Karaman Ecem Fatma, Abudayyak Mahmoud, Guler Zeynep Rana, Ozden Sibel
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Biruni University, Topkapi, 34015, Istanbul, Turkey.
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Beyazit, 34116, Istanbul, Turkey.
Chem Biol Interact. 2025 Sep 5;418:111585. doi: 10.1016/j.cbi.2025.111585. Epub 2025 May 28.
Zearalenone (ZEA), a non-steroidal estrogenic mycotoxin produced by Fusarium species, is well-known for its potent estrogen-like effects, which can lead to reproductive toxicity and toxicity in various organs. Although several studies have reported its nephrotoxic effects, the molecular mechanisms underlying ZEA-induced toxicity remain poorly understood. The present study investigates the effects of ZEA on the expression levels of apoptosis and endoplasmic reticulum (ER) stress-related genes, as well as selected chromatin-modifying enzyme coding genes, miRNA profiles associated with cancer pathways, and global histone modifications (H3K4me3, H3K9me3, H3K27me3, and H3K9ac) in human embryonic kidney epithelial (HEK-293) cells exposed to 1-50 μM ZEA for 24 h. The results indicated that 10 and 50 μM ZEA induced apoptosis through upregulating Bcl-2, CASP3, CASP9, and p53. Alterations in the expression levels of ER stress-related genes, such as GRP78, PERK, ATF4, IRE2, CHOP, and eIF2α, could contribute to ZEA-induced toxicity. No significant changes were observed in the expression levels of chromatin-modifying enzyme coding genes, including EZH2, G9a, HAT1, RIZ1, SETD1A, and SIRT1, DNA methylation-related genes such as DNMT1, DNMT3A, and DNMT3B. However, SETD8 and Suv39h1 exhibited significant changes at 50 μM of ZEA. Moreover, global histone modification levels significantly decreased at 50 μM ZEA exposure for 24 h. Chromatin immunoprecipitation (ChIP) results revealed significant changes in H3K27me3, H3K9me3, and H3K9ac modifications on the ATF4, CHOP, Bcl-2, and p53 genes following ZEA exposure. miRNA array analysis showed notable and significant reductions in the expression levels of several miRNAs. The results obtained from this comprehensive study are expected to make a significant contribution to the elucidation of ZEA toxicity.
玉米赤霉烯酮（ZEA）是一种由镰刀菌属产生的非甾体雌激素类霉菌毒素，以其强大的雌激素样作用而闻名，这种作用可导致生殖毒性和多器官毒性。尽管多项研究报道了其肾毒性作用，但ZEA诱导毒性的分子机制仍知之甚少。本研究调查了ZEA对人胚肾上皮（HEK - 293）细胞中凋亡和内质网（ER）应激相关基因的表达水平、选定的染色质修饰酶编码基因、与癌症通路相关的miRNA谱以及整体组蛋白修饰（H3K4me3、H3K9me3、H3K27me3和H3K9ac）的影响，这些细胞暴露于1 - 50 μM ZEA 24小时。结果表明，10和50 μM ZEA通过上调Bcl - 2、CASP3、CASP9和p53诱导细胞凋亡。ER应激相关基因（如GRP78、PERK、ATF4、IRE2、CHOP和eIF2α）表达水平的改变可能导致ZEA诱导的毒性。在包括EZH2、G9a、HAT1、RIZ1、SETD1A和SIRT1在内的染色质修饰酶编码基因以及DNA甲基化相关基因（如DNMT1、DNMT3A和DNMT3B）的表达水平上未观察到显著变化。然而，在50 μM ZEA时，SETD8和Suv39h1表现出显著变化。此外，在暴露于50 μM ZEA 24小时时，整体组蛋白修饰水平显著降低。染色质免疫沉淀（ChIP）结果显示，ZEA暴露后，ATF4、CHOP、Bcl - 2和p53基因上的H3K27me3、H3K9me3和H3K9ac修饰发生了显著变化。miRNA阵列分析显示几种miRNA的表达水平有显著降低。这项综合研究获得的结果有望为阐明ZEA毒性做出重大贡献。
