N-acetyl cysteine alters the genotoxic and estrogenic properties of Alternaria toxins in naturally occurring mixtures

Aichinger, Georg; Grgic, Dino; Beisl, Julia; Crudo, Francesco; Warth, Benedikt; Varga, Elisabeth; Marko, Doris

doi:10.1016/j.emcon.2021.12.004

Cited by 9 publications

(3 citation statements)

References 39 publications

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“…In addition to ATX-II, several other metabolites that are present in the CE, including ATX-I ( Jarolim et al, 2017 ) and the dibenzo-α-pyrones AOH and AME ( Tiessen et al, 2013a ), were previously reported to interact with the nuclear factor erythroid 2–related factor 2 (Nrf2). An activation of the Nrf2 pathway ultimately leads to an increased expression of enzymes that are critical for phase II xenobiotic metabolism ( Itoh et al, 1997 ), but also to an enhanced biosynthesis and release of cellular antioxidants like glutathione and other cysteine derivatives ( Steele et al, 2013 ), compounds that were recently demonstrated to detoxify ATX-II in vitro ( Jarolim et al, 2017 ; Aichinger et al, 2022 ). Thus, if ATX-II indeed is one of the driving forces behind the genotoxicity of Alternaria toxin mixtures, the additional interplay with Nrf2 by co-occurring metabolites could be a viable explanation for the reduced genotoxicity of the CE in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…These chemicals directly alkylate guanine and possibly also cytosine bases of the DNA ( Soukup et al, 2020 ), leading to bulky adduct formation and thus extensive DNA damage in vitro ( Fleck et al, 2012 ; Schwarz et al, 2012 ; Fleck et al, 2016 ). Even as ATX-II was recently for the first time described in food sample ( Puntscher et al, 2020 ), there are doubts whether epoxy-carrying perylene quinones would be able to even reach the gastrointestinal tract due to their limited stability that is probably related to their chemical reactivity with co-occurring food constituents ( Aichinger et al, 2018 ; Aichinger et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Markers for DNA damage are induced in the rat colon by the Alternaria toxin altertoxin-II, but not a complex extract of cultured Alternaria alternata

Aichinger

Pahlke²,

Puntscher³

et al. 2022

Front. Toxicol.

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Mycotoxins produced by Alternaria spp. act genotoxic in cell-based studies, but data on their toxicity in vivo is scarce and urgently required for risk assessment. Thus, male Sprague-Dawley rats received single doses of a complex Alternaria toxin extract (CE; 50 mg/kg bw), altertoxin II (ATX-II; 0.21 mg/kg bw) or vehicle by gavage, one of the most genotoxic metabolites in vitro and were sacrificed after 3 or 24 h, respectively. Using SDS-PAGE/Western Blot, a significant increase of histone 2a.X phosphorylation and depletion of the native protein was observed for rats that were exposed to ATX-II for 24 h. Applying RT-PCR array technology we identified genes of interest for qRT-PCR testing, which in turn confirmed an induction of Rnf8 transcription in the colon of rats treated with ATX-II for 3 h and CE for 24 h. A decrease of Cdkn1a transcription was observed in rats exposed to ATX-II for 24 h, possibly indicating tissue repair after chemical injury. In contrast to the observed response in the colon, no markers for genotoxicity were induced in the liver of treated animals. We hereby provide the first report of ATX-II as a genotoxicant in vivo. Deviating results for similar concentrations of ATX-II in a natural Alternaria toxin mixture argue for substantial mixture effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Markers for DNA damage are induced in the rat colon by the Alternaria toxin altertoxin-II, but not a complex extract of cultured Alternaria alternata

Aichinger

Pahlke²,

Puntscher³

et al. 2022

Front. Toxicol.

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“…Of note, a previous study suggested that the actual occurrence may even exceed the present estimate [ 7 ]. With respect to its toxicological properties, AOH has been extensively reported to exert estrogenic effects [ 8 , 9 ] as well as to induce different types of DNA damage, including single-strand breaks (SSB), double-strand breaks (DSB), and oxidative DNA damage through mechanisms that involve the generation of reactive oxygen species and the poisoning of DNA topoisomerases (TOPOs), especially the IIα isoform [ 10 ]. TOPOs are a family of enzymes that regulate the DNA topological state by breaking one (TOPO I) or both (TOPO II) strands of the DNA which are subsequently rejoined.…”

Section: Introductionmentioning

confidence: 99%

Genotoxic and Mutagenic Effects of the Alternaria Mycotoxin Alternariol in Combination with the Process Contaminant Acrylamide

Crudo,

Hong,

Varga

et al. 2023

Toxins

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Humans are constantly exposed to mixtures of different xenobiotics through their diet. One emerging concern is the Alternaria mycotoxin alternariol (AOH), which can occur in foods typically contaminated by the process contaminant acrylamide (AA). AA is a byproduct of the Maillard reaction produced in carbohydrate-rich foods during thermal processing. Given the genotoxic properties of AOH and AA as single compounds, as well as their potential co-occurrence in food, this study aimed to assess the cytotoxic, genotoxic, and mutagenic effects of these compounds in combination. Genotoxicity was assessed in HepG2 cells by quantifying the phosphorylation of the histone γ-H2AX, induced as a response to DNA double-strand breaks (DSBs). Mutagenicity was tested in Salmonella typhimurium strains TA98 and TA100 by applying the Ames microplate format test. Our results showed the ability of AOH and AA to induce DSBs and increase revertant numbers in S. typhimurium TA100, with AOH being more potent than AA. However, no synergistic effects were observed during the combined treatments. Notably, the results of the study suggest that the compounds exert mutagenic effects primarily through base pair substitutions. In summary, the data indicate no immediate cause for concern regarding synergistic health risks associated with the consumption of foods co-contaminated with AOH and AA.

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Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health

Louro,

Vettorazzi,

López de Cerain

et al. 2023

Arch Toxicol

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Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.

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N-acetyl cysteine alters the genotoxic and estrogenic properties of Alternaria toxins in naturally occurring mixtures

Cited by 9 publications

References 39 publications

Markers for DNA damage are induced in the rat colon by the Alternaria toxin altertoxin-II, but not a complex extract of cultured Alternaria alternata

Markers for DNA damage are induced in the rat colon by the Alternaria toxin altertoxin-II, but not a complex extract of cultured Alternaria alternata

Genotoxic and Mutagenic Effects of the Alternaria Mycotoxin Alternariol in Combination with the Process Contaminant Acrylamide

Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health

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