Evaluation of ochratoxin A for mutagenicity in a battery of bacterial and mammalian cell assays

Bendele, Alison M.; Neal, Steven B.; Oberly, T.J.; Thompson, Christina Z.; Bewsey, B.J.; Hill, Leo E.; Rexroat, Marcia A.; Carlton, William W.; Probst, Gregory S.

doi:10.1016/0278-6915(85)90107-3

Cited by 44 publications

(29 citation statements)

References 20 publications

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“…In studies of Wu¨rgler et al 1991, Bendele et al (1985 and Wehner et al (1978), no mutagenicity was found in the Salmonella mutagenicity assay. Recently, OTA tested positive when mouse kidney microsomes were used as metabolic activators instead of rat liver microsomes (ObrechtPflumio et al 1999), and more DNA adducts were found on OTA activation by kidney microsomes than on activation by liver microsomes (Obrecht-Pflumio and Dirheimer 2000).…”

Section: Introductionmentioning

confidence: 81%

Effects of the mycotoxin ochratoxin A in a bacterial and a mammalian in vitro mutagenicity test system

Föllmann

Lucas

2003

Arch Toxicol

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Ochratoxin A (OTA), a mycotoxin produced by several Aspergillus and Penicillium species, is a worldwide contaminant of food and feedstuffs. It is nephrotoxic, immunosuppressive and carcinogenic in several animal species. The mechanism by which OTA acts is not fully understood up to now. Here, OTA was evaluated for mutagenicity in the Salmonella typhimurium assay (Ames assay) and in the HPRT assay with V79 hamster fibroblasts. In the bacterial assay using the strains TA 98, TA 100, TA 1535, TA 1538, TA 102 and TA 104, OTA was not mutagenic at a concentration range from 0.01 to 500 micro M in the presence and absence of an external metabolising enzyme system (rat liver S9 enzyme mix). In V79 fibroblasts, cytotoxicity of OTA was estimated with the neutral red uptake assay. An IC(50) of 11.6 micro M was found in the absence and an IC(50) of 6.4 micro M in the presence of S9 mix. In the subsequent HPRT (hypoxanthine-guanine-phosphoribosyl-transferase) assay with V79 cells the negative result of the bacterial assay was confirmed using OTA in concentrations from 0.1 to 100 micro M. In order to obtain converted OTA metabolites from viable, metabolically competent cells, a preincubation of primary cultured rat hepatocytes with 0.016 to 0.8 micro M OTA was performed. The resulting culture medium, which contained OTA metabolites, was tested in both mutagenicity assays. Again, no mutagenic effect was detected either in the bacterial or in the mammalian test assay. In accordance with several literature data, the present results imply that OTA does not act as direct mutagen. Additionally, the OTA metabolites derived from cultured rat hepatocytes or rat liver S9 mix, also, do not have a mutagenic potency in the test systems used.

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Section: Introductionmentioning

confidence: 81%

Effects of the mycotoxin ochratoxin A in a bacterial and a mammalian in vitro mutagenicity test system

Föllmann

Lucas

2003

Arch Toxicol

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“…However, OTA did not induce unscheduled DNA synthesis in primary cultures of rat hepatocytes exposed to concentrations of OTA ranging from 60 pm to 1 mm and SCEs in cells from in vivo OTA-treated Chinese hamsters [10], and 10-25 lm OTA concentrations did not produce an increase in SCE frequency in human peripheral blood lymphocytes [11]. Although contradictory results have been found for genotoxicity of OTA, fundamentally it has been demonstrated that OTA induces SCEs and micronuclei (MN) in mammalian cells in vitro; a dose-dependent increase in SCE frequency has been reported in cultured porcine urinary bladder epithelial cells at concentrations between 100 pm and 100 nm OTA [12] and the frequency of micronuclei was increased in ovine seminal vesicle (OSV) cell cultures by higher OTA concentrations (12-30 lm) [13].…”

Section: Introductionmentioning

confidence: 89%

Effects of ochratoxin A on micronucleus frequenncy in human lymphocytes

Dönmez-Altuntaş

Hamurcu

İmamoğlu

et al. 2003

Nahrung

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Ochratoxin A (OTA), a nephrotoxic and carcinogenic mycotoxin, was investigated to examine its potency to induce micronuclei (MN) in cultured human lymphocytes. Lymphocyte cultures were treated for the last 48 h with OTA at concentrations of 25 microM, 10 microM, 1 microM, 100 nM, 10 nM, 1 nM, and 100 microM and absolute ethanol. At the highest concentration, OTA was found to induce MN in cytokinesis-blocked lymphocytes (p < 0.05). The 25 microM OTA concentration also led to a clear decrease in the percentage of binucleated cells, probably due to cytotoxicity. OTA at the other concentrations tested did not induce MN frequency. These results indicate that a high concentration of OTA is genotoxic in cultured human lymphocytes.

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“…Furthermore, concentrations ranging between 60 pM and 1 mM could not induce unscheduled DNA synthesis in primary hepatocytes nor SCE in ovary cells from Chinese hamsters, which had been treated with OTA in vivo. 109 The ability of OTA to induce an increase in micronucleus frequency was investigated by Donmez-Altuntas and coworkers. 110 These authors reported OTA, at concentrations ranging from 100 pM to 10 µM, to have no effect on the frequency of micronuclei in cultures of primary human lymphocytes.…”

Section: Is Ota (Or One Of Its Metabolites) Genotoxic?mentioning

confidence: 99%

Ochratoxin A: The Continuing Enigma

O'Brien

Dietrich

2005

Critical Reviews in Toxicology

359

212

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The mycotoxin ochratoxin A (OTA) has been linked to the genesis of several disease states in both animals and humans. It has been described as nephrotoxic, carcinogenic, teratogenic, immunotoxic, and hepatotoxic in laboratory and domestic animals, as well as being thought to be the probable causal agent in the development of nephropathies (Balkan Endemic Nephropathy, BEN and Chronic Interstitial Nephropathy, CIN) and urothelial tumors in humans. As a result, several international agencies are currently attempting to define safe legal limits for OTA concentration in foodstuffs (e.g., grain, meat, wine, and coffee), in processed foods, and in animal fodder. In order to achieve this goal, an accurate risk assessment of OTA toxicity including mechanistic and epidemiological studies must be carried out. Ochratoxin has been suggested by various researchers to mediate its toxic effects via induction of apoptosis, disruption of mitochondrial respiration and/or the cytoskeleton, or, indeed, via the generation of DNA adducts. Thus, it is still unclear if the predominant mechanism is of a genotoxic or an epigenetic nature. One aspect that is clear, however, is that the toxicity of OTA is subject to and characterized by large species-and sex-specific differences, as well as an apparently strict structure-activity relationship. These considerations could be crucial in the investigation of OTA-mediated toxicity. Furthermore, the use of appropriate in vivo and in vitro model systems appears to be vital in the generation of relevant experimental data. The intention of this review is to collate and discuss the currently available data on OTA-mediated toxicity with particular focus on their relevance for the in vivo situation, and also to suggest possible future strategies for unlocking the secrets of ochratoxin A.

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Evaluation of ochratoxin A for mutagenicity in a battery of bacterial and mammalian cell assays

Cited by 44 publications

References 20 publications

Effects of the mycotoxin ochratoxin A in a bacterial and a mammalian in vitro mutagenicity test system

Effects of the mycotoxin ochratoxin A in a bacterial and a mammalian in vitro mutagenicity test system

Effects of ochratoxin A on micronucleus frequenncy in human lymphocytes

Ochratoxin A: The Continuing Enigma

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