Chemotaxonomy of Mycotoxigenic Small-Spored Alternaria Fungi – Do Multitoxin Mixtures Act as an Indicator for Species Differentiation?

Zwickel, Theresa; Kahl, Sandra M.; Rychlik, Michael; Müller, Marina

doi:10.3389/fmicb.2018.01368

Cited by 44 publications

(65 citation statements)

References 65 publications

(118 reference statements)

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“…The characterization of the full extract by LC-MS revealed TeA, a rather weak toxin, to be the most abundant constituent. However, the most outstanding result of the extract analysis arises from comparison of the toxin pattern to the metabolome of other Alternaria strains (Zwickel et al 2018). Under the applied culture conditions, DSM 62010 apparently produces much higher amounts of the perylene quinones ATX-I, ATX-II, AP and STE-III (Table 1).…”

Section: Discussionmentioning

confidence: 99%

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Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro

et al. 2019

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Alternaria molds can produce a variety of different mycotoxins, often resulting in food contamination with chemical mixtures, posing a challenge for risk assessment. Some of these metabolites possess estrogenic properties, an effect whose toxicological relevance is questioned in the light of the strong genotoxic and cytotoxic properties of co-occurring toxins. Thus, we tested a complex extract from A. alternata for estrogenic properties in Ishikawa cells. By assessing alkaline phosphatase activity, we did not observe estrogen receptor (ER) activation at non-cytotoxic concentrations (≤ 10 µg/ml). Furthermore, an extract stripped of highly genotoxic perylene quinones also did not mediate estrogenic effects, despite diminished genotoxic properties in the comet assay (≥ 10 µg/ml). Interestingly, both extracts impaired the estrogenicity of 17β-estradiol (E2) at non-cytotoxic concentrations (5-10 µg/ml), indicating anti-estrogenic effects which could not be explained by the presence of known mycoestrogens. A mechanism for this unexpected result might be the activation of the aryl hydrocarbon receptor (AhR) by Alternaria metabolites, as indicated by the induction of CYP1A1 transcription. While a direct influence on the metabolism of E2 could not be confirmed by LC-MS/MS, literature describing a direct interplay of the AhR with estrogenic pathways points to a corresponding mode of action. Taken together, the present study indicates AhR-mediated anti-estrogenic effects as a novel mechanism of naturally co-occurring Alternaria toxin mixtures. Furthermore, our results confirm their genotoxic activity and raise questions about the contribution of still undiscovered metabolites to toxicological properties.

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Section: Discussionmentioning

confidence: 99%

“…Alternaria spp. produce a cocktail of secondary metabolites, whereby the composition depends on the fungal strain and the respective growth conditions (Zwickel et al 2016(Zwickel et al , 2018. The metabolite of highest prevalence in food samples is usually tenuazonic acid (TeA), a tetramic acid derivative (Fig.…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro

et al. 2019

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“…are tenuazonic acid, a substance with quite low and solely acute toxic properties, and alternariol (AOH, Fig. 1) (Zwickel et al 2018). Regarding the toxicity of Alternaria contaminations, the latter is considered a lead compound, as it was repeatedly found in commercial food samples and was reported to exert a number of distinct adverse bioactivities (Ostry 2008;Puntscher et al 2018b).…”

Section: Introductionmentioning

confidence: 99%

“…Several additional metabolites, e.g., altenusin, altenuene, iso-altenuene or altenuisol are produced by Alternaria spp. in considerably low concentrations (Zwickel et al 2018) and although a few studies addressed potential adverse effects, they still need to be thoroughly characterized from a toxicological point of view.…”

Section: Introductionmentioning

confidence: 99%

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

et al. 2020

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Emerging mycotoxins produced by Alternaria spp. were previously reported to exert cytotoxic, genotoxic, but also estrogenic effects in human cells. The involved mechanisms are very complex and not fully elucidated yet. Thus, we followed an in silico target fishing approach to extend knowledge on the possible biological targets underlying the activity of alternariol, taken as the signature compound of Alternaria toxins. Combining ligand-based screening and structure-based modeling, the ubiquitous casein kinase 2 (CK2) was identified as a potential target for the compound. This result was validated in a cellfree in vitro CK2 activity assay, where alternariol inhibited CK2 with an IC 50 of 707 nM. As CK2 was recently discussed to influence estrogen receptor (ER) transcription and DNA-binding affinity, we assessed a potential impact on the mRNA levels of ERα or ERβ by qRT-PCR and on nuclear localization of the receptors by confocal microscopy, using estrogen-sensitive Ishikawa cells as a model. While AOH did not affect the transcription of ERα or ERβ, an increase in nuclear localization of ERα after incubation with 10 µM AOH was observed. However, this effect might be due to ER binding affinity and therefore estrogenicity of AOH. Furthermore, in silico docking simulation revealed not only AOH, but also a number of other Alternaria toxins as potential inhibitors of CK2, including alternariol monomethyl ether and the perylene quinone derivative altertoxin II (ATX-II). These findings were representatively confirmed in vitro for the perylene quinone derivative altertoxin II, which was found to inhibit the kinase with an IC 50 of 5.1 µM. Taken together, we propose CK2 inhibition as an additional mechanism to consider in future studies for alternariol and several other Alternaria toxins.

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“…The analysis of further genes resulted in distinct Alternaria species clusters . As DNA‐based studies did not always match the species‐groups defined in morphological surveys, excreted metabolites produced by the fungi were analyzed by HPLC‐UV and LC‐MS/MS and used for their differentiation . The species group of A .…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of the Alternaria Mycobolome Using Mass Spectrometry Based Metabolomics

Gotthardt

Kanawati

Schmidt

et al. 2020

Molecular Nutrition Food Res

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Scope: Alternaria fungi are widely distributed plant pathogens infecting grains and vegetables and causing major harvest losses in the field and during postharvest storage. Besides, consumers are endangered by the formation of toxic secondary metabolites. Some of these secondary metabolites are chemically characterized as mycotoxins, but the majority of the Alternaria mycobolome still remains unknown. Methods and results: Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS) and LC-MS/MS are combined for the non-targeted and targeted analysis of the metabolome of three A. alternata isolates and one A. solani isolate. Due to the ultra-high resolution of FTICR-MS, unique molecular formulae are assigned to measured m/z signals. The molecular formulae are matched to entries of the databases Antibase and Kyoto Encyclopedia of Genes and Genomes. The non-targeted analysis of the fungal extracts reveals variations in the secondary metabolite profile of A. alternata and A. solani. Differences in the biosynthesis of dibenzo--pyrones, perylene quinones, tentoxin, and tenuazonic acid of the A. alternata and A. solani isolates are determined applying targeted LC-MS/MS. Conclusion: FTICR-MS analyses reveal clear differences in the metabolic profile of the A. solani and the A. alternata isolates.

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Chemotaxonomy of Mycotoxigenic Small-Spored Alternaria Fungi – Do Multitoxin Mixtures Act as an Indicator for Species Differentiation?

Cited by 44 publications

References 65 publications

Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro

Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

Comprehensive Analysis of the Alternaria Mycobolome Using Mass Spectrometry Based Metabolomics

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