Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
Exp Mol Pathol. 2014 Jun;96(3):300-6. doi: 10.1016/j.yexmp.2014.03.008. Epub 2014 Mar 27.
It is well known that benzene is a hematotoxic carcinogen. PTEN promoter methylation is a representative example of transcriptional silencing of tumor suppressor genes. However, the effect of PTEN methylation on benzene-induced hematotoxicity has not yet been elucidated. In this study, the animal model of benzene hematotoxicity was successfully established. WBC significantly decreased in experimental groups (P < 0.01). Compared with the control group, the weight of rats increased slowly and even declined with increasing doses of benzene in the benzene-treated groups. An increase in the level of PTEN methylation was observed in the low dose group, and PTEN methylation level increased significantly in a dose-dependent manner. However, it was interesting that PTEN mRNA expression increased in the low dose group, but declined with increasing doses of benzene. The decrease of tumor suppressor function caused by PTEN methylation may be an important mechanism of benzene hematotoxicity. Furthermore, lymphoblast cell line F32 was incubated by benzene and then treated with 5-aza and TSA, alone or in combination. A dramatic decrease in the PTEN mRNA expression and a significant increase of PTEN methylation level in benzene-treated cells were also shown. PTEN mRNA expression was up regulated and PTEN methylation level was reduced by the epigenetic inhibitors, 5-aza and TSA. In conclusion, PTEN methylation is involved in benzene-induced hematotoxicity through suppressing PTEN mRNA expression.
众所周知，苯是一种血液毒性致癌物质。PTEN 启动子甲基化是肿瘤抑制基因转录沉默的代表性例子。然而，PTEN 甲基化对苯诱导的血液毒性的影响尚未阐明。在本研究中，成功建立了苯血液毒性的动物模型。实验组的白细胞（WBC）显著减少（P<0.01）。与对照组相比，随着苯剂量的增加，苯处理组大鼠的体重增长缓慢，甚至下降。在低剂量组观察到 PTEN 甲基化水平升高，并且 PTEN 甲基化水平呈剂量依赖性显著增加。然而，有趣的是，低剂量组中 PTEN mRNA 表达增加，但随着苯剂量的增加而下降。PTEN 甲基化引起的肿瘤抑制功能的丧失可能是苯血液毒性的重要机制。此外，用苯孵育淋巴母细胞系 F32，然后单独或联合用 5-氮杂胞苷和 TSA 处理。苯处理细胞中也显示出 PTEN mRNA 表达显著降低和 PTEN 甲基化水平显著增加。表观遗传抑制剂 5-氮杂胞苷和 TSA 可上调 PTEN mRNA 表达并降低 PTEN 甲基化水平。总之，PTEN 甲基化通过抑制 PTEN mRNA 表达参与苯诱导的血液毒性。
