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.
摘要：
伏马菌素B1（FB1）对动物和人类健康构成风险。虽然FB1对鞘脂代谢的影响是有据可查的，只有有限的研究涵盖了与FB1肾毒性引起的致癌途径相关的表观遗传修饰和早期分子改变.本研究调查了FB1对全局DNA甲基化的影响，染色质修饰酶，暴露24小时后，人肾细胞（HK-2）中p16基因的组蛋白修饰水平。在100μmol/L时观察到5-甲基胞嘧啶（5-mC）的水平增加（2.23倍），这种变化独立于DNA甲基转移酶1（DNMT1）在50和100μmol/L时的基因表达水平下降；然而，DNMT3a和DNMT3b在100μmol/L的FB1时显著上调。FB1暴露后观察到染色质修饰基因的剂量依赖性下调。此外,染色质免疫沉淀结果显示，10μmol/L的FB1诱导H3K9ac显著降低，H3K9me3和H3K27me3修饰p16，而100µmol/L的FB1导致p16的H3K27me3水平显着增加。一起来看,结果提示表观遗传机制可能通过DNA甲基化在FB1癌变过程中发挥作用,以及组蛋白和染色质修饰。
