, Roy S (2010) Role of GSH in the amelioration of chromium-induced membrane damage. Toxicol. Environ. Chem. 92 (2): 261–269. DOI: 10.1080/02772240902955669.

114. Susa N, Ueno S, Furukawa Y, Michiba N MS (1989) Induction of lipid peroxidation in mice by hexalent chromium and its relation to tthe toxicity. Japanese J. Vet. Sci. 51 (6): 1103–1110. DOI: 10.1292/jvms1939.51.1103.

115. Huang YL, Chen CY, Sheu JY, Chuang IC, Pan JH, Lin TH (1999) Lipid peroxidation in workers exposed to hexavalent chromium. J. Toxicol. Environ. Heal. - Part A. 56 (4): 235–247. DOI: 10.1080/009841099158088.

116. F MA and A (2016) Lipid peroxidation and biochemical abnormalities in tannery workers exposed to hexavalent chromium. Res. J. Biotechnol. 11 (7): 75–82.

117. Ahmad MK, Syma S, Mahmood R (2011) Cr(VI) induces lipid peroxidation, protein oxidation and alters the activities of antioxidant enzymes in human erythrocytes. Biol. Trace Elem. Res. 144 (1–3): 426–435. DOI: 10.1007/s12011-011-9119-5.

118. Kalahasthi RB, Rao RHR, Murthy RBK, Kumar MK (2006) Effect of chromium(VI) on the status of plasma lipid peroxidation and erythrocyte antioxidant enzymes in chromium plating workers. Chem. Biol. Interact. 164 (3): 192–199. DOI: 10.1016/j.cbi.2006.09.012.

119. Asatiani N, Kartvelishvili T, Abuladze M, Asanishvili L, Sapojnikova N (2011) Chromium (VI) can activate and impair antioxidant defense system. Biol. Trace Elem. Res. 142 (3): 388–397. DOI: 10.1007/s12011-010-8806-y.

120. Bagchi D, Vuchetich PJ, Bagchi M, Hassoun EA, Tran MX, Tang L, Stohs SJ (1997) Induction of oxidative stress by chronic administration of sodium dichromate [chromium VI] and cadmium chloride [cadmium II] to rats. Free Radic. Biol. Med. 22 (3): 471–478. DOI: 10.1016/S0891-5849(96)00352-8.

121. Patlolla AK, Barnes C, Yedjou C, Velma VR TP (2006) Oxidative stress, DNA damage, and antioxidant enzyme activity induced by hexavalent chromium in Sprague-Dawley Rats. Environ. Toxicol. 24 (1): 66-73.

122. Sahu BD, Koneru M, Bijargi SR, Kota A, Sistla R (2014) Chromium-induced nephrotoxicity and ameliorative effect of carvedilol in rats: Involvement of oxidative stress, apoptosis and inflammation. Chem. Biol. Interact. 223: 69–79. DOI: 10.1016/j.cbi.2014.09.009.

123. Madejczyk MS, Baer CE, Dennis WE, Minarchick VC, Leonard SS, Jackson DA, Stallings JD, Lewis JA (2015) Temporal changes in rat liver gene expression after acute cadmium and chromium exposure. PLoS One 10 (5): 1–27. DOI: 10.1371/journal.pone.0127327.

124. Mehany HA, Abo-youssef AM, Ahmed LA, Arafa E-SA, Abd El-Latif HA (2013) Protective effect of vitamin E and atorvastatin against potassium dichromate-induced nephrotoxicity in rats. Beni-Suef Univ. J. Basic Appl. Sci. 2 (2): 96–102. DOI: 10.1016/j.bjbas.2013.02.002.

125. Banerjee S, Joshi N, Mukherjee R, Singh PK, Baxi D, Ramachandran A V. (2017) Melatonin protects against chromium (VI) induced hepatic oxidative stress and toxicity: Duration dependent study with realistic dosage. Interdiscip. Toxicol. 10 (1): 20–29. DOI: 10.1515/intox-2017-0003.

126. Han B, Li S, Lv Y, Yang D, Li J, Yang Q, Wu P, Lv Z, Zhang Z (2019) Dietary melatonin attenuates chromium-induced lung injury: Via activating the Sirt1/Pgc-1α/Nrf2 pathway. Food Funct. 10 (9): 5555–5565.

127. Ren Z, He H, Zuo Z, Xu Z, Wei Z, Deng J  (2019) The role of different SIRT1-mediated signaling pathways in toxic injury. Cell. Mol. Biol. Lett. 24:36. doi: 10.1186/s11658-019-0158-9.

128. Chang HC, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab. 25 (3): 1–8. DOI: 10.1016/j.tem.2013.12.001.

129. Sathya M, Moorthi P, Premkumar P, Kandasamy M, Jayachandran KS, Anusuyadevi M (2017) Resveratrol intervenes cholesterol-and isoprenoid-mediated amyloidogenic processing of AβPP in familial Alzheimer’s disease. J. Alzheimer’s Dis. 60 (1): S3–S23.

130. Austin S, St-pierre J (2012) PGC1 a and mitochondrial metabolism – emerging concepts and relevance in ageing and neurodegenerative disorders. J. Cell Sci. 125: 4963–4971.

131. Rius-pérez S, Torres-cuevas I, Millán I, Ortega ÁL, Pérez S (2020) PGC-1α , inflammation , and oxidative stress : an integrative view in metabolism. Oxid. Med. Cell. Longev. 2020: 1452696.

132. Awe J, Yao Z, Vicencio JM, Karkucinska-Wieckowska A, Szabadkai G (2012) PGC-1 family coactivators and cell fate: Roles in cancer, neurodegeneration, cardiovascular disease and retrograde mitochondria-nucleus signalling. Mitochondrion 12 (1): 86–99. DOI: 10.1016/j.mito.2011.09.009.

133. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1 (6): 361–370. DOI: 10.1016/j.cmet.2005.05.004.

134. Cantó C, Auwerx J (2009) PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20 (2): 98–105. DOI: 10.1097/MOL.0b013e328328d0a4.

135. Wang S-J, Zhao X-H, Chen W, Bo N, Wang X-J, Chi Z-F, Wu W (2015) Sirtuin 1 activation enhances the PGC-1α/mitochondrial antioxidant system pathway in status epilepticus. Mol. Med. Rep. 11 (1): 521–526. DOI: 10.3892/mmr.2014.2724.

136. Zheng X, Li S, Li J, Lv Y, Wang X, Wu P, Yang Q, Tang Y, Liu Y, Zhang Z (2020) Hexavalent chromium induces renal apoptosis and autophagy via disordering the balance of mitochondrial dynamics in rats. Ecotoxicol. Environ. Saf. 204: 1–9. DOI: 10.1016/j.ecoenv.2020.111061.

137. Tonelli C, Chio IIC, Tuveson DA (2018) Transcriptional regulation by Nrf2. Antioxid. Redox. Signal. 29 (17): 1727–1745. DOI: 10.1089/ars.2017.7342.

138. Saha S, Buttari B, Panieri E, Profumo E, Saso L (2020) An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 25 (22): 5474. DOI: 10.3390/molecules25225474.

139. Li L, Dong H, Song E, Xu X, Liu L, Song Y (2013) Nrf2/ARE pathway activation , HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. Chem. Biol. Interact. 209: 56-67 DOI: 10.1016/j.cbi.2013.12.005.

140. Ross D, Siegel D (2017) Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Front. Physiol. 8: 1–10. DOI: 10.3389/fphys.2017.00595.

141. Shen J, Rasmussen M, Dong Q, Tepel M, Scholze A (2017) Expression of the NRF2 target gene NQO1 is enhanced in mononuclear cells in human chronic kidney disease. Oxid. Med. Cell. Longev. 2017: 1–8. DOI: 10.1155/2017/9091879.

142. Torisu-Itakura H, Furue M, Kuwano M, Ono M (2000) Co-expression of thymidine phosphorylase and heme oxygenase-1 in macrophages in human malignant vertical growth melanomas. Jpn J. Cancer Res. 91 (9): 906–910. DOI: 10.1111/j.1349-7006.2000.tb01033.x.

143. Jeong JY, Cha H, Choi EO, Kim CH, Kim G, Yoo YH, Hwang H, Park HT, Yoon HM, Choi YH (2019) Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of baicalein against oxidative stress-induced DNA damage and apoptosis in HEI193 Schwann cells. Int. J. Med. Sci. 16 (1): 145–155. DOI: 10.7150/ijms.27005.

144. Zhang X, Ding M, Zhu P, Huang H, Zhuang Q, Shen J, Cai Y, Zhao M, He Q (2019) New insights into the Nrf-2/HO-1 signaling axis and its application in pediatric respiratory diseases. Oxid. Med. Cell. Longev. 2019: 1–9. DOI: 10.1155/2019/3214196.

145. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell. Mol. Life Sci. 73 (17): 3221–3247. DOI: 10.1007/s00018-016-2223-0.

146. Chau L (2015) Heme oxygenase-1: emerging target of cancer therapy. J. Biomed. Sci. 22 (1): 22. DOI: 10.1186/s12929-015-0128-0.

147. MacFie A, Hagan E, Zhitkovich A (2010) Mechanism of DNA-protein cross-linking by chromium. Chem. Res. Toxicol. 23 (2): 341–347. DOI: 10.1021/tx9003402.

148. Das A, Mishra S (2008) Hexavalent chromium (VI) : Environment pollution and health hazard. J. Environ. Res. Dev. 2 (3): 386–392.

149. Zhitkovich A (2005) Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI). Chem. Res. Toxicol. 18 (3): 3–11. DOI: 10.1021/tx049774+.

150. Jozefczak M, Remans T, Vangronsveld J, Cuypers A (2012) Glutathione is a key player in metal-induced oxidative stress defenses. Int. J. Mol. Sci. 13 (3): 3145–3175. DOI: 10.3390/ijms13033145.

151. Wiegand HJ, Ottenwälder H, Bolt HM 1985. (1985) The Formation of glutathione-chromium complexes and their possible role in chromium disposition. In: Receptors and other targets for toxic substances. 1985. p. 319–321. DOI: 10.1007/978-3-642-69928-3_61.

152.  Connett PH, Wetterhahn KE (1985) In vitro reaction of the carcinogen chromate with cellular thiols and carboxylic acids. J. Am. Chem. Soc. 107 (14): 4282–4288. DOI: 10.1021/ja00300a035.

153. Misra HP (1974) Generation of superoxide free radical during the autoxidation of thiols. J. Biol. Chem. 249 (7): 2151–2155.

154. Rowley DA, Halliwell B (1982) Superoxide-dependent formation of hydroxyl radicals in the presence of thiol compounds. FEBS Lett. 138 (1): 33–36. DOI: 10.1016/0014-5793(82)80388-8.

155. O’Brien P, Wang G, Wyatt PB (1992) Studies of the kinetics of the reduction of chromate by glutathione and related thiols. Polyhedron 11 (24): 3211–3216. DOI: 10.1016/S0277-5387(00)83664-5.

156. Kortenkamp A, Oetken G, Beyersmann D (1990) The DNA cleavage induced by a chromium(V) complex and by chromate and glutathione is mediated by activated oxygen species. Mutat. Res. - Fundam. Mol. Mech. Mutagen. 232 (2): 155–161. DOI: 10.1016/0027-5107(90)90120-S.

157. P.faux S, Gao M, Chipman JK, Levy LS (1992) Production of 8-hydroxydeoxyguanosine in isolated DNA by chromium(VI) and chromium(V). Carcinogenesis 13 (9): 1667–1669. DOI: 10.1093/carcin/13.9.1667.

158. Valko M, Izakovic M, Mazur M, Rhodes CJ TJ (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem. 266 (1–2): 37–56. DOI: 10.1023/b:mcbi.0000049134.69131.89.

159. Tsou T, Chen C, Liu T, Yang J (1996) Induction of 8-hydroxydeoxyguanosine in DNA by chromium(III) plus hydrogen peroxide and its prevention by scavengers. Carcinogenesis 17 (1): 103–108. DOI: 10.1093/carcin/17.1.103.

160. Kuo HW, Chang SF, Wu KY, Wu FY (2003) Chromium (VI) induced oxidative damage to DNA: Increase of urinary 8-hydroxydeoxyguanosine concentrations (8-OHdG) among electroplating workers. Occup. Environ. Med. 60 (8): 590–594. DOI: 10.1136/oem.60.8.590.

161. Zhang XH, Zhang X, Wang XC, Jin LF, Yang ZP, Jiang CX, Chen Q, Ren X Bin, Cao JZ, Wang Q, Zhu YM (2011) Chronic occupational exposure to hexavalent chromium causes DNA damage in electroplating workers. BMC Public Health. 11 (224): 1–8. DOI: 10.1186/1471-2458-11-224.

162. Pan CH, Jeng HA, Lai CH (2018) Biomarkers of oxidative stress in electroplating workers exposed to hexavalent chromium. J. Expo. Sci. Environ. Epidemiol. 28 (1): 76–83. DOI: 10.1038/jes.2016.85.

163. Li P, Gu Y, Yu S, Li Y, Yang J, Jia G (2014) Assessing the suitability of 8-OHdG and micronuclei as genotoxic biomarkers in chromate-exposed workers: A cross-sectional study. BMJ Open 4 (10): 1–7. DOI: 10.1136/bmjopen-2014-005979.

164. Setyaningsih Y, Husodo AH, Astuti I (2015) Detection of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels as a biomarker of oxidative DNA damage among home industry workers exposed to chromium. Procedia Environ. Sci. 23: 290–296. DOI: 10.1016/j.proenv.2015.01.043.

165. Zhitkovich A (2001) Non-oxidative mechanisms are responsible for the induction of mutagenesis by reduction of Cr(VI) with cysteine: Role of ternary DNA adducts in Cr(III)-dependent mutagenesis. Biochemistry 40 (2): 549–560. DOI: 10.1021/bi0015459.

166. Ning J, Grant MH (2000) The role of reduced glutathione and glutathione reductase in the cytotoxicity of chromium (VI) in osteoblasts. Toxicol. Vitr. 14 (4): 329–335. DOI: 10.1016/S0887-2333(00)00024-2.

167. Lalaouni A, Henderson C, Kupper C, Grant MH (2007) The interaction of chromium (VI) with macrophages: Depletion of glutathione and inhibition of glutathione reductase. Toxicology 236 (1–2): 76–81. DOI: 10.1016/j.tox.2007.04.002.

168. Wiegand HJ, Ottenwälder H, Bolt HM (1984) The reduction of chromium (VI) to chromium (III) by glutathione: An intracellular redox pathway in the metabolism of the carcinogen chromate. Toxicology 33 (3–4): 341–348. DOI: 10.1016/0300-483X(84)90050-7.

169. Lu SC (2013) Glutathione synthesis. Biochim. Biophys. Acta. 1830 (5): 3143–3153. DOI: 10.1016/j.bbagen.2012.09.008.

170. Standeven AM, Wetterhahn KE (1991) Possible role of glutathione in chromium(VI) metabolism and toxicity in rats. Pharmacol. Toxicol. 68 (6): 469–476. DOI: 10.1111/j.1600-0773.1991.tb01272.x.

171. Na KJ, Jeong SY, Lim CH (1992) The role of glutathione in the acute nephrotoxicity of sodium dichromate. Arch. Toxicol. 66 (9): 646–651. DOI: 10.1007/BF01981504.

172. Cupo DY, Wetterhahn KE (1985) Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes. Proc. Natl. Acad. Sci. U. S. A. 82 (20): 6755–6759. DOI: 10.1073/pnas.82.20.6755.

173. Standeven AM, Wetterhahn KE (1991) Ascorbate is the principal reductant of chromium(VI) in rat liver and kidney ultrafiltrates. Carcinogenesis 12 (9): 1733–1737. DOI: 10.1093/carcin/12.9.1733.

174. Gunaratnam M, Grant MH (2001) The role of glutathione reductase in the cytotoxicity of chromium (VI) in isolated rat hepatocytes. Chem. Biol. Interact. 134 (2): 191–202. DOI: 10.1016/S0009-2797(01)00153-3.

175. Suzuki Y, Fukuda K (1990) Reduction of hexavalent chromium by ascorbic acid and glutathione with special reference to the rat lung. Arch. Toxicol. 64 (3): 169–176. DOI: 10.1007/BF02010721.

176. Standeven AM, Wetterhahn KE, Kato R (1992) Ascorbate is the principal reductant of chromium(vi) in rat lung ultrafiltrates and cytosols, and mediates chromium-DNA binding in vitro. Carcinogenesis 13 (8): 1319–1324. DOI: 10.1093/carcin/13.8.1319.

177. Stearns DM, Wetterhahn KE (1994) Reaction of chromium(VI) with ascorbate produces chromium(V), chromium(IV), and carbon-based radicals. Chem. Res. Toxicol. 7 (2): 219–230. DOI: 10.1021/tx00038a016.

178. Stearns DM, Courtney KD, Giangrande PH, Phieffer LS, Wetterhahn KE (1994) Chromium(VI) reduction by ascorbate: Role of reactive intermediates in DNA damage in vitro. Environ. Health Perspect. 102 (3): 21–25. DOI: 10.1289/ehp.94102s321.

179. Goodgame DML, Joy AM (1987) EPR study of the Cr(V) and radical species produced in the reduction of Cr(VI) by ascorbate. Inorganica Chim. Acta. 135 (2): 115–118. DOI: 10.1016/S0020-1693(00)83273-9.

180. Steams DM, Kennedy LJ, Courtney KD, Giangrande PH, Phieffer LS, Wetterhahn KE (1995) Reduction of chromium(VI) by ascorbate leads to chromium-dna binding and DNA strand breaks in vitro. Biochemistry 34 (3): 910–919. DOI: 10.1021/bi00003a025.

181. Bielski BHJ, Allen AO, Schwarz HA (1981) Mechanism of disproportionation of ascorbate radicals. J. Am. Chem. Soc. 103 (12): 3516–3518. DOI: 10.1021/ja00402a042.

182. Sugiyama M, Ando A, Ogura R (1989) Effect of vitamin E on survival, glutathione reductase and formation of chromium (V) in Chinese hamster V-79 cells treated with sodium chromate (VI). Carcinogenesis 10 (4): 737–741. DOI: 10.1093/carcin/10.4.737.

183. Poljsak B, Gazdag Z, Jenko-Brinovec S, Fujs S, Pesti M, Belagyi J, Plesničar S, Raspor P (2005) Pro-oxidative vs antioxidative properties of ascorbic acid in chromium(VI)-induced damage: An in vivo and in vitro approach. J. Appl. Toxicol. 25 (6): 535–548. DOI: 10.1002/jat.1093.

184. Quievryn G, Messer J, Zhitkovich A (2006) Lower mutagenicity but higher stability of Cr-DNA adducts formed during gradual chromate activation with ascorbate. Carcinogenesis 27 (11): 2316–2321. DOI: 10.1093/carcin/bgl076.

185. Quievryn G, Peterson E, Messer J, Zhitkovich A (2003) Genotoxicity and mutagenicity of chromium(VI)/ascorbate-generated DNA adducts in human and bacterial cells. Biochemistry. 42 (4): 1062–1070. DOI: 10.1021/bi0271547.

186. Kortenkamp A, O’Brien P (1994) The generation of DNA single-strand breaks during the reduction of chromate by ascorbic acid and/or glutathione in vitro. Environ. Health Perspect. 102 (SUPPL 3): 237–241. DOI: 10.1289/ehp.94102s3237.

187. Flora SD BB and LA (1984) Distinctive mechanisms for interaction of hexavalent and trivalent chromium with DNA? Toxicol. Environ. Chem. 8 (4): 287–294. DOI: 10.1080/02772248409357060.

188. Sugiyama M (1992) Role of physiological antioxidants in chromium (VI)- induced cellular injury. Free Radic. Biol. Med. 12 (5): 397–407. DOI: 10.1016/0891-5849(92)90089-y.

189. Tsapakos MJ, Wetterhahn KE (1983) The interaction of chromium with nucleic acids. Chem. Biol. Interact. 46 (2): 265–277. DOI: 10.1016/0009-2797(83)90034-0.

190. Arakawa H, Weng MW, Chen WC, Tang MS (2012) Chromium (VI) induces both bulky DNA adducts and oxidative DNA damage at adenines and guanines in the p53 gene of human lung cells. Carcinogenesis 33 (10): 1993–2000. DOI: 10.1093/carcin/bgs237.

191. Rossi SC, Wetterhahn KE (1989) Chromium (V) is produced upon reduction of chromate by mitochondrial electron transport chain complexes. Carcinogenesis 10 (5): 913–930. DOI: 10.1093/carcin/10.5.913.

192. Myers CR (2012) The effects of chromium(VI) on the thioredoxin system: Implications for redox regulation. Free Radic. Biol. Med. 52 (10): 2091–2107. DOI: 10.1016/j.freeradbiomed.2012.03.013.

193. Arillo A, Melodia F, Frache R (1987) Reduction of hexavalent chromium by mitochondria: Methodological implications and possible mechanisms. Ecotoxicol. Environ. Saf. 14 (2): 164–177. DOI: 10.1016/0147-6513(87)90059-5.

194. Myers JM, Antholine WE, Myers CR (2011) The intracellular redox stress caused by hexavalent chromium is selective for proteins that have key roles in cell survival and thiol redox control. Toxicology 281 (1–3): 37–47. DOI: 10.1016/j.tox.2011.01.001.

195.  Myers JM, Myers CR (2009) The effects of hexavalent chromium on thioredoxin reductase and peroxiredoxins in human bronchial epithelial cells. Free Radic. Biol. Med. 47 (10): 1477–1485. DOI: 10.1016/j.freeradbiomed.2009.08.015.

196. Bhattacharya M, Shriwastav A, Bhole S, Silori R, Mansfeldt T, Kretzschmar R, Singh A (2020) Processes governing chromium contamination of groundwater and soil from a chromium waste source. ACS Earth Sp. Chem. 4 (1): 35–49. DOI: Https://doi.org/10.1021/acsearthspacechem.9b00223.

197. Hald M, Agner T, Blands J, Ravn H, Johansen JD (2009) Allergens associated with severe symptoms of hand eczema and a poor prognosis. Contact Dermatitis 61 (2): 101–108.

198.  Hansen MB, Menné T, Johansen JD (2006) Cr(III) reactivity and foot dermatitis in Cr(VI) positive patients. Contact Dermatitis 54 (3): 140–144. DOI: 10.1111/j.0105-1873.2006.00802.x.

199. Wang BJ, Wu J De, Sheu SC, Shih TS, Chang HY, Guo YL, Wang YJ, Chou TC (2011) Occupational hand dermatitis among cement workers in Taiwan. J. Formos. Med. Assoc. 110 (12): 775–779. DOI: 10.1016/j.jfma.2011.11.008.

200. Thyssen JP, Jensen P, Carlsen BC, Engkilde K, Menné T, Johansen JD (2009) The prevalence of chromium allergy in Denmark is currently increasing as a result of leather exposure. Br. J. Dermatol. 161 (6): 1288–1293. DOI: 10.1111/j.1365-2133.2009.09405.x.

201. Caroe C, Andersen KE, Thyssen JP, Mortz CG (2010) Fluctuations in the prevalence of chromate allergy in Denmark and exposure to chrome-tanned leather. Contact Dermatitis 63 (6): 340–346. DOI: 10.1111/j.1600-0536.2010.01798.x.

202. Thyssen JP, Menné T (2010) Metal allergys-A review on exposures, penetration, genetics, prevalence, and clinical implications. Chem. Res. Toxicol. 23 (2): 309–318. DOI: 10.1021/tx9002726.

203. Stocks SJ, McNamee R, Turner S, Carder M, Agius RM (2012) Has European Union legislation to reduce exposure to chromate in cement been effective in reducing the incidence of allergic contact dermatitis attributed to chromate in the UK? Occup. Environ. Med. 69 (2): 150–DOI: 10.1136/oemed-2011-100220.

204.  Hansen MB, Johansen JD, Menné T (2003) Chromium allergy: Significance of both Cr(III) and Cr(VI). Contact Dermatitis 49 (4): 206–212. DOI: 10.1111/j.0105-1873.2003.0230.x.

205. Hedberg YS, Lidén C, Odnevall Wallinder I (2015) Chromium released from leather - I: Exposure conditions that govern the release of chromium(III) and chromium(VI). Contact Dermatitis 72 (4): 206–215. DOI: 10.1111/cod.12329.

206. Sharma P, Bihari V, Agarwal SK, Verma V, Kesavachandran CN, Pangtey BS, Mathur N, Singh KP, Srivastava M, Goel SK (2012) Groundwater contaminated with hexavalent chromium [Cr(VI)]: A health survey and clinical examination of community inhabitants (Kanpur, India). PLoS One 7 (10): 3–9. DOI: 10.1371/journal.pone.0047877.

207. Singhal VK, Deswal BS, Singh BN (2015) Study of skin and mucous membrane disorders among workers engaged in the sodium dichromate manufacturing industry and chrome plating industry. Indian J. Occup. Environ. Med. 19 (3): 129–133. DOI: 10.4103/0019-5278.173994.

208. Wedeen RP, Qian LF (1991) Chromium-induced kidney disease. Environ. Health Perspect 92 : 71–74. DOI: 10.1289/ehp.92-1519395.

209. Pieri C, Moroni F, Marra M, Marcheselli F, Recchioni R (1995) Melatonin is an efficient antioxidant. Arch. Gerontol. Geriatr. 20 (2): 159–165. DOI: 10.1016/0167-4943(94)00593-V.

210. Poeggeler B, Reiter RJ, Hardeland R, Tan DX, Barlow-Walden LR (1996) Melatonin and structurally-related, endogenous indoles act as potent electron donors and radical scavengers in vitro. Redox Rep. 2 (3): 179–184. DOI: 10.1080/13510002.1996.11747046.

211. Tan D, Reiter R, Manchester L, Yan M, El-Sawi M, Sainz R, Mayo J, Kohen R, Allegra M, Hardelan R (2005) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr. Top. Med. Chem. 2 (2): 181–197. DOI: 10.2174/1568026023394443.

212. Reiter RJ, Melchiorri D, Sewerynek E, Poeggeler B, Barlow‐Walden L, Chuang J, Ortiz GG, AcuñaCastroviejo D (1995) A review of the evidence supporting melatonin’s role as an antioxidant. J. Pineal Res. 18 (1): 1–11. DOI: 10.1111/j.1600-079X.1995.tb00133.x.

213. Sofic E, Rimpapa Z, Kundurovic Z, Sapcanin A, Tahirovic I, Rustembegovic A, Cao G (2005) Antioxidant capacity of the neurohormone melatonin. J. Neural Transm. 112 (3): 349–358. DOI: 10.1007/s00702-004-0270-4.

214. Loren P, Sánchez R, Arias ME, Felmer R, Risopatrón J, Cheuquemán C (2017) Melatonin scavenger properties against oxidative and nitrosative stress: Impact on gamete handling and in vitro embryo production in humans and other mammals. Int. J. Mol. Sci. 18 (6): 1–17. DOI: 10.3390/ijms18061119.

215. Reiter RJ, Tan DX, Manchester LC, Lopez-Burillo S, Sainz RM, Mayo JC (2003) Melatonin: Detoxification of oxygen and nitrogen-based toxic reactants. Adv. Exp. Med. Biol. 527: 539–548. DOI: 10.1007/978-1-4615-0135-0_62.

216. Arnao MB, Hernández-Ruiz J (2019) Melatonin and reactive oxygen and nitrogen species: a model for the plant redox network. Melatonin Res. 2 (3): 152–168. DOI: 10.32794/11250036.

217. Acuna-Castroviejo D, Escames G, Rodriguez MI, Lopez LC (2007) Melatonin role in the mitochondrial function. Front. Biosci. 12 (3): 947–963. DOI: 10.2741/2116.

218. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: A physicochemical examination. J. Pineal Res. 51 (1): 1–16. DOI: 10.1111/j.1600-079X.2011.00916.x.

219. Chan TY, Tang PL (1996) Characterization of the antioxidant effects of melatonin and related indoleamines in vitro. J. Pineal Res. 20 (4): 187–191. DOI: 10.1111/j.1600-079X.1996.tb00257.x.

220. Cagnoli CM, Atabay C, Kharlamova E, Manev H (1995) Melatonin protects neurons from singlet oxygen‐induced apoptosis. J. Pineal Res. 18 (4): 222–226. DOI: 10.1111/j.1600-079X.1995.tb00163.x.

221. Matuszak Z, Bilska MA, Reszka KJ, Chignell CF, Bilski P (2003) Interaction of singlet molecular oxygen with melatonin and related indoles. Photochem. Photobiol. 78 (5): 449. DOI: 10.1562/0031-8655(2003)078<0449:iosmow>2.0.co;2.

222. Schaefer M, Hardeland R (2009) The melatonin metabolite N¹-acetyl-5-methoxykynuramine is a potent singlet oxygen scavenger. J. Pineal Res. 46 (1): 49–52. DOI: 10.1111/j.1600-079X.2008.00614.x.

223. Zang LY, Cosma G, Gardner H, Vallyathan V (1998) Scavenging of reactive oxygen species by melatonin. Biochim. Biophys. Acta - Gen. Subj. 1425 (3): 469–477. DOI: 10.1016/S0304-4165(98)00099-3.

224. Mayo JC, Tan DX, Sainz RM, Lopez-Burillo S, Reiter RJ (2003) Oxidative damage to catalase induced by peroxyl radicals: Functional protection by melatonin and other antioxidants. Free Radic. Res. 37 (5): 543–553. DOI: 10.1080/1071576031000083206.

225. Longoni B, Salgo MG, Pryor WA, Marchiafava PL (1998) Effects of melatonin on lipid peroxidation induced by oxygen radicals. Life Sci. 62 (10): 853–859. DOI: 10.1016/S0024-3205(98)00002-2.

226. Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F (1994) Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sci. 55 (15): 271–276. DOI: 10.1016/0024-3205(94)00666-0.

227. Marshall KA, Reiter RJ, Poeggeler B, Aruoma OI, Halliwell B (1996) Evaluation of the antioxidant activity of melatonin in vitro. Free Radic. Biol. Med. 21 (3): 307–315. DOI: 10.1016/0891-5849(96)00046-9.

228. Matuszak Z, Reszka KJ, Chignell CF (1997) Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic. Biol. Med. 23 (3): 367–372. DOI: 10.1016/S0891-5849(96)00614-4.

229. Stasica P, Paneth P, Rosiak JM (2000) Hydroxyl radical reaction with melatonin molecule: A computational study. J. Pineal Res. 29 (2): 125–127. DOI: 10.1034/j.1600-079X.2000.290209.x.

230. Tan DX, Chen LD, Poeggeler B, Manchester LC  and RR (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr. J. 1 : 57–60.

231. Ceraulo L, Ferrugia M, Tesoriere L, Segreto S, Livrea MA, Turco Liveri V (1999) Interactions of melatonin with membrane models: Portioning of melatonin in AOT and lecithin reversed micelles. J. Pineal Res. 26 (2): 108–112. DOI: 10.1111/j.1600-079X.1999.tb00570.x.

232. Kaya H, Delibas N, Serteser M, Ulukaya E, Özkaya O (1999) The effect of melatonin on lipid peroxidation during radiotherapy in female rats. Strahlentherapie und Onkol. 175 (6): 285–288. DOI: 10.1007/BF02743581.

233. Taysi S, Koc M, Büyükokuroǧlu ME, Altinkaynak K, Şahin YN (2003) Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J. Pineal Res. 34 (3): 173–177. DOI: 10.1034/j.1600-079X.2003.00024.x.

234. Daniels WMU, Van Rensburg SJ, Van Zyl JM, Taljaard JJF (1998) Melatonin prevents β-amyloid-induced lipid peroxidation. J. Pineal Res. 24 (2): 78–82. DOI: 10.1111/j.1600-079X.1998.tb00370.x.

235. Karbownik M, Lewiński A (2003) Melatonin reduces fenton reaction-induced lipid peroxidation in porcine thyroid tissue. J. Cell. Biochem. 90 (4): 806–811. DOI: 10.1002/jcb.10689.

236. García JJ, Reiter RJ, Guerrero JM, Escames G, Yu BP, Oh CS, Munoz-Hoyos A (1997) Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett. 408 (3): 297–300. DOI: 10.1016/S0014-5793(97)00447-X.

237. García JJ, Reiter RJ, Ortiz GG, Oh CS, Tang L, Yu BP, Escames G (1998) Melatonin enhances tamoxifen’s ability to prevent the reduction in microsomal membrane fluidity induced by lipid peroxidation. J. Membr. Biol. 162 (1): 59–65. DOI: 10.1007/s002329900342.

238. Livrea MA, Tesoriere L, Arpa D, Morreale M (1997) Reaction of melatonin with lipoperoxyl radicals in phospholipid bilayers. Free Radic. Biol. Med. 23 (5): 706–711. DOI: 10.1016/S0891-5849(97)00018-X.

239. Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S (2001) Free radical-mediated molecular damage: Mechanisms for the protective actions of melatonin in the central nervous system. Ann. N. Y. Acad. Sci. 939: 200–215. DOI: 10.1111/j.1749-6632.2001.tb03627.x.

240. Manda K, Ueno M, Anzai K (2007) AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J. Pineal Res. 42 (4): 386–393. DOI: 10.1111/j.1600-079X.2007.00432.x.

241. Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, Reiter RJ (2004) Regulation of antioxidant enzymes: A significant role for melatonin. J. Pineal Res. 36 (1): 1–9. DOI: 10.1046/j.1600-079X.2003.00092.x.

242. Mayo JC, Sainz RM, Antolín I, Herrera F, Martin V, Rodriguez C (2002) Melatonin regulation of antioxidant enzyme gene expression. Cell. Mol. Life Sci. 59 (10): 1706–1713. DOI: 10.1007/PL00012498.

243. Reiter RJ, Tan DX, Carmen O EG (2000) Actions of melatonin in the reduction of oxidative stress. J. Biomed. Sci. 7 (6): 444–458. DOI: 10.1007/BF02253360.

244. Acuña-Castroviejo D, Escames G, León J, Carazo A, Khaldy H (2003) Mitochondrial regulation by melatonin and its metabolites. Adv. Exp. Med. Biol. 527: 549–557. DOI: 10.1007/978-1-4615-0135-0_63.

245. Siu AW, Ortiz GG, Benitez-King G, To CH, Reiter RJ (2004) Effect of melatonin on the nitric oxide treated retina. Br. J. Ophthalmol. 88 (8): 1078–1081. DOI: 10.1136/bjo.2003.037879.

246. Tapias V, Escames G, López LC, López A, Camacho E, Carrión MD, Entrena A, Gallo MA, Espinosa A, Acuña-Castroviejo D (2009) Melatonin and its brain metabolite N1-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in Parkinsonian mice. J. Neurosci. Res. 87 (13): 3002–3010. DOI: 10.1002/jnr.22123.

247. Zhang H, Squadrito GL, Uppu R, Pryor WA (1999) Reaction of peroxynitrite with melatonin: A mechanistic study. Chem. Res. Toxicol. 12 (6): 526–534. DOI: 10.1021/tx980243t.

248. Pozo D, Reiter RJ, Calvo JR, Guerrero JM (1994) Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci. 55 (24): 455–460. DOI: 10.1016/0024-3205(94)00532-X.

249. Guo P, Pi H, Xu S, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J (2014) Melatonin improves mitochondrial function by promoting cadmium-induced hepatotoxicity in vitro. Toxicol. Sci. 142 (1): 182–195.

250. Naaz S, Mishra S, Pal PK, Chattopadhyay A, Das AR, Bandyopadhyay D (2020) Activation of SIRT1/PGC 1α/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury. Heliyon 6 (10). DOI: 10.1016/j.heliyon.2020.e05159.

251. Kumar J, Haldar C, Verma R (2020) Fluoride compromises testicular redox sensor, gap junction protein, and metabolic status: amelioration by melatonin. Biol. Trace Elem. Res. 196 (2): 552–564. DOI: 10.1007/s12011-019-01946-6.

252. Kleszczyński K, Zillikens D, Fischer TW (2016) Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (γ-GCS, HO-1, NQO1) in ultraviolet rad. J. Pineal Res. 61 (2): 187–197. DOI: 10.1111/jpi.12338.

253. Kumar J, Verma R, Haldar C (2021) Melatonin ameliorates bisphenol S induced testicular damages by modulating Nrf-2/HO-1 and SIRT-1/FOXO-1 expressions. Environ. Toxicol. 36 (3): 396–407. DOI: 10.1002/tox.23045.

254. Mitra E, Bhattacharjee B, Pal PK, Ghosh AK, Mishra S, Chattopadhyay A, Bandyopadhyay D (2019) Melatonin protects against cadmium-induced oxidative damage in different tissues of rat: a mechanistic insight. Melatonin Res. 2 (2): 1–21. DOI: 10.32794/mr11250018.

255. Urata Y, Honma S, Goto S, Todoroki S, Iida T, Cho S, Honma K, Kondo T (1999) Melatonin induces γ-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic. Biol. Med. 27 (7–8): 838–847. DOI: 10.1016/S0891-5849(99)00131-8.

256. Ionescu JG, Poljsak B (2011) Metal ions mediated pro-oxidative reactions with vitamin c: Possible implications for treatment of different malignancies. Cancer Prev. Res. Perspect 3 (3): 149–182.

257. Porter WL (1993) Paradoxical behavior of antioxidants in food and biological systems. Toxicol. Ind. Health. 9 (1–2): 93–122. DOI: 10.1177/0748233793009001-209.

258. Guajardo MH, Terrasa AM, Catalá A (2006) Lipid-protein modifications during ascorbate-Fe²⁺ peroxidation of photoreceptor membranes: Protective effect of melatonin. J. Pineal Res. 41 (3): 201–210. DOI: 10.1111/j.1600-079X.2006.00352.x.

259. Du J, Wagner BA, Buettner GR, Cullen JJ (2015) Role of labile iron in the toxicity of pharmacological ascorbate. Free Radic. Biol. Med. 84: 289–295. DOI: 10.1016/j.freeradbiomed.2015.03.033.

260. Ghosh AK, Naaz S, Bhattacharjee B, Ghosal N, Chattopadhyay A, Roy S, Reiter RJ, Bandyopadhyay D (2017) Mechanism of melatonin protection against copper-ascorbate-induced oxidative damage in vitro through isothermal titration calorimetry. Life Sci. 180: 123–136. DOI: 10.1016/j.lfs.2017.05.022.

261. Kobayashi S UK, Morita J SH, T K (1988) DNA damage induced by ascorbate in the presence of Cu²⁺. Biochim. Biophys. Acta - Gene Struct. Expr. 949 (1): 143–147. DOI: 10.1016/0167-4781(88)90065-6.

262. Qi W, Reiter RJ, Tan DX, Manchester LC, Siu AW, Garcia JJ (2000) Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: Protection by melatonin and related molecules. J. Pineal Res. 29 (1): 54–61. DOI: 10.1034/j.1600-079X.2000.290108.x.

263. Hneihen AS, Standeven AM, Wetterhahn KE (1993) Differential binding of chromium(VI) and chromium(III) complexes to salmon sperm nuclei and nuclear DNA and isolated calf thymus DNA. Carcinogenesis 14 (9): 1795–1803. DOI: 10.1093/carcin/14.9.1795.

264. Susa N, Ueno S, Furukawa Y, Ueda J, Sugiyama M (1997) Potent protective effect of melatonin on chromium(VI)-induced DNA single-strand breaks, cytotoxicity, and lipid peroxidation in primary cultures of rat hepatocytes. Toxicol. Appl. Pharmacol. 144 (2): 377–384. DOI: 10.1006/taap.1997.8151.

265. Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, Reiter RJ (2001) Melatonin, mitochondria, and cellular bioenergetics. J. Pineal Res. 30 (2): 65–74. DOI: 10.1034/j.1600-079X.2001.300201.x.

266. Menendez‐Pelaez A, Reiter RJ (1993) Distribution of melatonin in mammalian tissues: The relative importance of nuclear versus cytosolic localization. J. Pineal Res. 15 (2): 59–69. DOI: 10.1111/j.1600-079X.1993.tb00511.x.

267. Menendez‐Pelaez A, Poeggeler B, Reiter RJ, Barlow‐Walden L, Pablos MI, Tan DX (1993) Nuclear localization of melatonin in different mammalian tissues: Immunocytochemical and radioimmunoassay evidence. J. Cell. Biochem. 53 (4): 373–382. DOI: 10.1002/jcb.240530415.

268. Peter Bozner, Valentina Grishko, Susan P. LeDoux, Glenn L. Wilson Y-CC and MAP (1997) The amyloid β protein induces oxidative damage of mitochondrial DNA. J. Neuropathol. Exp. Neurol. 56 (12): 1356–1362. DOI: Doi: 10.1097/00005072-199712000-00010.

269. León J, Acuña-Castroviejo D, Escames G, Tan DX, Reiter RJ (2005) Melatonin mitigates mitochondrial malfunction. J. Pineal Res. 38 (1): 1–9. DOI: 10.1111/j.1600-079X.2004.00181.x.

270. Leon J, Acuña-Castroviejo D, Sainz RM, Mayo JC, Tan DX, Reiter RJ (2004) Melatonin and mitochondrial function. Life Sci. 75 (7): 765–790. DOI: 10.1016/j.lfs.2004.03.003.

271. Reiter RJ, Paredes SD, Korkmaz A, Tan DX, Jou MJ (2008) Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip. Toxicol. 1 (2): 137–149.

272. Li J, Zheng X, Ma X, Xu X, Du Y, Lv Q, Li X, Wu Y, Sun H, Yu L, Zhang Z (2019) Melatonin protects against chromium(VI)-induced cardiac injury via activating the AMPK/Nrf2 pathway. J. Inorg. Biochem. 97: 110698. doi: 10.1016/j.jinorgbio.2019.110698.

273. Shagirtha K, Muthumani M, Milton Prabu S (2011) Melatonin abrogates cadmium induced oxidative stress related neurotoxicity in rats. Eur. Rev. Med. Pharmacol. Sci. 15 (9): 1039–1050.

274. El-Sokkary GH, Nafady AA, Shabash EH (2010) Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat. Ecotoxicol. Environ. Saf. 73 (3): 456–463. DOI: 10.1016/j.ecoenv.2009.09.014.

275. Yang Q, Zhu J, Luo X, Li F, Cong L, Wang Y, Sun Y (2019) Melatonin attenuates cadmium-induced ovulatory dysfunction by suppressing endoplasmic reticulum stress and cell apoptosis. Reprod. Biol. Endocrinol. 17 (1): 61. DOI: 10.1186/s12958-019-0502-y.

276. Othman AI, El-Missiry MA, Amer MA, Arafa M (2008) Melatonin controls oxidative stress and modulates iron, ferritin, and transferrin levels in adriamycin treated rats. Life Sci. 83 (15–16): 563–568. DOI: 10.1016/j.lfs.2008.08.004.

277. Abd Elkader MAE, Aly HF (2015) Protective effect of melatonin against iron overload-induced toxicity in rats. Int. J. Pharm. Pharm. Sci. 7 (9): 116–121.

278. Parmar P, Limson J, Nyokong T, Daya S (2002) Melatonin protects against copper-mediated free radical damage. J. Pineal Res. 32 (4): 237–242. DOI: 10.1034/j.1600-079X.2002.01859.x.

279. Şener G, Şehirli AO, Ayanoglu-Dülger G (2003) Melatonin protects against mercury(II)-induced oxidative tissue damage in rats. Pharmacol. Toxicol. 93 (6): 290–296. DOI: 10.1111/j.1600-0773.2003.pto930607.x.

280. Rao MV, Chhunchha B (2010) Protective role of melatonin against the mercury induced oxidative stress in the rat thyroid. Food Chem. Toxicol. 48 (1): 7–10. DOI: 10.1016/j.fct.2009.06.038.

281. Rao MV, Gangadharan B (2008) Antioxidative potential of melatonin against mercury induced intoxication in spermatozoa in vitro. Toxicol. Vitr. 22 (4): 935–942.

282. Jindal M, Garg GR, Mediratta PK, Fahim M (2011) Protective role of melatonin in myocardial oxidative damage induced by mercury in murine model. Hum. Exp. Toxicol. 30 (10): 1489–1500.

283. Tapan AP, Mandava VR (2016) Melatonin modulates mercury induced oxidative stress in rat liver. World J. Pharm. Res. 5 (2): 1198–1211.

284. Rao MV, Purohit AR (2011) Neuroprotection by melatonin on mercury induced toxicity in the rat brain. Pharmacol. Amp. Pharm. 02 (04): 375–385.

285. Uygur R, Aktas C, Caglar V, Uygur E, Erdogan H, Ozen OA (2016) Protective effects of melatonin against arsenic-induced apoptosis and oxidative stress in rat testes. Toxicol. Ind. Health 32 (5): 848–859.

286. Dutta S, Saha S, Mahalanobish S, Sadhukhan P, Sil PC (2018) Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice. Food Chem. Toxicol. 118: 303-316. doi: 10.1016/j.fct.2018.05.032

287. Singh SS, Deb A, Sutradhar S (2019) Effect of melatonin on arsenic-induced oxidative stress and expression of MT1 and MT2 receptors in the kidney of laboratory mice. Biol. Rhythm Res. 00 (00): 1–15. DOI: 10.1080/09291016.2019.1566993.

288. Durappanavar PN, Nadoor P, Waghe P, Pavithra BH, Jayaramu GM (2019) Melatonin ameliorates neuropharmacological and neurobiochemical alterations induced by subchronic exposure to arsenic in Wistar Rats. Biol. Trace Elem. Res. 190 (1): 124–139. DOI: 10.1007/s12011-018-1537-1.

289. Pal S, Chatterjee AK (2006) Possible beneficial effects of melatonin supplementation on arsenic-induced oxidative stress in Wistar rats. Drug Chem. Toxicol. 29 (4): 423–433.

290. Pal S, Chatterjee AK (2005) Prospective protective role of melatonin against arsenic-induced metabolic toxicity in Wistar rats. Toxicology 208 (1): 25–33.

291. Hernández-Plata E, Quiroz-Compeán F, Ramírez-Garcia G, Barrientos EY, Rodríguez-Morales NM, Flores A, Wrobel K, Wrobel K, Méndez I, Díaz-Muñoz M, Robles J, Martínez-Alfaro M (2015) Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment. Toxicol. Lett. 233 (2): 78–83. DOI: 10.1016/j.toxlet.2015.01.009.

292. Bandyopadhyay D (2014) Melatonin protects against lead-induced oxidative stress in stomach, duodenum and spleen of male Wistar rats. J. Pharmacy Res.  1 (11):  997–1004.

293. Al-Olayan EM, El-Khadragy MF, Abdel Moneim AE (2015) The protective properties of melatonin against aluminium-induced neuronal injury. Int. J. Exp. Pathol. 96 (3): 196–202. DOI: 10.1111/iep.12122.

294. Allagui MS, Feriani A, Saoudi M, Badraoui R, Bouoni Z, Nciri R, Murat JC, Elfeki A (2014) Effects of melatonin on aluminium-induced neurobehavioral and neurochemical changes in aging rats. Food Chem. Toxicol. 70 : 84–93. DOI: 10.1016/j.fct.2014.03.043.

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