Evidence for a Role of Oxidative Stress in the Carcinogenicity of Ochratoxin A

Marin-Kuan, M.; Ehrlich, V.; Delatour, T.; Cavin, C.; Schilter, B.

doi:https://doi.org/10.1155/2011/645361

Journal of Toxicology

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Review Article | Open Access

Volume 2011 | Article ID 645361 | https://doi.org/10.1155/2011/645361

Evidence for a Role of Oxidative Stress in the Carcinogenicity of Ochratoxin A

M. Marin-Kuan,¹V. Ehrlich,¹T. Delatour,¹C. Cavin,¹and B. Schilter¹

Academic Editor: Brad Upham

Received30 Sept 2010

Accepted20 Apr 2011

Published22 Jun 2011

Abstract

The in vitro and in vivo evidence compatible with a role for oxidative stress in OTA carcinogenicity has been collected and described. Several potential oxido-reduction mechanisms have been identified in the past. More recently, the possibility of a reduction of cellular antioxidant defense has been raised as an indirect source of oxidative stress. Consequences resulting from the production of oxidative stress are observed at different levels. First, OTA exposure has been associated with increased levels of oxidative DNA, lipid, and protein damage. Second, various biological processes known to be mobilized under oxidative stress were shown to be altered by OTA. These effects have been observed in both in vitro and in vivo test systems. In vivo, active doses were often within doses documented to induce renal tumors in rats. In conclusion, the evidence for the induction of an oxidative stress response resulting from OTA exposure can be considered strong. Because the contribution of the oxidative stress response in the development of cancers is well established, a role in OTA carcinogenicity is plausible. Altogether, the data reviewed above support the application of a threshold-based approach to establish safe level of dietary human exposure to OTA.

1. Introduction

Ochratoxin A (OTA) is a mycotoxin produced by several food-borne species of Aspergillus and Penicillium fungi. OTA occurs in various food materials and therefore humans are continuously exposed to relatively small amounts of it. Because of its wide occurrence and consequent exposure, together with a potent carcinogenic potential in animal models, OTA has attracted significant public health attention over the last few years. Several national and international food safety organizations and expert groups have conducted a thorough review of the situation as well as risk assessments in order to provide an insight on the health significance of OTA in food.

Human epidemiology has been inconclusive: a number of studies have suggested a correlation between exposure to OTA and Balkan Endemic Nephropathy (BEN) and mortality from urinary tract tumors [1, 2]. Epidemiological data were recently reviewed by several expert groups [3–6]. All concluded that causality between intake of OTA and human nephropathy could not be established. Therefore, the IARC statement that there is inadequate evidence for carcinogenicity in humans (group 2B) [7] appears still valid. Recently, other nephrotoxic agents have been put forward as the primary cause of BEN [6, 8, 9].

In absence of adequate human data, risk assessments have relied on animal data. Kidney has been considered as the key target organ of OTA toxicity. In all animal species studied, OTA was found to produce renal toxicity, while in rodents renal carcinogenicity was clearly established. Recently, OTA renal and hepatic carcinogenicity was also observed in chicks [10]. Using a LOAEL of 8 mcg/kg bw/day based on early markers of renal toxicity in pig (the most sensitive animal species) and applying an uncertainty factor of 450, EFSA [4] allocated a Tolerable Weekly Intake (TWI) of 120 ng/kg bw. Analysis of dietary exposure throughout Europe revealed that the current average OTA exposure (50–60 ng/kg bw/week) is well within the TWI [4]. The joint FAO/WHO Expert Committee on Food Additives (JECFA) first evaluated OTA at their 37th meeting [11]. Based on the LOAEL in pig, and applying an uncertainty factor of 500, JECFA allocated a Provisional Tolerable Weekly Intake (PTWI) of 112 ng/kg bw [11]. This value was rounded to 100 ng/kg bw/week and confirmed in several subsequent meetings [12, 13].

In 2008, JECFA applied a benchmark dose (BMD) modeling approach using carcinogenicity data [14]. The BMD is the dose estimated to cause a predefined increase (e.g., 10% for the BMD10) in tumor incidence over background. The BMDL is the lower limit of a one-sided 95% confidence interval of the BMD. The occurrence of combined adenomas and carcinomas in the kidneys of male rats was considered by JECFA to be the most appropriate data for modeling. Values of 18–33 mcg/kg bw/d and 15–25 mcg/kg bw/day were calculated for, respectively, the BMD10 and BMDL10. Because the BMD approach did not provide a lower point of departure than the LOAEL in pig, JECFA decided to reconfirm the PTWI of 100 ng/kg bw/day [14].

A recent health risk assessment, performed by Health Canada [15] recommends to regulate OTA as a nonthreshold carcinogen, because of the uncertainties regarding the mode of action. The authors defined a negligible cancer risk intake (NCRI, risk level 1 : 100 000) using the tumorigenic dose at which 5% of rats are likely to develop tumors (TD₀₅, derived through modeling) as point of departure. Importantly, there is considerable convergence between the NCRI established in this assessment and the TDI derived by EFSA.

In the risk assessment of carcinogenic substances, consideration of the mode of action (MOA) is essential, determining the method to be applied in order to define levels of exposure below which a low safety concern is expected. The key events analysis framework of the MOA has not yet been formally applied to OTA. However, the approach used by most expert groups (EFSA, JECFA, ILSI) to establish the safe level of exposure of OTA (based on uncertainty factors) implies the consideration of key events compatible with a threshold effect. For these groups, amongst the mechanisms of action highlighted as possible, oxidative stress has been presented as one of the most probable [5, 14].

1.1. Scope of the Paper

Over the last decades, studies aimed at elucidating the modes of action implicated in OTA toxicity and carcinogenicity have been published [16]. There has been considerable debate for many years over the genotoxicity of OTA and its actual role in carcinogenicity [3–5, 11–15, 17, 18].

Although genotoxicity is likely to play a role in OTA carcinogenicity [3, 4], the actual molecular mechanism involved, either through covalent adduct formation, through other indirect modifications, or both is still unclear. The potential of OTA to form covalent DNA adducts has been subjected to debate due to conflicting data in the literature. Using ³²P-postlabelling analysis, large numbers of putative OTA-derived DNA adducts have been reported to be present in a wide range of tissues from OTA-treated rats, mice as well as pigs [2, 17, 19–22]. However, so far, these adducts have never been observed by any other highly specific techniques such as radioactivity measurements using ³H-labelled OTA (³H-OTA) [23], accelerator mass spectrometry (AMS) [24], or liquid chromatography-tandem mass spectrometry (LC-MS/MS) [25].

The present paper is not intended to provide a thorough review of the complex and controversial scientific literature on DNA-adduct formation. However, it is important to keep in mind that DNA adducts are increasingly considered as markers of exposures and not only of effects [26, 27] and that DNA-covalent binding does not necessarily determine the shape of the dose-response at low level of exposure [28, 29]. According to Mantle and coworkers [21, 30], experimental dose-response data for OTA’s renal carcinogenesis makes a compelling case for OTA being a thresholded carcinogen in male rat. In this context, it appears important to also consider other potential modes of action, which could potentially contribute to OTA carcinogenicity. In the near future, the application of the mode of action framework [28] will likely help to understand the individual contribution of all mechanisms described up to now for OTA.

The focus of the present short paper was to collect and highlight the evidence associated with a role for oxidative stress as a plausible mechanism to consider for OTA. A list of the studies used to illustrate the main messages of the present paper is provided in Table 1. Although not exhaustive, the list shows that over the last two decades, numerous investigators have documented the generation of oxidative stress as a result of OTA treatment in both in vitro and in vivo model systems.

2. Sources of OTA-Mediated Oxygen-Species Generation

Production of reactive oxygen species (ROS) leading to oxidative stress and macromolecular damage is known to contribute to the pathogenesis of age-related as well as chronic diseases including cancer [31–35]. A number of studies are available documenting that OTA is associated with the production of reactive oxygen species and resulting oxidative stress through various direct and indirect mechanisms.

2.1. Oxido-Reduction Mechanisms

Several oxido-reduction mechanisms elicited by OTA have been proposed. In a reconstituted system consisting of phospholipid vesicles, the flavoprotein NADPH-cytochrome P450 reductase and Fe³⁺, OTA was found to chelate ferric ions (Fe³⁺), facilitating their reduction to ferrous ions (Fe²⁺), which in the presence of oxygen, provided the active species initiating lipid peroxidation [36]. Results indicated that the hydroxyl radical was not involved in the process. A role for cytochrome P450 in this reaction was also suggested [36]. In contrast, others found that OTA induced oxidative damage through the generation of hydroxyl radicals. This reaction conducted with microsomes, in presence of NADPH and O₂ did not require exogenous Fe [20]. Structure-activity studies have also suggested that the toxicity of OTA may be attributable to its isocoumarin moiety and that the lactone carbonyl group may be involved in its toxicity. Using a Bacillus brevis model, Hoehler’s et al. showed that OTA behaved as a cell pro-oxidant through mobilization of Fe²⁺ and Ca²⁺ pathway leading to uncoupling oxidative phosphorylation and increased production of hydroxyl radical via the Fenton reaction [37]. However, in other studies using OTA and structural analogs, a direct correlation between toxicity and iron chelating capacity was only partially supported [38].

The generation of an OTA hydroquinone/quinone couple from the oxidation of OTA (phenol oxidation) by electrochemical, photochemical, and chemical processes was reported [39, 40]. The quinone is thought to undergo reductions to form hydroquinone, postulated to be responsible for the formation of the glutathione conjugate of OTA. Such events are likely to result in redox cycling and in the generation of reactive oxygen species [20, 40, 41]. The formation of OTA-derived quinones has been observed in cell cultures in vitro [41] as well as in vivo [42, 43].

2.2. Reduction of Antioxidant Defenses

OTA was found to reduce the expression of several genes regulated by nuclear factor-erythroid 2 p45-relatetd factor (Nrf2) [44–47]. This was observed at the RNA and protein levels, both in vitro and in vivo test systems. Nrf2 is involved in both the basal expression as well as in the induction of genes encoding detoxification, cytoprotective, and antioxidant enzymes [48, 49]. A reduction of the expression of these genes is likely to result in decrease in antioxidant defenses leading to oxidative stress and macromolecular damage. This was confirmed with OTA. Through in vitro and in vivo studies, a correlation was observed between the OTA-dependent reduction of the Nrf2 pathway and an increased production of oxidative damage [46]. In this context, it is interesting to note that OTA was found to increase the expression of inducible nitric oxide synthase (iNOs) [50–52], an enzyme responsible for the production of nitric oxide (NO). An association between iNOs expression and the development of cancers was suggested in humans and animals in vivo [53]. In excess, NO may behave as a toxic radical producing nitrosative stress. NO is known to react with oxygen anion radical superoxide to form the pro-oxidant peroxynitrite. Under physiological conditions, peroxynitrite rapidly decomposes to generate a nitro radical intermediate leading to protein and DNA nitration. OTA was shown to stimulate protein and possibly DNA nitration [52, 53] indicating that OTA exposure may be considered as a source of both oxygen and also reactive nitrogen radicals/species (RNS).

3. OTA-Mediated Oxidative Damage

3.1. DNA-Damage

ROS, such as hydroxyl radicals and nitric oxide, are capable of forming oxidized DNA bases that directly produce diverse types of DNA damage [54–56]. The oxidized DNA bases appear to be capable of inducing mutations that are commonly observed in neoplasia [33]. As illustrated in Table 1, diverse biomarkers have been analyzed showing that OTA induces DNA damage. In cell cultures, the OTA-dependent production of ROS was correlated with an increased formation of 8-oxoguanine [57–59]. Moreover, OTA was shown to induce DNA strand breaks as assessed by comet assay in liver, kidney, and spleen of F344 rats given 0, 0.25, 0.50, 1.0, and 2.0 mg/kg bw/day by gavage for 2 weeks [60]. In liver and kidney, the extent of DNA damage analyzed by comet assay was further enhanced in the presence of formamidopyrimidine glycosylase (Fpg), an enzyme involved in excision repair of oxidized DNA bases [57, 58, 61]. Another study [62] detected DNA-strand breaks (using the comet assay) in the kidney of female Wistar rats treated intraperitoneally with OTA (0.5 mg/kg bw/day for 7, 14, and 21 days; per group). The severity of the DNA lesions in the kidney increased according to the OTA dose and was at maximum after 21 days of treatment. Other authors have observed oxidative DNA-damage in various tissues of animals treated with a wide range of OTA doses and treatment durations [46, 60, 63, 64].

3.2. Protein Damage

Carbonylation of proteins occurs through a variety of oxidative pathways [54, 65–67]. Carbonylation is an important protein modification associated with alterations of protein (enzymes) function, protein misfolding, protein fate, and proteolysis. An increase in protein carbonyl content of tissues has been associated with a number of pathological disorders. Due to their abundance in mammalian cells, cytoskeletal proteins like actin are common targets for a variety of ROS and low-molecular weight reactive carbonyl species [67]. Inconsistent data have been reported on the potential impact of OTA on protein carbonylation [52, 59, 63, 68, 69]. No increase in protein oxidation was observed in liver and kidney of F344 rats treated with OTA at 0.3 mg/kg bw per day for 4 weeks [69]. The same finding was reported in liver of Wistar rats treated with OTA at 289 μg/kg bw for 90 days [63]. In contrast, in another in vivo study measuring protein oxidation in Wistar rats treated with OTA (0.5 mg/kg bw/day) for 24 h, 7, 14 and 21 days, a significant increase in protein carbonyls was found after 14 and 21 days of treatment in, respectively, the kidney and the liver [68]. Oxidative protein modification was observed in vitro [52].

3.3. Lipid Damage

Lipid peroxidation is among the most extensively investigated processes induced by free radicals. Of these, the by-products, 4-hydroxy-2-nonenal (HNE), the tautomer malondialdehyde (MDA), acrolein and crotonaldehyde have been widely studied. The ability of these reactive electrophiles to modify DNA bases, yielding promutagenic lesions, is considered to contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced lipid peroxidation. HNE and MDA have increasingly been implicated in carcinogenesis [33, 70–72]. OTA has been reported to increase MDA formation. Initially, Rahimtula’s group [73] observed that OTA was able to stimulate lipid peroxidation when added to liver or kidney microsomes or when administered to rats in vivo. Stimulation of lipid peroxidation by OTA-iron complex facilitating the reduction of iron was further reported [36]. Moreover, additional studies [74] indicated that OTA induced lipid peroxidation accompanied by leakage of calcium from calcium-loaded microsomes. Increased formation of MDA was observed in animal models treated orally with different doses of OTA [75–79]. HNE-protein adducts were measured in cell cultures treated with OTA [52].

4. OTA-Mediated Biological Response

It is widely acknowledged that reactive oxygen and nitrosative species can trigger biological responses such as stimulation or inhibition of signal transduction and gene expression. Such biological responses are considered to contribute to the expression of the carcinogenic potential of the reactive chemicals. A number of in vitro and in vivo studies are consistent with a role of oxidative and probably nitrosative stress as messengers involved in the adverse biological effects of OTA (Table 1).

5. Cell Signaling

ROS induces release of calcium from intracellular stores, resulting in the activation of kinases, such as protein kinase C (PKC). ROS species play also a critical role in the selective mobilization of other cell signaling responses. Cell signaling phosphoproteins of mitogen-activated protein (MAP) kinases including ERK, c-Jun N-terminal kinases (JNK), and p38 kinases are involved in proliferation, differentiation, and apoptosis. Activation of these molecules has been observed in response to changes in the cellular redox balance and are considered as vectors of ROS biological effects [33]. In vitro experiments provided evidence of an effect of OTA on intracellular calcium (Ca²⁺) homeostasis [74, 80–82]. Ca²⁺ homeostasis modulation by OTA was also observed in vivo [83]. An increased rate of microsomal Ca²⁺ uptake was observed after OTA administration in vivo and in vitro [84]. Gene profiling analysis suggested a modulation of genes involved in calcium homeostasis by OTA [47, 85]. These data indicate that Ca²⁺ dependent signal transduction pathways may be affected by OTA treatment. Interferences were observed with other cell signaling pathways. OTA was shown to stimulate phosphorylation of ERK1/2, SAP/JNK, and p38 using in vitro models [82, 86, 87]. Using an in vivo model ERK1/2 a specific signaling response was also observed with mobilization of the atypical protein kinase C (PKCζ) and the insulin-like growth factor-1 (IGF-1) system [88]. Gene profiling data supported a potential role of the (IGF)-PI3K-PKB pathway in OTA-mediated renal toxicity in male rats [89].

5.1. Redox Modulation of Transcription Factors

Numerous reports have characterized interactions of ROS and RNS with activity of transcription factors [90–92]. Transcription factors contain a conserved redox sensitive cysteine residue; the oxidation of this residue inactivates the DNA-binding domain of the factor. Several studies have observed an inactivation of transcription factors resulting from increased concentrations of ROS [93–95]. For example, it was shown that the complex AP-1 is a basic leucine zipper protein, which is highly sensitive to changes in redox environment due to a cysteine residue in the DNA-binding domain [96]. Gene expression profile studies performed using in vivo models have shown that OTA impairs the antioxidant defense system regulated by Nrf2 [47]. This effect was supported by further studies [44–46]. Using in vitro models together with electrophoretic mobility shift assay, an inhibition of Nrf2 and AP-1 activity was shown as a result of OTA treatment [46]. Interestingly, Nrf2 binding site represents a bZip domain that interacts with the Antioxidant Response Element (ARE) DNA-binding site triggering the transcription of Nrf2 regulated genes. The ARE motif (5′-A/GTGAC/TnnnGCA/G-3′) shares structural similarity with AP-1 binding site (5′-TGACTCA) involving both cysteine rich residues, the target of ROS oxidation [97, 98]. These data strongly suggest a correlation between the generation of ROS by OTA and the subsequent inactivation of Nrf2 as previously described for AP-1. This molecular mechanism appears as a likely molecular component explaining the reduction of the defense response observed under OTA treatment.

In vivo experiments provided direct evidence that S-nitrosylation can interfere with transcription [91, 92]. Nitric oxide (NO) induces the nitrosylation of cysteine residues (thiol groups) within or near the DNA-binding domain and/or insertion of the zinc finger, which is a DNA-binding motif, resulting in the inhibition of the DNA-binding activity of transcription factors [99–101]. This is illustrated by the example of the suppression of P450 gene expression by NO. NO-donors were found to suppress CYP2D6 promoter activity through inhibition of the transcription factor called hepatocyte nuclear factor 4 (HNF4) [94, 95]. Interestingly, in a gene expression study performed by our group, OTA was associated with a significant reduction of the expression of genes regulated by HNF4 suggesting an indirect evidence of the role oxidative stress and the transcription factors regulation by OTA [47].

5.2. Alterations of Gap-Junction Intercellular Communication (GJIC)

A strong correlation between the ability of a compound to block cell-to-cell communication in cultured cells and its ability to induce rodent tumors through nongenotoxic mechanisms has been documented [33, 128–131]. Disruption of gap junction intercellular communication was specifically reported in human renal cancer cell lines [132]. For example, Connexin 32 (Cx32) was discovered to be generally downregulated in human renal cell carcinoma (RCC) cell lines and in cancerous regions of the kidney [133]. ROS such as H₂O₂, an established tumor promoter, is known to modulate cell-to-cell communication. Likewise, certain chemicals inducing ROS were shown to inhibit intercellular communication in a variety of cells in culture systems [33]. Data on the potential effects of OTA on GJIC are inconsistent. Kidney epithelial cells treated with OTA resulted in modulation of gap junction-mediated intercellular communication, through a reduced expression of the gap-junction protein CX43 [134]. In addition, OTA strongly reduced the expression of other gap-junction proteins, CX26, CX32, and CX43, in liver of rats treated with OTA [63]. In another study, even though a strong reduction of CX43 was found in renal cells in vitro, OTA inhibited GJIC only in liver but not in kidney [135].

6. Prevention of OTA-Induced Oxidative Stress

6.1. Counteracting OTA-Mediated Reduction of Nrf2 Activity

As mentioned earlier, OTA was found to reduce the expression of antioxidant enzymes through inhibition of Nrf2 activity [46]. This reduction in antioxidant gene expression was correlated with increased oxidative damage of protein and DNA [46]. To further confirm the actual role of the reduction of defense mechanisms in the induction of cellular oxidative damage, inducers of Nrf2 were applied in cell cultures in vitro. All reported OTA effects at the levels of Nrf2 activity, Nrf2-regulated gene expression, and DNA damage were prevented in cell pretreated with Nrf2 inducers [46], strongly indicating a causal relationship between Nrf2 effects and oxidative damage.

6.2. Application of Radical Scavengers

Several studies have been performed to try to counteract the adverse effects of oxygen radicals generated under OTA-treatment. A number of molecules with various antioxidant properties were tested, including inula crithmoides, cyanidin 3-O-b-D-glucoside, catechins, melatonin, superoxide dismutase, catalase, and N-acetyl-L-cysteine (NAC), using in vivo or in vitro models. Protection against OTA-induced DNA damage, lipid peroxidation as well as cytotoxicity was observed [75, 79, 102, 105, 106, 116, 118, 127] further confirming the link between OTA exposure and oxidative macromolecular damage. However, up to now, the application of chemicals known to possess antioxidant properties failed to prevent the development of OTA-induced tumors in animal models. Authors reported protection against nephrotoxicity but not carcinogenicity induced by ochratoxin A, implicating two separate pathways [122, 123].

6.3. Application of Peroxidase Inhibitors

Indomethacin and aspirin were found to prevent OTA genotoxicity in the urinary bladder and kidney of mice [136]. These data suggested the possible co-oxidation of OTA by enzymes involved in arachidonic acid biotransformation, especially prostaglandin-H-synthase (PGHS) and/or lipoxygenase [124]. Such reactions thought to produce activated OTA metabolites are also known to generate ROS which then may induce oxidation [124].

7. Conclusion

The carcinogenic mycotoxin OTA has been reviewed by a number of expert groups [3–5, 14, 137]. These expert groups identified the production of oxidative stress as an important event in the mode of action of OTA-induced nephrocarcinogenicity. In the present paper, the actual evidence available supporting such hypothesis was collected and reviewed.

It has been clearly shown that OTA generates oxidative stress predominantly in kidney through potentially direct (redox cycling) and indirect (reduction of cellular antioxidant defenses) mechanisms. Interestingly, these two mechanisms may interact with each other. The reduction of defense may amplify the impact of the direct production of radicals. Consequences resulting from the production of oxidative stress were observed at different levels. High kidney susceptibility to oxidative stress conditions may explain the target-specific toxicity of OTA. Oxidative stress has been incriminated in a number of kidney pathological pathways [138–140].

As depicted in Figure 1, first, OTA exposure was associated with increased levels of oxidative DNA, lipid, and protein damage. Second, various biological pathways known to be mobilized under oxidative stress were shown to be altered by OTA. Importantly, these effects were observed in both in vitro and in vivo test systems. Active in vivo doses were within doses known to induce tumors in kidney. These mechanisms are likely to be relevant for humans.

Figure 1

Scheme to illustrate the oxidative stress-mediated mode of action proposed for OTA. Increased production of ROS, RNS, and RCS is likely to originate either from direct redox reactions involving OTA or through the inhibition of cellular defenses such as through the inhibition of transcription factors as Nrf2 which regulates enzymes with antioxidant properties. The generation of radicals will induce macromolecular oxidative damage such as oxidized DNA bases which may be converted into mutation resulting into generation of transformed cells. In addition, radicals will trigger biological responses which may impair intercellular communication and induce cell proliferation as well as reduction in cellular defense in oxidative stress. This last effect is likely to amplify the oxidative stress-mediated effects of OTA. Altogether, these molecular mechanisms will result in cancer development.

In conclusion, the evidence for the induction of an oxidative stress response resulting from OTA exposure can be considered strong. Because the contribution of the oxidative stress response in the development of cancers is well established, a role in OTA carcinogenicity is plausible. Altogether, the data reviewed above support the application of a threshold-based approach to establish safe level of dietary human exposure to OTA.

References

C. A. Tatu, D. Drugarin, V. Paunescu, D. I. Stanescu, and F. Schneider, “Balkan endemic nephropathy, the haematopoietic system and the environmental connection,” Food and Chemical Toxicology, vol. 36, no. 3, pp. 245–247, 1998.
View at: Publisher Site | Google Scholar
A. Pfohl-Leszkowicz and R. A. Manderville, “Ochratoxin A: an overview on toxicity and carcinogenicity in animals and humans,” Molecular Nutrition and Food Research, vol. 51, no. 1, pp. 61–99, 2007.
View at: Publisher Site | Google Scholar
J. Fink-Gremmels, “Conclusions from the workshops on Ochratoxin A in Food: recent developments and significance, organized by ILSI Europe in Baden (Austria), 29 June-1 July 2005,” Food Additives and Contaminants, vol. 22, supplement 1, pp. 1–5, 2005.
View at: Publisher Site | Google Scholar
EFSA, “Opinion of the Scientific Panel on Contaminants in the food chain on a request from the commission related to Ochratoxin A in Food,” 365, 1-56, 2006.
View at: Google Scholar
JECFA, “Ochratoxin A,” WHO Technical Report Series 947. IPCS, WHO, Geneva, Switzerland, pp. 169–180. 2007.
View at: Google Scholar
Symposium on Recent Advances in Endemic Nephropathy: the role of toxins in an environmental disease, Croatia, 2006.
IARC, Some Naturally Occuring Substances: Food Items and Constituents, Hetrocyclic Aromatic Amines and Mycotoxins, IARC Monographs on the Evaluation of Carcinogenic Risk to Humans, IARC, Lyon, France, 1993.
A. P. Grollman and B. Jelaković, “Role of environmental toxins in endemic (Balkan) nephropathy,” Journal of the American Society of Nephrology, vol. 18, no. 11, pp. 2817–2823, 2007.
View at: Publisher Site | Google Scholar
A. P. Grollman, S. Shibutani, M. Moriya et al., “Aristolochic acid and the etiology of endemic (Balkan) nephropathy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 29, pp. 12129–12134, 2007.
View at: Publisher Site | Google Scholar
S. D. Stoev, “Studies on some feed additives and materials giving partial protection against the suppressive effect of ochratoxin A on egg production of laying hens,” Research in Veterinary Science, vol. 88, pp. 486–491, 2010.
View at: Publisher Site | Google Scholar
JECFA, “Evaluation of certain food additives and contaminants: ochratoxin A,” WHO Technical Report Series 806, WHO, Geneva, Switzerland, 1991.
View at: Google Scholar
JECFA, “Evaluation of certain food additives and contaminants: ochratoxin A,” WHO Technical Report Series 859, WHO, Geneva, Switzerland, 1995.
View at: Google Scholar
JECFA, “Evaluation of certain mycotoxins in food: ochratoxin A,” WHO Technical Report Series 906, WHO, Geneva, Switzerland, 2002.
View at: Google Scholar
JECFA, “Ochratoxin A (addendum),” WHO Food Additive Series 59: Safety Evaluations of certain food additives and contaminants. IPCS, WHO, Geneva, Switzerland, 2008.
View at: Google Scholar
T. Kuiper-Goodman, C. Hilts, S. M. Billiard, Y. Kiparissis, I. D. K. Richard, and S. Hayward, “Health risk assessment of ochratoxin a for all age-sex strata in a market economy,” Food Additives and Contaminants A, vol. 27, no. 2, pp. 212–240, 2010.
View at: Publisher Site | Google Scholar
B. Schilter, M. Marin-Kuan, T. Delatour, S. Nestler, P. Mantle, and C. Cavin, “Ochratoxin A: potential epigenetic mechanisms of toxicity and carcinogenicity,” Food Additives and Contaminants, vol. 22, supplement 1, pp. 88–93, 2005.
View at: Publisher Site | Google Scholar
R. A. Manderville, “A case for the genotoxicity of ochratoxin a by bioactivation and covalent DNA adduction,” Chemical Research in Toxicology, vol. 18, no. 7, pp. 1091–1097, 2005.
View at: Publisher Site | Google Scholar
R. J. Turesky, “Perspective: ochratoxin A is not a genotoxic carcinogen,” Chemical Research in Toxicology, vol. 18, no. 7, pp. 1082–1090, 2005.
View at: Publisher Site | Google Scholar
V. Faucet, A. Pfohl-Leszkowicz, J. Dai, M. Castegnaro, and R. A. Manderville, “Evidence for covalent DNA adduction by ochratoxin A following chronic exposure to rat and subacute exposure to pig,” Chemical Research in Toxicology, vol. 17, no. 9, pp. 1289–1296, 2004.
View at: Publisher Site | Google Scholar
R. A. Manderville and A. Pfohl-Leszkowicz, “Chapter 4 genotoxicity of chlorophenols and ochratoxin A,” Advances in Molecular Toxicology, vol. 1, pp. 85–138, 2006.
View at: Publisher Site | Google Scholar
P. G. Mantle, V. Faucet-Marquis, R. A. Manderville, B. Squillaci, and A. Pfohl-Leszkowicz, “Structures of covalent adducts between DNA and ochratoxin a: a new factor in debate about genotoxicity and human risk assessment,” Chemical Research in Toxicology, vol. 23, no. 1, pp. 89–98, 2010.
View at: Publisher Site | Google Scholar
A. Pfohl-Leszkowicz and M. Castegnaro, “Further arguments in favour of direct covalent binding of Ochratoxin A (OTA) after metabolic biotransformation,” Food Additives and Contaminants, vol. 22, supplement 1, pp. 75–87, 2005.
View at: Publisher Site | Google Scholar
C. Schlatter, J. Studer-Rohr, and T. Rásonyi, “Carcinogenicity and kinetic aspects of ochratoxin A,” Food Additives and Contaminants, vol. 13, supplement, pp. 43–44, 1996.
View at: Google Scholar
A. Mally, H. Zepnik, P. Wanek et al., “Ochratoxin A: lack of formation of covalent DNA adducts,” Chemical Research in Toxicology, vol. 17, no. 2, pp. 234–242, 2004.
View at: Publisher Site | Google Scholar
T. Delatour, A. Mally, J. Richoz et al., “Absence of 2′-deoxyguanosine-carbon 8-bound ochratoxin A adduct in rat kidney DNA monitored by isotope dilution LC-MS/MS,” Molecular Nutrition and Food Research, vol. 52, no. 4, pp. 472–482, 2008.
View at: Publisher Site | Google Scholar
A. M. Jarabek, L. H. Pottenger, L. S. Andrews et al., “Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization,” Critical Reviews in Toxicology, vol. 39, no. 8, pp. 659–678, 2009.
View at: Publisher Site | Google Scholar
J. A. Swenberg, E. Fryar-Tita, Y. C. Jeong et al., “Biomarkers in toxicology and risk assessment: informing critical dose-response relationships,” Chemical Research in Toxicology, vol. 21, no. 1, pp. 253–265, 2008.
View at: Publisher Site | Google Scholar
A. R. Boobis, G. P. Daston, R. J. Preston, and S. S. Olin, “Application of key events analysis to chemical carcinogens and noncarcinogens,” Critical Reviews in Food Science and Nutrition, vol. 49, no. 8, pp. 690–707, 2009.
View at: Publisher Site | Google Scholar
G. E. Johnson, S. H. Doak, S. M. Griffiths et al., “Non-linear dose-response of DNA-reactive genotoxins: recommendations for data analysis,” Mutation Research, vol. 678, no. 2, pp. 95–100, 2009.
View at: Publisher Site | Google Scholar
P. G. Mantle, “Minimum tolerable exposure period and maximum threshold dietary intake of ochratoxin A for causing renal cancer in male Dark Agouti rats,” Food and Chemical Toxicology, vol. 47, no. 10, pp. 2419–2424, 2009.
View at: Publisher Site | Google Scholar
S. Loft and H. E. Poulsen, “Cancer risk and oxidative DNA damage in man,” Journal of Molecular Medicine, vol. 74, no. 6, pp. 297–312, 1996.
View at: Publisher Site | Google Scholar
J. E. Klaunig, Y. Xu, J. S. Isenberg et al., “The role of oxidative stress in chemical carcinogenesis,” Environmental Health Perspectives, vol. 106, supplement 1, pp. 289–295, 1998.
View at: Google Scholar
J. E. Klaunig and L. M. Kamendulis, “The role of oxidative stress in carcinogenesis,” Annual Review of Pharmacology and Toxicology, vol. 44, pp. 239–267, 2004.
View at: Publisher Site | Google Scholar
M. Valko, C. J. Rhodes, J. Moncol, M. Izakovic, and M. Mazur, “Free radicals, metals and antioxidants in oxidative stress-induced cancer,” Chemico-Biological Interactions, vol. 160, no. 1, pp. 1–40, 2006.
View at: Publisher Site | Google Scholar
M. E. Goetz and A. Luch, “Reactive species: a cell damaging rout assisting to chemical carcinogens,” Cancer Letters, vol. 266, no. 1, pp. 73–83, 2008.
View at: Publisher Site | Google Scholar
R. F. Omar, B. B. Hasinoff, F. Mejilla, and A. D. Rahimtula, “Mechanism of ochratoxin a stimulated lipid peroxidation,” Biochemical Pharmacology, vol. 40, no. 6, pp. 1183–1191, 1990.
View at: Publisher Site | Google Scholar
D. Hoehler, R. R. Marquardt, A. R. Mclntosh, and H. Xiao, “Free radical generation as induced by ochratoxin A and its analogs in bacteria (Bacillus brevis),” Journal of Biological Chemistry, vol. 271, no. 44, pp. 27388–27394, 1996.
View at: Publisher Site | Google Scholar
H. Xiao, S. Madhyastha, R. R. Marquardt et al., “Toxicity of ochratoxin A, its opened lactone form and several of its analogs: structure-activity relationships,” Toxicology and Applied Pharmacology, vol. 137, no. 2, pp. 182–192, 1996.
View at: Publisher Site | Google Scholar
J. Dai, G. Park, M. W. Wright, M. Adams, S. A. Akman, and R. A. Manderville, “Detection and characterization of a glutathione conjugate of ochratoxin A,” Chemical Research in Toxicology, vol. 15, no. 12, pp. 1581–1588, 2002.
View at: Publisher Site | Google Scholar
I. G. Gillman, T. N. Clark, and R. A. Manderville, “Oxidation of ochratoxin A by an Fe-porphyrin system: model for enzymatic activation and DNA cleavage,” Chemical Research in Toxicology, vol. 12, no. 11, pp. 1066–1076, 1999.
View at: Publisher Site | Google Scholar
V. Faucet-Marquis, F. Pont, F. C. Størmer, T. Rizk, M. Castegnaro, and A. Pfohl-Leszkowicz, “Evidence of a new dechlorinated ochratoxin A derivative formed in opossum kidney cell cultures after pretreatment by modulators of glutathione pathways: correlation with DNA-adduct formation,” Molecular Nutrition and Food Research, vol. 50, no. 6, pp. 530–542, 2006.
View at: Publisher Site | Google Scholar
R. A. Manderville, “Pfohl-Leszkowicz bioactivation and DNA adduction as a rationale for ochratoxin A carcinogenesis,” World Mycotoxin Journal, vol. 1, pp. 357–367, 2008.
View at: Google Scholar
A. Pfohl-Leszkowicz, “Ochratoxin A and aristolochic acid involvement in nephropathies and associated urothelial tract tumours,” Arhiv za Higijenu Rada i Toksikologiju, vol. 60, no. 4, pp. 465–483, 2009.
View at: Publisher Site | Google Scholar
C. Boesch-Saadatmandi, A. Loboda, A. Jozkowicz et al., “Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells,” Food and Chemical Toxicology, vol. 46, no. 8, pp. 2665–2671, 2008.
View at: Publisher Site | Google Scholar
C. Boesch-Saadatmandi, A. E. Wagner, A. C. Graeser, C. Hundhausen, S. Wolffram, and G. Rimbach, “Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells,” Journal of Animal Physiology and Animal Nutrition, vol. 93, no. 5, pp. 547–554, 2009.
View at: Publisher Site | Google Scholar
C. Cavin, T. Delatour, M. Marin-Kuan et al., “Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity,” Toxicological Sciences, vol. 96, no. 1, pp. 30–39, 2007.
View at: Publisher Site | Google Scholar
M. Marin-Kuan, S. Nestler, C. Verguet et al., “A toxicogenomics approach to identify new plausible epigenetic mechanisms of ochratoxin a carcinogenicity in rat,” Toxicological Sciences, vol. 89, no. 1, pp. 120–134, 2006.
View at: Publisher Site | Google Scholar
J. D. Hayes, S. A. Chanas, C. J. Henderson et al., “The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin,” Biochemical Society Transactions, vol. 28, no. 2, pp. 33–41, 2000.
View at: Google Scholar
T. W. Kensler, N. Wakabayashi, and S. Biswal, “Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway,” Annual Review of Pharmacology and Toxicology, vol. 47, pp. 89–116, 2007.
View at: Publisher Site | Google Scholar
M. G. Zurich, S. Lengacher, O. Braissant, F. Monnet-Tschudi, L. Pellerin, and P. Honegger, “Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin a in aggregating rat brain cell cultures,” Neuroscience, vol. 134, no. 3, pp. 771–782, 2005.
View at: Publisher Site | Google Scholar
M. C. Ferrante, G. M. Raso, M. Bilancione, E. Esposito, A. Iacono, and R. Meli, “Differential modification of inflammatory enzymes in J774A.1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide,” Toxicology Letters, vol. 181, no. 1, pp. 40–46, 2008.
View at: Publisher Site | Google Scholar
C. Cavin, T. Delatour, M. Marin-Kuan et al., “Ochratoxin A—mediated DNA and protein damage: roles of nitrosative and oxidative stresses,” Toxicological Sciences, vol. 110, no. 1, pp. 84–94, 2009.
View at: Publisher Site | Google Scholar
J. A. Crowell, V. E. Steele, C. C. Sigman, and J. R. Fay, “Is inducible nitric oxide synthase a target for chemoprevention?” Molecular Cancer Therapeutics, vol. 2, no. 8, pp. 815–823, 2003.
View at: Google Scholar
R. De Bont and N. van Larebeke, “Endogenous DNA damage in humans: a review of quantitative data,” Mutagenesis, vol. 19, no. 3, pp. 169–185, 2004.
View at: Publisher Site | Google Scholar
Y. Hiraku and S. Kawanishi, “Immunohistochemical analysis of 8-nitroguanine, a nitrative DNA lesion, in relation to inflammation-associated carcinogenesis,” Methods in Molecular Biology, vol. 512, pp. 3–13, 2009.
View at: Publisher Site | Google Scholar
L. I. Shukla, A. Adhikary, R. Pazdro, D. Becker, and M. D. Sevilla, “Formation of 8-oxo-7,8-dihydroguanine-radicals in γ-irradiated DNA by multiple one-electron oxidations,” Nucleic Acids Research, vol. 32, no. 22, pp. 6565–6574, 2004.
View at: Publisher Site | Google Scholar
L. Arbillaga, A. Azqueta, O. Ezpeleta, and A. L. De Cerain, “Oxidative DNA damage induced by ochratoxin A in the HK-2 human kidney cell line: evidence of the relationship with cytotoxicity,” Mutagenesis, vol. 22, no. 1, pp. 35–42, 2007.
View at: Publisher Site | Google Scholar
H. G. Kamp, G. Eisenbrand, J. Schlatter, K. Würth, and C. Janzowski, “Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity and apoptosis in mammalian cell lines and primary cells,” Toxicology, vol. 206, no. 3, pp. 413–425, 2005.
View at: Publisher Site | Google Scholar
G. J. Schaaf, S. M. Nijmeijer, R. F. M. Maas, P. Roestenberg, E. M. De Groene, and J. Fink-Gremmels, “The role of oxidative stress in the ochratoxin A-mediated toxicity in proximal tubular cells,” Biochimica et Biophysica Acta, vol. 1588, no. 2, pp. 149–158, 2002.
View at: Publisher Site | Google Scholar
A. Mally, G. Pepe, S. Ravoori et al., “Ochratoxin A causes DNA damage and cytogenetic effects but no DNA adducts in rats,” Chemical Research in Toxicology, vol. 18, no. 8, pp. 1253–1261, 2005.
View at: Publisher Site | Google Scholar
L. Arbillaga, A. Azqueta, J. H. M. van Delft, and A. López de Cerain, “In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A,” Toxicology and Applied Pharmacology, vol. 220, no. 2, pp. 216–224, 2007.
View at: Publisher Site | Google Scholar
D. Zeljezic, A. M. Domijan, and M. Peraica, “DNA damage by ochratoxin A in rat kidney assessed by the alkaline comet assay,” Brazilian Journal of Medical and Biological Research, vol. 39, no. 12, pp. 1563–1568, 2006.
View at: Publisher Site | Google Scholar
N. Gagliano, I. D. Donne, C. Torri et al., “Early cytotoxic effects of ochratoxin A in rat liver: a morphological, biochemical and molecular study,” Toxicology, vol. 225, no. 2-3, pp. 214–224, 2006.
View at: Publisher Site | Google Scholar
H. G. Kamp, G. Eisenbrand, C. Janzowski et al., “Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats,” Molecular Nutrition and Food Research, vol. 49, no. 12, pp. 1160–1167, 2005.
View at: Publisher Site | Google Scholar
I. Dalle-Donne, R. Rossi, D. Giustarini, A. Milzani, and R. Colombo, “Protein carbonyl groups as biomarkers of oxidative stress,” Clinica Chimica Acta, vol. 329, no. 1-2, pp. 23–38, 2003.
View at: Publisher Site | Google Scholar
I. Dalle-Donne, D. Giustarini, R. Colombo, R. Rossi, and A. Milzani, “Protein carbonylation in human diseases,” Trends in Molecular Medicine, vol. 9, no. 4, pp. 169–176, 2003.
View at: Publisher Site | Google Scholar
I. Dalle-Donne, R. Rossi, R. Colombo, D. Giustarini, and A. Milzani, “Biomarkers of oxidative damage in human disease,” Clinical Chemistry, vol. 52, no. 4, pp. 601–623, 2006.
View at: Publisher Site | Google Scholar
A. M. Domijan, K. Rudeš, and M. Peraica, “The effect of ochratoxin A on the concentration of protein carbonyls in rats,” Arhiv za Higijenu Rada i Toksikologiju, vol. 56, no. 4, pp. 311–315, 2005.
View at: Google Scholar
H. G. Kamp, G. Eisenbrand, C. Janzowski et al., “Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats,” Molecular Nutrition and Food Research, vol. 49, no. 12, pp. 1160–1167, 2005.
View at: Publisher Site | Google Scholar
L. J. Marnett, “Lipid peroxidation—DNA damage by malondialdehyde,” Mutation Research, vol. 424, no. 1-2, pp. 83–95, 1999.
View at: Publisher Site | Google Scholar
L. J. Marnett, “Oxy radicals, lipid peroxidation and DNA damage,” Toxicology, vol. 181-182, pp. 219–222, 2002.
View at: Publisher Site | Google Scholar
U. Nair, H. Bartsch, and J. Nair, “Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans,” Free Radical Biology and Medicine, vol. 43, no. 8, pp. 1109–1120, 2007.
View at: Publisher Site | Google Scholar
A. D. Rahimtula, J. C. Bereziat, V. Bussacchini-Griot, and H. Bartsch, “Lipid peroxidation as a possible cause of ochratoxin a toxicity,” Biochemical Pharmacology, vol. 37, no. 23, pp. 4469–4477, 1988.
View at: Google Scholar
S. Khan, M. Martin, H. Bartsch, and A. D. Rahimtula, “Perturbation of liver microsomal calcium homeostasis by ochratoxin A,” Biochemical Pharmacology, vol. 38, no. 1, pp. 67–72, 1989.
View at: Publisher Site | Google Scholar
M. A. Abdel-Wahhab, M. M. Abdel-Galil, and M. El-Lithey, “Melatonin counteracts oxidative stress in rats fed an ochratoxin A contaminated diet,” Journal of Pineal Research, vol. 38, no. 2, pp. 130–135, 2005.
View at: Publisher Site | Google Scholar
A. M. Domijan, M. Peraica, A. L. Vrdoljak, B. Radić, V. Žlender, and R. Fuchs, “The involvement of oxidative stress in ochratoxin A and fumonisin B toxicity in rats,” Molecular Nutrition and Food Research, vol. 51, no. 9, pp. 1147–1151, 2007.
View at: Publisher Site | Google Scholar
J. C. Gautier, D. Holzhaeuser, J. Markovic, E. Gremaud, B. Schilter, and R. J. Turesky, “Oxidative damage and stress response from ochratoxin A exposure in rats,” Free Radical Biology and Medicine, vol. 30, no. 10, pp. 1089–1098, 2001.
View at: Publisher Site | Google Scholar
J. Petrik, T. Žanić-Grubišić, K. Barišić et al., “Apoptosis and oxidative stress induced by ochratoxin A in rat kidney,” Archives of Toxicology, vol. 77, no. 12, pp. 685–693, 2003.
View at: Publisher Site | Google Scholar
E. Sutken, E. Aral, F. Ozdemir, S. Uslu, O. Alatas, and O. Colak, “Protective role of melatonin and coenzyme Q in ochratoxin A toxicity in rat liver and kidney,” International Journal of Toxicology, vol. 26, no. 1, pp. 81–87, 2007.
View at: Publisher Site | Google Scholar
A. Benesic, S. Mildenberger, and M. Gekle, “Nephritogenic ochratoxin A interferes with hormonal signalling in immortalized human kidney epithelial cells,” Pflugers Archiv European Journal of Physiology, vol. 439, no. 3, pp. 278–287, 2000.
View at: Publisher Site | Google Scholar
X. Chong and A. D. Rahimtula, “Alterations in ATP-dependent calcium uptake by rat renal cortex microsomes following ochratoxin A administration in vivo or addition in vitro,” Biochemical Pharmacology, vol. 44, no. 7, pp. 1401–1409, 1992.
View at: Publisher Site | Google Scholar
M. Gekle, C. Sauvant, and G. Schwerdt, “Ochratoxin A at nanomolar concentrations: a signal modulator in renal cells,” Molecular Nutrition and Food Research, vol. 49, no. 2, pp. 118–130, 2005.
View at: Publisher Site | Google Scholar
E. Rached, G. C. Hard, K. Blumbach et al., “Ochratoxin A: 13-week oral toxicity and cell proliferation in male F344/ N rats,” Toxicological Sciences, vol. 97, no. 2, pp. 288–298, 2007.
View at: Publisher Site | Google Scholar
A. D. Rahimtula and X. Chong, “Alterations in calcium homeostasis as a possible cause of ochratoxin A nephrotoxicity,” IARC Scientific Publications, no. 115, pp. 207–214, 1991.
View at: Google Scholar
L. Arbillaga, A. Vettorazzi, A. G. Gil, J. H. van Delft, J. A. García-Jalón, and A. López de Cerain, “Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration,” Toxicology and Applied Pharmacology, vol. 230, no. 2, pp. 197–207, 2008.
View at: Publisher Site | Google Scholar
M. Gekle, G. Schwerdt, R. Freudinger et al., “Ochratoxin A induces JNK activation and apoptosis in MDCK-C7 cells at nanomolar concentrations,” Journal of Pharmacology and Experimental Therapeutics, vol. 293, no. 3, pp. 837–844, 2000.
View at: Google Scholar
C. Sauvant, H. Holzinger, and M. Gekle, “Proximal tubular toxicity of ochratoxin A is amplified by simultaneous inhibition of the extracellular signal-regulated kinases 1/2,” Journal of Pharmacology and Experimental Therapeutics, vol. 313, no. 1, pp. 234–241, 2005.
View at: Publisher Site | Google Scholar
M. Marin-Kuan, S. Nestler, C. Verguet et al., “MAPK-ERK activation in kidney of male rats chronically fed ochratoxin A at a dose causing a significant incidence of renal carcinoma,” Toxicology and Applied Pharmacology, vol. 224, no. 2, pp. 174–181, 2007.
View at: Publisher Site | Google Scholar
K. Stemmer, H. Ellinger-Ziegelbauer, H. J. Ahr, and D. R. Dietrich, “Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis,” Cancer Research, vol. 67, no. 9, pp. 4052–4068, 2007.
View at: Publisher Site | Google Scholar
A. P. Arrigo, “Gene expression and the thiol redox state,” Free Radical Biology and Medicine, vol. 27, no. 9-10, pp. 936–944, 1999.
View at: Publisher Site | Google Scholar
H. E. Marshall, K. Merchant, and J. S. Stamler, “Nitrosation and oxidation in the regulation of gene expression,” FASEB Journal, vol. 14, no. 13, pp. 1889–1900, 2000.
View at: Google Scholar
C. Vossen and M. Erard, “Down-regulation of nuclear receptor DNA-binding activity by nitric oxide—HNF4 as a model system,” Medical Science Monitor, vol. 8, no. 10, pp. RA217–RA220, 2002.
View at: Google Scholar
G. I. Giles, “The redox regulation of thiol dependent signaling pathways in cancer,” Current Pharmaceutical Design, vol. 12, no. 34, pp. 4427–4443, 2006.
View at: Publisher Site | Google Scholar
H. Hara and T. Adachi, “Contribution of hepatocyte nuclear factor-4 to down-regulation of CYP2D6 gene expression by nitric oxide,” Molecular Pharmacology, vol. 61, no. 1, pp. 194–200, 2002.
View at: Publisher Site | Google Scholar
R. Vuppugalla and R. Mehvar, “Hepatic disposition and effects of nitric oxide donors: rapid and concentration-dependent reduction in the cytochrome P450-mediated drug metabolism in isolated perfused rat livers,” Journal of Pharmacology and Experimental Therapeutics, vol. 310, no. 2, pp. 718–727, 2004.
View at: Publisher Site | Google Scholar
S. Karimpour, J. Lou, L. L. Lin et al., “Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation,” Oncogene, vol. 21, no. 41, pp. 6317–6327, 2002.
View at: Publisher Site | Google Scholar
K. Iwasaki, E. L. MacKenzie, K. Hailemariam, K. Sakamoto, and Y. Tsuji, “Hemin-mediated regulation of an antioxidant-responsive element of the human ferritin H gene and role of ref-1 during erythroid differentiation of K562 cells,” Molecular and Cellular Biology, vol. 26, no. 7, pp. 2845–2856, 2006.
View at: Publisher Site | Google Scholar
Y. Tsuji, “JunD activates transcription of the human ferritin H gene through an antioxidant response element during oxidative stress,” Oncogene, vol. 24, no. 51, pp. 7567–7578, 2005.
View at: Publisher Site | Google Scholar
K. D. Kröncke, L. O. Klotz, C. V. Suschek, and H. Sies, “Comparing nitrosative versus oxidative stress toward zinc finger-dependent transcription. Unique role for NO,” Journal of Biological Chemistry, vol. 277, no. 15, pp. 13294–13301, 2002.
View at: Publisher Site | Google Scholar
K. D. Kröncke, “Nitrosative stress and transcription,” Biological Chemistry, vol. 384, no. 10-11, pp. 1365–1377, 2003.
View at: Publisher Site | Google Scholar
D. Nikitovic, A. Holmgren, and G. Spyrou, “Inhibition of AP-1 DNA binding by nitric oxide involving conserved cysteine residues in Jun and Fos,” Biochemical and Biophysical Research Communications, vol. 242, no. 1, pp. 109–112, 1998.
View at: Publisher Site | Google Scholar
M. A. Abdel-Wahhab, S. H. Abdel-Azim, and A. A. El-Nekeety, “Inula crithmoides extract protects against ochratoxin A-induced oxidative stress, clastogenic and mutagenic alterations in male rats,” Toxicon, vol. 52, no. 4, pp. 566–573, 2008.
View at: Publisher Site | Google Scholar
W. Hassen, I. Ayed-Boussema, A. Bouslimi, and H. Bacha, “Heat shock proteins (Hsp 70) response is not systematic to cell stress. Case of the mycotoxin ochratoxin A,” Toxicology, vol. 242, no. 1–3, pp. 63–70, 2007.
View at: Publisher Site | Google Scholar
N. Palma, S. Cinelli, O. Sapora, S. H. Wilson, and E. Dogliotti, “Ochratoxin A-induced mutagenesis in mammalian cells is consistent with the production of oxidative stress,” Chemical Research in Toxicology, vol. 20, no. 7, pp. 1031–1037, 2007.
View at: Publisher Site | Google Scholar
C. Di Giacomo, R. Acquaviva, A. Piva et al., “Protective effect of cyanidin 3-O-β-d-glucoside on ochratoxin A-mediated damage in the rat,” British Journal of Nutrition, vol. 98, no. 5, pp. 937–943, 2007.
View at: Publisher Site | Google Scholar
S. Costa, A. Utan, R. Cervellati, E. Speroni, and M. C. Guerra, “Catechins: natural free-radical scavengers against ochratoxin A-induced cell damage in a pig kidney cell line (LLC-PK1),” Food and Chemical Toxicology, vol. 45, no. 10, pp. 1910–1917, 2007.
View at: Publisher Site | Google Scholar
D. Lambert, P. J. Padfield, J. McLaughlin, S. Cannell, and C. A. O'Neill, “Ochratoxin A displaces claudins from detergent resistant membrane microdomains,” Biochemical and Biophysical Research Communications, vol. 358, no. 2, pp. 632–636, 2007.
View at: Publisher Site | Google Scholar
V. Sava, A. Velasquez, S. Song, and J. Sanchez-Ramos, “Adult hippocampal neural stem/progenitor cells in vitro are vulnerable to the mycotoxin ochratoxin-A,” Toxicological Sciences, vol. 98, no. 1, pp. 187–197, 2007.
View at: Publisher Site | Google Scholar
K. Stemmer, H. Ellinger-Ziegelbauer, H. J. Ahr, and D. R. Dietrich, “Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis,” Cancer Research, vol. 67, no. 9, pp. 4052–4068, 2007.
View at: Publisher Site | Google Scholar
V. Sava, O. Reunova, A. Velasquez, R. Harbison, and J. Sánchez-Ramos, “Acute neurotoxic effects of the fungal metabolite ochratoxin-A,” NeuroToxicology, vol. 27, no. 1, pp. 82–92, 2006.
View at: Publisher Site | Google Scholar
V. Sava, O. Reunova, A. Velasquez, and J. Sanchez-Ramos, “Can low level exposure to ochratoxin-A cause parkinsonism?” Journal of the Neurological Sciences, vol. 249, no. 1, pp. 68–75, 2006.
View at: Publisher Site | Google Scholar
M. C. Ferrante, M. Bilancione, G. M. Raso et al., “Expression of COX-2 and hsp72 in peritoneal macrophages after an acute ochratoxin A treatment in mice,” Life Sciences, vol. 79, no. 13, pp. 1242–1247, 2006.
View at: Publisher Site | Google Scholar
A. M. Domijan, D. Želježić, N. Kopjar, and M. Peraica, “Standard and Fpg-modified comet assay in kidney cells of ochratoxin A- and fumonisin B-treated rats,” Toxicology, vol. 222, no. 1-2, pp. 53–59, 2006.
View at: Publisher Site | Google Scholar
M. Tozlovanu, V. Faucet-Marquis, A. Pfohl-Leszkowicz, and R. A. Manderville, “Genotoxicity of the hydroquinone metabolite of ochratoxin A: structure-activity relationships for covalent DNA adduction,” Chemical Research in Toxicology, vol. 19, no. 9, pp. 1241–1247, 2006.
View at: Publisher Site | Google Scholar
L. Alvarez-Erviti, C. Leache, E. González-Peñas, and A. López De Cerain, “Alterations induced in vitro by ochratoxin A in rat lymphoid cells,” Human and Experimental Toxicology, vol. 24, no. 9, pp. 459–466, 2005.
View at: Publisher Site | Google Scholar
M. C. Guerra, F. Galvano, L. Bonsi et al., “Cyanidin-3-O-β-glucopyranoside, a natural fee-radical scavenger against aflatoxin B1-and ochratoxin A-induced cell damage in a human hepatoma cell line (Hep G2) and a human colonic adenocarcinoma cell line (CaCo-2),” British Journal of Nutrition, vol. 94, no. 2, pp. 211–220, 2005.
View at: Publisher Site | Google Scholar
C. Hundhausen, C. Bösch-Saadatmandi, K. Augustin, R. Blank, S. Wolffram, and G. Rimbach, “Effect of vitamin E and polyphenols on ochratoxin A-induced cytotoxicity in liver (HepG2) cells,” Journal of Plant Physiology, vol. 162, no. 7, pp. 818–822, 2005.
View at: Publisher Site | Google Scholar
A. Russo, L. La Fauci, R. Acquaviva et al., “Ochratoxin A-induced DNA damage in human fibroblast: protective effect of cyanidin 3-O-β-D-glucoside,” Journal of Nutritional Biochemistry, vol. 16, no. 1, pp. 31–37, 2005.
View at: Publisher Site | Google Scholar
S. Knasmüller, C. Cavin, A. Chakraborty et al., “Structurally related mycotoxins ochratoxin A, ochratoxin B, and citrinin differ in their genotoxic activities and in their mode of action in human-derived liver (HepG2) cells: implications for risk assessment,” Nutrition and Cancer, vol. 50, no. 2, pp. 190–197, 2004.
View at: Publisher Site | Google Scholar
V. Ehrlich, F. Darroudi, M. Uhl et al., “Genotoxic effects of ochratoxin A in human-derived hepatoma (HepG2) cells,” Food and Chemical Toxicology, vol. 40, no. 8, pp. 1085–1090, 2002.
View at: Publisher Site | Google Scholar
A. Lühe, H. Hildebrand, U. Bach, T. Dingermann, and H. J. Ahr, “A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays,” Toxicological Sciences, vol. 73, no. 2, pp. 315–328, 2003.
View at: Publisher Site | Google Scholar
W. C. Son, K. Kamino, Y. S. Lee, and K. S. Kang, “Lack of effects of sodium 2-mercaptoethane sulfonate (mesna) on Ochratoxin A induced renal tumorigenicity following life-time oral administration of Ochratoxin A in DA and Lewis rats,” Toxicology Letters, vol. 142, no. 1-2, pp. 19–27, 2003.
View at: Publisher Site | Google Scholar
A. Pfohl-Leszkowicz, H. Bartsch, B. Azémar, U. Mohr, J. Estève, and M. Castegnaro, “MESNA protects rats against nephrotoxicity but not carcinogenicity induced by ochratoxin A, implicating two separate pathways,” Facta Universitatis Series Medicine and Biology, vol. 9, pp. 57–63, 2002.
View at: Google Scholar
E. Pinelli, C. El Adlouni, B. Pipy, F. Quartulli, and A. Pfohl-Leszkowicz, “Roles of cyclooxygenase and lipoxygenases in ochratoxin A genotoxicity in human epithelial lung cells,” Environmental Toxicology and Pharmacology, vol. 7, no. 2, pp. 95–107, 1999.
View at: Publisher Site | Google Scholar
D. Hoehler, R. R. Marquardt, A. R. McIntosh, and G. M. Hatch, “Induction of free radicals in hepatocytes, mitochondria and microsomes of rats by ochratoxin A and its analogs,” Biochimica et Biophysica Acta, vol. 1357, no. 2, pp. 225–233, 1997.
View at: Publisher Site | Google Scholar
Y. Grosse, L. Chekir-Ghedira, A. Huc et al., “Retinol, ascorbic acid and α-tocopherol prevent DNA adduct formation in mice treated with the mycotoxins ochratoxin A and zearalenone,” Cancer Letters, vol. 114, no. 1-2, pp. 225–229, 1997.
View at: Publisher Site | Google Scholar
I. Baudrimont, A. M. Betbeder, A. Gharbi, A. Pfohl-Leszkowicz, G. Dirheimer, and E. E. Creppy, “Effect of superoxide dismutase and catalase on the nephrotoxicity induced by subchronical administration of ochratoxin A in rats,” Toxicology, vol. 89, no. 2, pp. 101–111, 1994.
View at: Publisher Site | Google Scholar
J. E. Klaunig, L. M. Kamendulis, and Y. Xu, “Epigenetic mechanisms of chemical carcinogenesis,” Human and Experimental Toxicology, vol. 19, pp. 543–555, 2000.
View at: Google Scholar
J. E. Trosko and R. J. Ruch, “Cell-cell communication in carcinogenesis,” Frontiers in Bioscience, vol. 3, pp. d208–d236, 1998.
View at: Google Scholar
J. E. Trosko, C. C. Chang, B. Upham, and M. Wilson, “Epigenetic toxicology as toxicant-induced changes in intracellular signalling leading to altered gap junctional intercellular communication,” Toxicology Letters, vol. 102-103, pp. 71–78, 1998.
View at: Publisher Site | Google Scholar
H. Yamasaki, V. Krutovskikh, M. Mesnil, A. Columbano, H. Tsuda, and N. Ito, “Gap junctional intercellular communication and cell proliferation during rat liver carcinogenesis,” Environmental Health Perspectives, vol. 101, supplement 5, pp. 191–197, 1993.
View at: Google Scholar
M. Noguchi, K. Nomata, J. I. Watanabe, H. Sato, H. Kanetake, and Y. Saito, “Disruption of gap junctional intercellular communication in human renal cancer cell lines,” Urology, vol. 53, no. 1, pp. 218–222, 1999.
View at: Publisher Site | Google Scholar
H. Sato, H. Hagiwara, Y. Ohde, H. Senba, N. Virgona, and T. Yano, “Regulation of renal cell carcinoma cell proliferation, invasion and metastasis by connexin 32 gene,” Journal of Membrane Biology, vol. 216, no. 1, pp. 17–21, 2007.
View at: Publisher Site | Google Scholar
A. Mally, M. Decker, M. Bekteshi, and W. Dekant, “Ochratoxin A alters cell adhesion and gap junction intercellular communication in MDCK cells,” Toxicology, vol. 223, no. 1-2, pp. 15–25, 2006.
View at: Publisher Site | Google Scholar
A. Horvath, B. L. Upham, V. Ganev, and J. E. Trosko, “Determination of the epigenetic effects of ochratoxin in a human kidney and a rat liver epithelial cell line,” Toxicon, vol. 40, no. 3, pp. 273–282, 2002.
View at: Publisher Site | Google Scholar
S. Obrecht-Pflumio, Y. Grosse, A. Pfohl-Leszkowicz, and G. Dirheimer, “Protection by indomethacin and aspirin against genotoxicity of ochratoxin A, particularly in the urinary bladder and kidney,” Archives of Toxicology, vol. 70, no. 3-4, pp. 244–248, 1996.
View at: Publisher Site | Google Scholar
Centre for Food Safety (CFS), “Ochratoxin A in Food,” Food and Environmental Hygiene Department. Risk Assessment Studies Report no. 23. The Government of the Hong Kong Special Administrative Region, Hong Kong, 2006.
View at: Google Scholar
P. J. Beisswenger, K. S. Drummond, R. G. Nelson, S. K. Howell, B. S. Szwergold, and M. Mauer, “Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress,” Diabetes, vol. 54, no. 11, pp. 3274–3281, 2005.
View at: Publisher Site | Google Scholar
C. Coşkun, A. Kural, Y. Döventaş et al., “Hemodialysis and protein oxidation products,” Annals of the New York Academy of Sciences, vol. 1100, pp. 404–408, 2007.
View at: Publisher Site | Google Scholar
B. Descamps-Latscha and V. Witko-Sarsat, “Importance of oxidatively modified proteins in chronic renal failure,” Kidney International, Supplement, vol. 59, no. 78, pp. S108–S113, 2001.
View at: Google Scholar

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Copyright © 2011 M. Marin-Kuan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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