Department of Environmental and Occupational Health, School of Public Health, Guangdong Medical College, Dongguan 523808, PR China.
Toxicol Lett. 2012 Mar 25;209(3):239-45. doi: 10.1016/j.toxlet.2011.12.020. Epub 2012 Jan 8.
Hydroquinone (HQ), one of the most important metabolites derived from benzene, is known to be associated with acute myelogenous leukemia (AML) risk, however, its carcinogenic mechanism remains unclear. In this study, the epigenetic mechanism of HQ exposure was investigated. We characterized the epigenomic response of TK6 cells to HQ exposure, and examined the mRNA expression of DNA methyltransferases (DNMTs) including DNMT1, DNMT3a and DNMT3b, methyl-CpG-binding domain protein 2 (MBD2) and six proto-oncogenes (MPL, RAF1, MYB, MYC, ERBB2 and BRAF). Compared to the control cells, HQ exposure (2.5, 5.0, 10.0 and 20.0 μM for 48 h) resulted in the decrease of DNMTs and MBD2 expression, the global hypomethylation and increase of MPL at mRNA level. Meanwhile, most of these changes were in dose-dependent manner. Moreover, inhibition of DNMTs induced by 5-aza-2'-deoxycytidine (5-AZA), an identified DNMT inhibitor, caused more induction of MPL expression at mRNA level compared to the HQ (10.0 μM) pre-treated group. Furthermore, treatment of HQ potentially led to MPL itself hypomethylation (10.0 and 20.0 μM reduced by 47% and 44%, respectively), further revealing that the activation of proto-oncogene MPL was related to hypomethylation in its DNA sequences. In conclusion, hypomethylation, including global and specific hypomethylation, might be involved in the activation of MPL, and the hypomethylation could be induced by decreased DNMTs in TK6 cells exposed to HQ.
对苯二酚（HQ）是苯的最重要代谢物之一，已知与急性髓细胞性白血病（AML）风险相关，但致癌机制尚不清楚。在这项研究中，研究了 HQ 暴露的表观遗传机制。我们描述了 TK6 细胞暴露于 HQ 后的表观基因组反应，并检查了包括 DNA 甲基转移酶（DNMT）1、DNMT3a 和 DNMT3b、甲基-CpG 结合域蛋白 2（MBD2）和六个原癌基因（MPL、RAF1、MYB、MYC、ERBB2 和 BRAF）在内的 DNA 甲基转移酶的 mRNA 表达。与对照细胞相比，HQ 暴露（2.5、5.0、10.0 和 20.0 μM 持续 48 h）导致 DNMTs 和 MBD2 表达降低、全局去甲基化和 MPL 在 mRNA 水平上的增加。同时，这些变化大多数呈剂量依赖性。此外，DNMT 抑制剂 5-氮杂-2'-脱氧胞苷（5-AZA）抑制 DNMTs 的作用，导致与 HQ（10.0 μM）预处理组相比，MPL 的 mRNA 表达水平更高。此外，HQ 处理可能导致 MPL 自身去甲基化（10.0 和 20.0 μM 分别减少 47%和 44%），进一步表明原癌基因 MPL 的激活与 DNA 序列的低甲基化有关。总之，低甲基化，包括全局和特定低甲基化，可能与 MPL 的激活有关，并且 HQ 暴露的 TK6 细胞中 DNMTs 的减少可能会诱导低甲基化。
