表观遗传诱导的细胞毒性变化及其机制——镰刀菌毒素（伏马菌素B1和镰刀菌酸）和展霉素的最新进展

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters Pub Date : 2025-09-01 DOI:10.1016/j.toxlet.2025.07.079

A. Chuturgoon, T. Ghazi

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引用次数: 0

摘要

镰刀菌毒素（伏马菌素B1和镰刀菌酸）和棒曲霉素是食源性真菌毒素，已知具有致突变、致癌和遗传毒性作用。最近的研究强调了它们诱导导致器官毒性的表观遗传修饰的能力。镰刀菌毒素是经济上最重要的毒素，其中伏马菌素B1 （FB1）毒性最大，镰刀菌酸（FA）是一种被忽视的毒素，被认为是轻度毒性。FB1抑制鞘脂生物合成并改变细胞存活和死亡过程，而FA被证明是一种降压剂，改变脑神经化学和一种假定的线粒体毒素。这两种毒素都会改变宿主的表观基因组，从而导致不良的健康结果。FB1通过调节DNA甲基化和组蛋白修饰来改变表观遗传景观，从而导致染色质不稳定和致癌。FB1增加PTEN启动子上的H3K4Me3，增强其转录，但通过miR-30c抑制其翻译，从而激活PI3K/AKT通路，损害DNA损伤检查点调节。FA触发整体DNA低甲基化，上调miR-29b并增加MBD2的表达。FA通过降低H3K9me3水平影响组蛋白修饰，从而破坏基因组不稳定性并诱导细胞凋亡，由青霉属产生的展曲霉素（Pat）诱导可导致肾损伤的表观遗传变化。Pat破坏α-1和α-2肾上腺素能受体信号通路并改变DNA甲基化模式；它上调DNMT1和MBD2（去甲基化酶），导致DNA低甲基化。这些表观遗传修饰影响基因表达，对健康造成不利影响。表观遗传修饰涉及多种人类疾病，包括致癌。FB1、FA和Pat诱导体外、动物模型和人的表观遗传变化。我们的数据显示，FA具有遗传毒性，并且翻译后修饰p53和m6A RNA甲基化。FB1诱导DNA整体低甲基化，调控miR27b表达和细胞凋亡；并促成了另一种肿瘤转化模式。此外，FB1在人类脑肿瘤组织样本中免疫定位（49/76），许多患者具有匹配的高血清FB1水平。总之，结果表明，这三种真菌毒素改变表观遗传景观和促进疾病。

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S12-01 Epigenetic induced changes and mechanisms of celluoar toxicity- an update on fusariotoxins (Fumonisin B1 and Fusaric acid) and Patulin

Fusariotoxins (Fumonisin B1 and Fusaric acid) and Patulin are foodborne mycotoxins known for their mutagenic, carcinogenic and genotoxic effects. Recent studies have highlighted their ability to induce epigenetic modifications that contribute to organ toxicity.

Fusarium mycotoxins are the most economically important toxins with fumonisin B1 (FB1) being the most toxic and fusaric acid (FA), a neglected toxin, regarded as mildly toxic. FB1 inhibits sphingolipid biosynthesis and modifies cell survival and cell death processes, whilst FA was shown to be a hypotensive agent, altered brain neurochemistry and a putative putative mitochondrial toxin. Both these toxins alter the host epigenome that can lead to adverse health outcomes. FB1 alters the epigenetic landscape by modulating DNA methylation and histone modifications which can lead to chromatin instability and carcinogenesis. FB1 increases H3K4Me3 at the PTEN promoter, enhancing its transcription but inhibiting its translation via miR-30c, thereby activating the PI3K/AKT pathway and impairing DNA damage checkpoint regulation.

FA triggers global DNA hypomethylation, upregulates miR-29b and increases expression of MBD2. FA affects histone modifications by reducing levels of H3K9me3, which disrupts genome instability and induces apoptosis Patulin (Pat), produced by Penicllium species, induces epigenetic changes that can lead to kidney injury. Pat disrupts α-1 and α-2 adrenergic receptor signalling pathways and alters DNA methylation patterns; it upregulates DNMT1 and MBD2 (demethylase) that results in DNA hypomethylation. These epigenetic modifications influence gene expression and contributes to adverse health effects.

Epigenetic modifications have been implicated in various human diseases, including carcinogenesis. FB1, FA and Pat induced epigenetic changes in in vitro, animal models and humans. Our data showed that FA was genotoxic and post-translationally modified p53 and m6A RNA methylation. FB1 induced global DNA hypomethylation, modulated miR27b expression and apoptosis; and contributed to an additional mode of neoplastic transformation. Further, FB1 was immunolocalised in human brain tumour tissue samples (49/76), with many patients having matched high serum FB1 levels.

In conclusion, the results show that that these three mycotoxins alter the epigenetic landscape and contribute to disease.

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