Resolving complexity: Identification of altersetin and toxin mixtures responsible for the immunomodulatory, antiestrogenic and genotoxic potential of a complex Alternaria mycotoxin extract

IF 3.5 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY Food and Chemical Toxicology Pub Date : 2025-02-09 DOI:10.1016/j.fct.2025.115315

Vanessa Partsch , Francesco Crudo , Daniel Piller , Elisabeth Varga , Giorgia Del Favero , Doris Marko

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Abstract

Alternaria mycotoxins may pose significant risks to human health due to their diverse spectrum of adverse effects and frequent occurrences in food. A previous study demonstrated the immunosuppressive, antiestrogenic, and genotoxic potential of a complex Alternaria mycotoxin extract (CE). The present study aimed to elucidate specific Alternaria mycotoxins or combinations thereof responsible for toxicity.

Following toxicity-guided fractionation of the CE, a multiparametric panel of assays was applied to assess different endpoints. These included immunomodulatory effects (NF-κB reporter gene assay in THP1-Lucia™ monocytes), estrogenicity/antiestrogenicity (alkaline phosphatase assay in Ishikawa cells) and genotoxicity (γH2AX and alkaline comet assays in HepG2 cells).

LC-MS/MS analysis revealed prominent mycotoxins in the active fractions, with altersetin (AST) identified as a novel key compound exhibiting immunoinhibitory (≥2 μM) and antiestrogenic (≥5 μM) properties in vitro. Additionally, while specific mycotoxin combinations explained the toxicity of active fractions, some effects remained unexplained, suggesting the presence of unidentified bioactive substances.

This study underscores the significance of AST and specific toxin mixtures as major contributors to CE toxicity. Further, it highlights the importance of considering combinatory effects in risk assessment of Alternaria mycotoxins as well as further investigation of unknown Alternaria metabolites, which may pose additional health risks.

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解决复杂性：鉴定替代素和毒素混合物负责免疫调节，抗雌激素和遗传毒性的复杂交替菌毒素提取物的潜力。

交替菌毒素的不良影响范围广泛，而且在食物中经常出现，可能对人类健康构成重大风险。先前的一项研究表明，复杂的交替菌毒素提取物（CE）具有免疫抑制、抗雌激素和遗传毒性的潜力。本研究旨在阐明特定的交替菌毒素或其组合负责毒性。在毒性指导下对CE进行分离后，采用多参数分析小组来评估不同的终点。这些包括免疫调节作用（在THP1-Lucia™单核细胞中进行NF-κB报告基因试验），雌激素性/抗雌激素性（在Ishikawa细胞中进行碱性磷酸酶试验）和遗传毒性（在HepG2细胞中进行γH2AX和碱性彗星试验）。LC-MS/MS分析显示，活性组分中含有明显的真菌毒素，其中altersetin （AST）是一个新的关键化合物，在体外具有免疫抑制（≥2 μM）和抗雌激素（≥5 μM）的特性。此外，虽然特定的真菌毒素组合解释了活性部分的毒性，但一些影响仍然无法解释，这表明存在未识别的生物活性物质。该研究强调了AST和特定毒素混合物作为CE毒性主要贡献者的重要性。此外，它还强调了在对交替菌真菌毒素进行风险评估以及进一步调查未知交替菌代谢物时考虑组合效应的重要性，这可能会造成额外的健康风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.