Repair of DNA damage induced by the mycotoxin alternariol involves tyrosyl-DNA phosphodiesterase 1

Fehr, Markus; Baechler, Simone A.; Kropat, Christopher; Mielke, Christian; Boege, Fritz; Pahlke, Gudrun; Marko, Doris

doi:10.1007/s12550-010-0063-6

Cited by 20 publications

(17 citation statements)

References 39 publications

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“…Cell proliferation studies on Ishikawa and Chinese hamster V79 cells by flow cytometry and microscopy indicated that AOH inhibited cell proliferation by interfering with the cell cycle . Genotoxic effects of AOH have also been reported in these cell lines and in human colon carcinoma cells (Fehr et al, 2010). Reduced cell proliferation has also been associated with DNA damaging effects of AOH (Solhaug et al, 2012).…”

Section: Contents Lists Available At Sciverse Sciencedirectmentioning

confidence: 90%

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An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

Frizzell

Ndossi

Kalayou

et al. 2013

Toxicology and Applied Pharmacology

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Section: Contents Lists Available At Sciverse Sciencedirectmentioning

confidence: 90%

“…AOH is a potent genotoxic, mutagenic, carcinogenic and oestrogenic compound (Brugger et al, 2006;Fehr et al, 2010;Lehmann et al, 2006;Liu et al, 1992). Some mycotoxins cause cytotoxicity to exposed cells whereas others increase cellular proliferation (Frizzell et al, 2011;Ndossi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

Frizzell

Ndossi

Kalayou

et al. 2013

Toxicology and Applied Pharmacology

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“…As expected by a topoisomerase inhibitor the human tyrosyl-DNA phosphodiesterase I (TDP1), a key enzyme in the repair of covalent DNA-topoisomerase adducts, affects AOH-induced genotoxicity. Human carcinoma cells overexpressing this enzyme presented significantly less DNA breakage than cells expressing a mutant inactive form of TDP1 while damage was increased in TDP1-suppressed cells (Fehr et al, 2010).…”

Section: Mechanism Of Genotoxicitymentioning

confidence: 94%

Scientific Opinion on the risks for animal and public health related to the presence ofAlternariatoxins in feed and food

2011

EFSA Journal

400

188

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The European Commission asked the European Food Safety Authority to review the safety of Alternaria toxins in food and feed. In addition to causing plant diseases on many crops such as cereals, oilseeds, tomatoes, apples and olives, some of these toxins are genotoxic in vitro and/or fetotoxic in rats. This opinion deals with alternariol, alternariol monomethyl ether, tenuazonic acid, iso-tenuazonic acid, altertoxins, tentoxin, altenuene and AAL-toxins (Alternaria alternata f. sp. lycopersici toxins). Two Member States provided 11,730 occurrence results in food and also data published in the scientific literature were considered. Generally these toxins were found in grains and grain-based products, tomato and tomato products, sunflower seeds and sunflower oil, fruits and fruit products, and beer and wine. The feed occurrence data (1150 results) were collected from the literature only. The knowledge on toxic effects of Alternaria toxins on farm and companion animals and occurrence data in feed were insufficient to assess the health risk for different species. For chicken there are indications that alternariol represents a health risk but it cannot be excluded that tenuazonic acid could also be of concern. Considering: (1) there are few or no relevant toxicity data on Alternaria toxins, (2) the chemical structure of several of them is known, (3) dietary exposure data exist for some of them, the Panel on Contaminants in the food chain used the threshold of toxicological concern (TTC) approach to assess the relative level of concern for dietary exposure of humans to these mycotoxins. For the genotoxic Alternaria toxins, alternariol and alternariol monomethyl ether, the estimated chronic dietary exposure exceeded the relevant TTC value indicating a need for additional toxicity data. The dietary exposure estimates for nongenotoxic tentoxin and tenuazonic acid are lower than the relevant TTC value and are considered unlikely to be a human health concern. SUMMARYAlternaria toxins are mycotoxins produced by Alternaria species that cause plant diseases on many crops. They are the principal contaminating fungi in wheat, sorghum and barley, and have also been reported to occur in oilseeds such as sunflower and rapeseed, tomato, apples, citrus fruits, olives and several other fruits and vegetables. Alternaria alternata is the most common Alternaria species in harvested fruits and vegetables, and is the most important mycotoxin-producing species. Due to their growth even at low temperature, Alternaria species are also responsible for spoilage of these commodities during refrigerated transport and storage.Alternaria species produce more than 70 phytotoxins, but a small proportion of them have been chemically characterised and reported to act as mycotoxins to humans and animals. Some toxins such as alternariol (AOH), alternariol monomethyl ether (AME), tenuazonic acid (TeA) and altertoxins (ATX) are described to induce harmful effects in animals, including fetotoxic and teratogenic effects. Culture extracts of A. altern...

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“…being a topoisomerase poison). Here, also the IIα isoform was preferentially targeted . The collision of the stabilized DNA complex with the DNA replication forks or transcriptional machinery may lead to DSB, thus providing a plausible mechanism for the clastogenic effects of AOH.…”

Section: Aoh‐induced Effects and Consequence – Suggested Mechanistic mentioning

confidence: 99%

Mechanisms of Action and Toxicity of the Mycotoxin Alternariol: A Review

Solhaug

Eriksen

Holme

2016

Basic Clin Pharma Tox

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The mycotoxin alternariol (AOH) is produced by Alternaria fungi. It occurs naturally in foodstuffs and is frequently found as contaminant in fruit and grain products. Most information regarding AOH toxicity and the potential mechanisms involved comes from in vitro studies, as only very limited in vivo studies have been performed. AOH forms reactive oxygen species (ROS) and interacts with DNA topoisomerase, thereby generating both single (SSB)-and double-strand DNA beaks (DSB). This triggers various DNA damage response pathways. AOH causes a marked reduction in proliferation in mammalian cells due to cell cycle arrest often in the G 2 /M-phase. After an additional inhibition of cytokinesis, cells with abnormal nuclei as well as polyploidy are reported. In macrophages, AOH may increase autophagic activity and induce senescence. Furthermore, AOH is found to change the morphology and phenotype of various human macrophage cell models. Studies so far indicate that the AOH-induced effects are primarily a result of DSB via its effects on topoisomerase activity. Thus, most probably there will be a threshold for the AOH-induced effects, typically seen in the 5-10 lM range. These in vitro mechanistic studies further support the in vivo studies suggesting low acute toxicity. However, a decreased immune response to infections and/or a disturbed balance of the adaptive immune system when exposed together with other mycotoxins cannot be excluded. This hypothesis needs to be further explored with proper in vivo studies.

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Repair of DNA damage induced by the mycotoxin alternariol involves tyrosyl-DNA phosphodiesterase 1

Cited by 20 publications

References 39 publications

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

Scientific Opinion on the risks for animal and public health related to the presence ofAlternariatoxins in feed and food

Mechanisms of Action and Toxicity of the Mycotoxin Alternariol: A Review

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