Reduction in Antioxidant Defenses may Contribute to Ochratoxin A Toxicity and Carcinogenicity

Cavin, Christophe; Delatour, Thierry; Marin-Kuan, Maricel; Holzhäuser, D.; Higgins, Larry G.; Bezençon, Claudine; Guignard, G.; Junod, Sylviane; Richoz-Payot, Janique; Gremaud, Eric; Hayes, John D.; Nestler, Sandra; Mantle, Peter G.; Schilter, Benoı̂t

doi:10.1093/toxsci/kfl169

Cited by 130 publications

(104 citation statements)

References 45 publications

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“…OTA-induced oxidative stress and ensuing DNA damage in combination with enhanced cell proliferation could increase the likelihood of neoplastic transformation (29). The presence of oxidative DNA damage, as also suggested by earlier findings (30)(31)(32), is supported by the up-regulation of the p53 pathway genes SUPT16H in both strains, MDM2 and CHEK2 in Eker rats, and RBBP6 in wild-type rats as well as by the time-dependent down-regulation of HSP 40-3, CN1, MSRA, and MGST1, responsible for the protection of cells against oxidative stress. Indeed, recent findings showed that overexpression of glia maturation growth factor h (GMFB) resulted in reduced antioxidant enzyme activities, subsequent accumulation of H 2 O 2 , and finally enhanced oxidative injury of renal proximal tubular cells (33).…”

Section: Discussionsupporting

confidence: 52%

Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

et al. 2007

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Eker rats heterozygous for a dominant germline mutation in the tuberous sclerosis 2 (Tsc2) tumor suppressor gene were used as a model to study renal carcinogenesis. Eker and corresponding wild-type rats were exposed to genotoxic aristolochic acid (AA) or non-genotoxic ochratoxin A (OTA) to elucidate early carcinogen-specific gene expression changes and to test whether Eker rats are more sensitive to carcinogeninduced changes in gene expression. Male Eker and wild-type rats were gavaged daily with AA (10 mg/kg body weight) or OTA (210 Mg/kg body weight). After 1, 3, 7, and 14 days of exposure, renal histopathology, tubular cell proliferation, and Affymetrix gene expression profiles from renal cortex/outer medulla were analyzed. AA-treated Eker and wild-type rats were qualitatively comparable in all variables assessed, suggesting a Tsc2-independent mechanism of action. OTA treatment resulted in slightly increased cortical pathology and significantly elevated cell proliferation in both strains, although Eker rats were more sensitive. Deregulated genes involved in the phosphatidylinositol 3-kinase-AKT-Tsc2-mammalian target of rapamycin signaling, among other important genes prominent in tumorigenesis, in conjunction with the enhanced cell proliferation and presence of preneoplastic lesions suggested involvement of Tsc2 in OTA-mediated toxicity and carcinogenicity, especially as deregulation of genes involved in this pathway was more prominent in the Tsc2 mutant Eker rat. [Cancer Res 2007;67(9):4052-68]

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Section: Discussionsupporting

confidence: 52%

Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

et al. 2007

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“…Besides, in some studies, an inhibition of the pathways regulated by Nrf2 have been described in kidney but not in liver (Marin-Kuan et al, 2006;Cavin et al, 2007). Thus, the protection of OTA against AFB1 genotoxicity would not be explained through this mechanism.…”

Section: Discussionmentioning

confidence: 97%

Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay

Corcuera

Vettorazzi

Arbillaga

et al. 2015

Food and Chemical Toxicology

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(max. 200 words)Aflatoxin B1 (AFB1) and Ochratoxin A (OTA) are genotoxic mycotoxins that can contaminate a variety of foodstuffs, the liver and the kidney being their target organ, respectively. The micronucleus (MN) assay (bone marrow) and the comet assay (liver and kidney) were performed simultaneously in F344 rats, treated with AFB1 (0.25 mg/kg b.w.), OTA (0.5 mg/kg b.w.) or both mycotoxins. After AFB1 treatment, histopathology and biochemistry analysis showed liver necrosis, focal inflammation and an increase in Alanine Aminotransferase and Aspartate Aminotransferase. OTA alone did not cause any alteration. The acute hepatotoxic effects caused by AFB1 were less pronounced in animals treated with both mycotoxins. With regard to the MN assay, after 24h, positive results were obtained for AFB1 and negative results were obtained for OTA, although both toxins caused bone marrow toxicity. In the combined treatment, OTA reduced the toxicity and the number of MN produced by AFB1. In the comet assay, after 3h, positive results were obtained for AFB1 in the liver and for OTA in the 1 kidney. The combined treatment reduced DNA damage in the liver and had no influence in the kidney. Altogether, these results may be indicative of an antagonistic relationship regarding the genotoxicity of both mycotoxins.

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“…The Ochratoxins are mycotoxins produced by some Aspergillus species such as A. Ochraceus and A. Niger, whereas some Penicillium species such as P. Verrucosum and P. Carbonarius are also found to produce Ochratoxins (32). Among all the types mentioned, Ochratoxin A is the most common and it has the highest degree of toxicity (33)(34)(35). The Ochratoxins can be found in cereals, coffee, dried fruit, and red wine.…”

Section: Types Of Mycotoxins and Their Natural Commoditiesmentioning

confidence: 99%

Effects of different mycotoxins on humans, cell genome and their involvement in cancer

et al. 2017

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Abstract. The chemical nature of most of the mycotoxins makes them highly liposoluble compounds that can be absorbed from the site of exposure such as from the gastrointestinal and respiratory tract to the blood stream where it can be dissimilated throughout the body and reach different organs such as the liver and kidneys. Mycotoxins have a strong tendency and ability to penetrate the human and animal cells and reach the cellular genome where it causes a major mutagenic change in the nucleotide sequence which leads to strong and permanent defects in the genome. This defect will eventually be transcribed, translated and lead to the development of cancer. In this review, the chemical and physical nature of mycotoxins, the action of mycotoxins on the cellular genome and its effect on humans, mycotoxins and their carcinogenicity and mycotoxins research gaps are discussed, and new research areas are suggested. The research review posed various questions. What are the different mycotoxins that can cause cancer, what is the role of mycotoxins in causing cancer and what types of cancers can be caused by mycotoxins? These questions have been selected due to the significant increase in the mycotoxin contamination and the cancer incidence rate in the contemporary world. By revealing and understanding the role of mycotoxins in developing cancer, measures to reduce the risks and incidents of cancer could be taken.

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Reduction in Antioxidant Defenses may Contribute to Ochratoxin A Toxicity and Carcinogenicity

Cited by 130 publications

References 45 publications

Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

Carcinogen-Specific Gene Expression Profiles in Short-term Treated Eker and Wild-type Rats Indicative of Pathways Involved in Renal Tumorigenesis

Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay

Effects of different mycotoxins on humans, cell genome and their involvement in cancer

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