The role of chromatin-modifying enzymes and histone modifications in the modulation of p16 gene in fumonisin B₁-induced toxicity in human kidney cells.

IF 2.6 4区医学 Q2 MYCOLOGY

Mycotoxin Research Pub Date : 2023-08-01 DOI:10.1007/s12550-023-00494-2

Ecem Fatma Karaman, Mahmoud Abudayyak, Sibel Ozden

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引用次数: 0

Abstract

Fumonisin B₁ (FB₁) poses a risk to animal and human health. Although the effects of FB₁ on sphingolipid metabolism are well documented, there are limited studies covering the epigenetic modifications and early molecular alterations associated with carcinogenesis pathways caused by FB₁ nephrotoxicity. The present study investigates the effects of FB₁ on global DNA methylation, chromatin-modifying enzymes, and histone modification levels of the p16 gene in human kidney cells (HK-2) after 24 h exposure. An increase (2.23-fold) in the levels of 5-methylcytosine (5-mC) at 100 µmol/L was observed, a change independent from the decrease in gene expression levels of DNA methyltransferase 1 (DNMT1) at 50 and 100 µmol/L; however, DNMT3a and DNMT3b were significantly upregulated at 100 µmol/L of FB₁. Dose-dependent downregulation of chromatin-modifying genes was observed after FB₁ exposure. In addition, chromatin immunoprecipitation results showed that 10 µmol/L of FB₁ induced a significant decrease in H3K9ac, H3K9me3 and H3K27me3 modifications of p16, while 100 µmol/L of FB₁ caused a significant increase in H3K27me3 levels of p16. Taken together, the results suggest that epigenetic mechanisms might play a role in FB₁ carcinogenesis through DNA methylation, and histone and chromatin modifications.

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染色质修饰酶和组蛋白修饰在伏马菌素b1诱导的人肾细胞毒性中p16基因调控中的作用。

伏马菌素B1 (FB1)对动物和人类健康构成风险。尽管FB1对鞘脂代谢的影响已被充分记录，但关于FB1肾毒性引起的与致癌途径相关的表观遗传修饰和早期分子改变的研究有限。本研究探讨了暴露24小时后，FB1对人肾细胞(HK-2) p16基因整体DNA甲基化、染色质修饰酶和组蛋白修饰水平的影响。在100µmol/L时观察到5-甲基胞嘧啶(5-mC)水平增加(2.23倍)，这一变化与DNA甲基转移酶1 (DNMT1)基因表达水平在50和100µmol/L时的下降无关;然而，DNMT3a和DNMT3b在100µmol/L FB1下显著上调。FB1暴露后，染色质修饰基因呈剂量依赖性下调。此外，染色质免疫沉淀结果显示，10µmol/L FB1诱导p16的H3K9ac、H3K9me3和H3K27me3修饰显著降低，而100µmol/L FB1诱导p16的H3K27me3修饰水平显著升高。综上所述，结果表明表观遗传机制可能通过DNA甲基化、组蛋白和染色质修饰在FB1致癌过程中发挥作用。

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来源期刊

Mycotoxin Research MYCOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

6.40

自引率

6.70%

发文量

期刊介绍： Mycotoxin Research, the official publication of the Society for Mycotoxin Research, is a peer-reviewed, scientific journal dealing with all aspects related to toxic fungal metabolites. The journal publishes original research articles and reviews in all areas dealing with mycotoxins. As an interdisciplinary platform, Mycotoxin Research welcomes submission of scientific contributions in the following research fields: - Ecology and genetics of mycotoxin formation - Mode of action of mycotoxins, metabolism and toxicology - Agricultural production and mycotoxins - Human and animal health aspects, including exposure studies and risk assessment - Food and feed safety, including occurrence, prevention, regulatory aspects, and control of mycotoxins - Environmental safety and technology-related aspects of mycotoxins - Chemistry, synthesis and analysis.