Activation of the Nrf2-ARE pathway by the Alternaria alternata mycotoxins altertoxin I and II

Jarolim, Katharina; Favero, Giorgia Del; Pahlke, Gudrun; Dostal, Victoria; Zimmermann, Kristin; Heiss, Elke H.; Ellmer, Doris; Stark, Timo D.; Hofmann, Thomas; Marko, Doris

doi:10.1007/s00204-016-1726-7

Cited by 36 publications

(40 citation statements)

References 33 publications

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“…The mechanisms behind its mode of action could not be clarified so far. Nevertheless, genotoxicity was observed at comparatively low concentrations, but no enhanced levels of reactive oxygen species, glutathione depletion, or topoisomerase inhibition [11, 12]. Besides, AOH, AME, and some of their metabolites additionally exhibit estrogenic potential [13, 14] which may be enhanced by combinatory toxic effects [15–17].…”

Section: Introductionmentioning

confidence: 99%

Tracking emerging mycotoxins in food: development of an LC-MS/MS method for free and modified Alternaria toxins

et al. 2018

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Mycotoxins produced by Alternaria fungi are ubiquitous food contaminants, but analytical methods for generating comprehensive exposure data are rare. We describe the development of an LC-MS/MS method covering 17 toxins for investigating the natural occurrence of free and modified Alternaria toxins in tomato sauce, sunflower seed oil, and wheat flour. Target analytes included alternariol (AOH), AOH-3-glucoside, AOH-9-glucoside, AOH-3-sulfate, alternariol monomethyl ether (AME), AME-3-glucoside, AME-3-sulfate, altenuene, isoaltenuene, tenuazonic acid (TeA), tentoxin (TEN), altertoxin I and II, alterperylenol, stemphyltoxin III, altenusin, and altenuic acid III. Extensive optimization resulted in a time- and cost-effective sample preparation protocol and a chromatographic baseline separation of included isomers. Overall, adequate limits of detection (0.03–9 ng/g) and quantitation (0.6–18 ng/g), intermediate precision (9–44%), and relative recovery values (75–100%) were achieved. However, stemphyltoxin III, AOH-3-sulfate, AME-3-sulfate, altenusin, and altenuic acid III showed recoveries in wheat flour below 70%, while their performance was stable and reproducible. Our pilot study with samples from the Austrian retail market demonstrated that tomato sauces (n = 12) contained AOH, AME, TeA, and TEN in concentrations up to 20, 4, 322, and 0.6 ng/g, while sunflower seed oil (n = 7) and wheat flour samples (n = 9) were contaminated at comparatively lower levels. Interestingly and of relevance for risk assessment, AOH-9-glucoside, discovered for the first time in naturally contaminated food items, and AME-3-sulfate were found in concentrations similar to their parent toxins. In conclusion, the established multi-analyte method proved to be fit for purpose for generating comprehensive Alternaria toxin occurrence data in different food matrices. Graphical abstractᅟ Electronic supplementary materialThe online version of this article (10.1007/s00216-018-1105-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Tracking emerging mycotoxins in food: development of an LC-MS/MS method for free and modified Alternaria toxins

et al. 2018

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“…The fate of ATXII during food production is still unknown and currently subject to intensive research, thus still hampering any reliable exposure estimation. Applied in mammalian cell culture, ATXII triggers genotoxic and mutagenic damage (Fleck et al 2012; Pahlke et al 2016; Schwarz et al 2012), enhances intracellular ROS (reactive oxygen species) levels and activates the redox-sensitive Nrf2/ARE pathway (Jarolim et al 2017; Pahlke et al 2016). In spite of that, it was recently described that the toxin may be rapidly and efficiently biotransformed in differentiated Caco2 cells (Fleck et al 2014a).…”

Section: Introductionmentioning

confidence: 99%

Functional impairment triggered by altertoxin II (ATXII) in intestinal cells in vitro: cross-talk between cytotoxicity and mechanotransduction

2018

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Intestinal cells are able to continuously integrate response to multiple stimuli/stressors; these include the concomitant activation of “chemically driven” pathways, of paramount importance in the response to toxicants, as well as physical stimulation derived from motility. Altertoxin II (ATXII, 0.1, 1 and 10 µM), a mycotoxin produced by the food contaminant fungus Alternaria alternata was studied in HT-29 intestinal adenocarcinoma cells and in non-transformed intestinal epithelial cells, HCEC. One-hour incubation with ATXII was sufficient to trigger irreversible cytotoxicity in both cell types, as well as to modify cellular responses to concomitant pro-oxidant challenge (H2O2, 100–500 µM, DCF-DA assay) suggesting that even relatively short-time exposure of the intestinal cells could be sufficient to alter their functionality. Combination of ATXII (1 µM) with physical stimulation typical of the intestinal compartment (shear stress) revealed differential response of tumor-derived epithelial cells HT-29 in comparison to HCEC, in particular in the localization of the transcription factor Nrf2 (NF-E2-related factor 2). Moreover, ATXII reduced the migratory potential of HCEC as well as their membrane fluidity, but had no respective impact on HT-29 cells. Taken together, ATXII appeared to alter predominantly membrane functionality in HCEC thus hampering crucial functions for cellular motility/turnover, as well as barrier function of healthy intestinal cells and had very limited activity on the tumor counterparts.

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“…Ethyl acetate extracts were prepared after 21 days of incubation from rice which was inoculated with Alternaria alternata strain DSM 62010 as described in Schwarz et al (2012a). Fractionation of the ethyl acetate extracts by solid-phase extraction (SPE) and isolation of the toxins with HPLC were conducted according to Jarolim et al (2016). For isolation individual fractions were collected, concentrated under reduced pressure (40 °C), and freeze-dried in duplicate, yielding ATX II and STTX III in high purities (>97 % HPLC–UV, 270 nm).…”

Section: Methodsmentioning

confidence: 99%

“…For isolation individual fractions were collected, concentrated under reduced pressure (40 °C), and freeze-dried in duplicate, yielding ATX II and STTX III in high purities (>97 % HPLC–UV, 270 nm). ATX I and ALP were re-purified using the HPLC system and column mentioned in Jarolim et al (2016) and the following gradient. Monitoring the effluent (4.2 ml/min) at 350 nm, chromatography was performed starting with a mixture (80/20, v/v) of aqueous formic acid (0.1 % in H 2 O) and MeCN, the MeCN content was increased to 45 % within 16 min and to 70 % within 4 min, followed by column washing and re-equilibration.…”

Section: Methodsmentioning

confidence: 99%

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Dual effectiveness of Alternaria but not Fusarium mycotoxins against human topoisomerase II and bacterial gyrase

et al. 2016

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Type II DNA-topoisomerases (topo II) play a crucial role in the maintenance of DNA topology. Previously, fungi of the Alternaria genus were found to produce mycotoxins that target human topo II. These results implied the question why a fungus should produce secondary metabolites that target a human enzyme. In the current work, the homology between human topo II and its bacterial equivalent, gyrase, served as basis to study a potential dual inhibition of both enzymes by mycotoxins. A total of 15 secondary metabolites produced by fungi of the genera Alternaria and Fusarium were assessed for their impact on topo II of human and bacterial origin in the decatenation and the supercoiling assay, respectively. In line with the theory of dual topo II inhibition, six of the tested Alternaria mycotoxins were active against both enzymes, the dibenzo-α-pyrones alternariol (AOH) and alternariol monomethyl ether (AME), as well as the perylene-quinones altertoxin I (ATX I) and II (ATX II), alterperylenol (ALP) and stemphyltoxin III (STTX III). The Alternaria metabolites altersetin (ALN), macrosporin (MAC), altenusine (ALS) and pyrenophorol (PYR) impaired the function of human topo II, but did not show any effect on gyrase. The potency to inhibit topo II activity declined in the row STTX III (initial inhibitory concentration 10 µM) > AOH (25 µM) = AME (25 µM) = ALS (25 µM) = ATX II (25 µM) > ALN (50 µM) = ATX I (50 µM) > ALP (75 µM) = PYR (75 µM) > MAC (150 µM). Inhibition of gyrase activity was most pronounced for AOH and AME (initial inhibitory concentration 10 µM) followed by ATX II (25 µM) > ATX I = ALP = STTX III (50 µM). In contrast, none of the investigated Fusarium mycotoxins deoxynivalenol (DON), fumonisin B1, fusarin C and moniliformin, as well as the Alternaria metabolite tentoxin, had any impact on the activity of neither human nor bacterial topo II.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1855-z) contains supplementary material, which is available to authorized users.

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Activation of the Nrf2-ARE pathway by the Alternaria alternata mycotoxins altertoxin I and II

Cited by 36 publications

References 33 publications

Tracking emerging mycotoxins in food: development of an LC-MS/MS method for free and modified Alternaria toxins

Tracking emerging mycotoxins in food: development of an LC-MS/MS method for free and modified Alternaria toxins

Functional impairment triggered by altertoxin II (ATXII) in intestinal cells in vitro: cross-talk between cytotoxicity and mechanotransduction

Dual effectiveness of Alternaria but not Fusarium mycotoxins against human topoisomerase II and bacterial gyrase

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