Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit, Istanbul, Turkey.
Department of Gastroenterology and Hepatology, School of Medicine, Koç University, 34010, Topkapi, Istanbul, Turkey.
Toxicol Lett. 2020 Jun 15;326:52-60. doi: 10.1016/j.toxlet.2020.02.015. Epub 2020 Feb 28.
Zearalenone, produced by various Fusarium species, is a non-steroidal estrogenic mycotoxin that contaminates cereals, resulting in adverse effects on human health. We investigated the effects of zearalenone and its metabolite alpha zearalenol on epigenetic modifications and its relationship with metabolic pathways in human hepatocellular carcinoma cells following 24 h of exposure. Zearalenone and alpha zearalenol at the concentrations of 1, 10 and 50 μM significantly increased global levels of DNA methylation and global histone modifications (H3K27me3, H3K9me3, H3K9ac). Expression levels of the chromatin modifying enzymes EHMT2, ESCO1, HAT1, KAT2B, PRMT6 and SETD8 were upregulated by 50 μM of zearalenone exposure using PCR arrays, consistent with the results of global histone modifications. Zearalenone and alpha zearalenol also changed expression levels of the AhR, LXRα, PPARα, PPARɣ, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to nuclear receptors and metabolic pathways. PPARɣ, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPARɣ promoter reduced methylation significantly following zearalenone exposure. Taken together, the epigenetic mechanisms of DNA methylation and histone modifications may be key mechanisms in zearalenone toxicity. Furthermore, effects of zearalenone in metabolic pathways could be mediated by epigenetic modifications.
玉米赤霉烯酮是由多种镰刀菌产生的一种非甾体类雌激素真菌毒素，可污染谷物，对人类健康造成不良影响。我们研究了玉米赤霉烯酮及其代谢物α-玉米赤霉烯醇在暴露 24 小时后对人肝癌细胞表观遗传修饰的影响及其与代谢途径的关系。1、10 和 50 μM 的玉米赤霉烯酮和α-玉米赤霉烯醇显著增加了 DNA 甲基化和组蛋白修饰（H3K27me3、H3K9me3、H3K9ac）的整体水平。使用 PCR 阵列检测到 50 μM 玉米赤霉烯酮暴露可上调染色质修饰酶 EHMT2、ESCO1、HAT1、KAT2B、PRMT6 和 SETD8 的表达水平，这与整体组蛋白修饰结果一致。玉米赤霉烯酮和α-玉米赤霉烯醇还改变了与核受体和代谢途径相关的 AhR、LXRα、PPARα、PPARγ、L-fabp、LDLR、Glut2、Akt1 和 HK2 基因的表达水平。在这些基因中，选择了关键的脂质代谢调节因子 PPARγ进行进一步分析。PPARγ启动子在玉米赤霉烯酮暴露后甲基化显著降低。综上所述，DNA 甲基化和组蛋白修饰的表观遗传机制可能是玉米赤霉烯酮毒性的关键机制。此外，玉米赤霉烯酮对代谢途径的影响可能是通过表观遗传修饰介导的。
