Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and α-zearalenol
Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and α-zearalenol
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DOI：
10.1016/j.toxlet.2020.02.015
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发表时间：
2020-06-15
影响因子：
3.5
通讯作者：
Ozden, Sibel
中科院分区：
文献类型：
--
作者：
Karaman, Ecem Fatma;Zeybel, Mujdat;Ozden, Sibel
玉米赤霉烯酮是一种由镰刀菌属真菌产生的非甾体类雌激素类真菌毒素，污染谷物，对人类健康产生不良影响。我们研究了玉米赤霉烯酮及其代谢产物α-玉米赤霉烯醇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。玉米赤霉烯酮和α-玉米赤霉烯醇在1、10和50 μ M的浓度下显著增加了DNA甲基化和组蛋白修饰的总体水平（H3 K27 me 3、H3 K9 me 3、H3 K9 ac）。染色质修饰酶EHMT 2，ESCO 1，HAT 1，KAT 2B，PRMT 6和SETD 8的表达水平上调50 μ M的玉米赤霉烯酮暴露使用PCR阵列，与全球组蛋白修饰的结果一致。玉米赤霉烯酮和α-玉米赤霉烯醇还改变了AhR、LXR α、PPAR α、PPAR γ、L-fabp、LDLR、Glut 2、Akt 1和HK 2基因的表达水平，这些基因与核受体和代谢途径有关。从这些基因中选择脂质代谢的关键调节因子PPARgamma用于进一步分析。在玉米赤霉烯酮暴露后，PPAR γ启动子显著降低甲基化。总之，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，玉米赤霉烯酮在代谢途径中的作用可能是通过表观遗传修饰介导的。
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 mu M 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 mu M 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, LXR alpha, PPAR alpha, PPAR gamma, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to nuclear receptors and metabolic pathways. PPAR gamma, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPAR gamma 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.