Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
Shantou Medical College, Shantou University, Guangdong, China.
Environ Pollut. 2018 Mar;234:127-135. doi: 10.1016/j.envpol.2017.11.042. Epub 2017 Nov 22.
In this study, we explore whether altered global histone modifications respond to low-level benzene exposure as well as their association with the hematotoxicity. We recruited 147 low-level benzene-exposed workers and 122 control workers from a petrochemical factory in Maoming City, Guangdong Province, China. The internal exposure marker level, urinary S-phenylmercapturic acid (SPMA), in benzene-exposed workers was 1.81-fold higher than that of the controls (P < 0.001). ELISA method was established to examine the specific histone modifications in human peripheral blood lymphocytes (PBLCs) of workers. A decrease in the counts of white blood cells (WBC), neutrophils, lymphocytes, and monocytes appeared in the benzene-exposed group (all P < 0.05) compared to the control group. Global trimethylated histone 3 lysine 4 (H3K4me3) modification was enhanced in the benzene-exposed group (P < 0.05) and was positively associated with the concentration of urinary SPMA (β = 0.103, P = 0.045) and the extent of DNA damage (% Tail DNA: β = 0.181, P = 0.022), but was negatively associated with the leukocyte count (WBC: β = -0.038, P = 0.023). The in vitro study revealed that H3K4me3 mark was enriched in the promoters of several DNA damage responsive (DDR) genes including CRY1, ERCC2, and TP53 in primary human lymphocytes treated with hydroquinone. Particularly, H3K4me3 modification was positively correlated with the expression of CRY1 in the PBLCs of benzene-exposed workers. These observations indicate that H3K4me3 modification might mediate the transcriptional regulation of DDR genes in response to low-dose benzene exposure.
在这项研究中，我们探讨了低水平苯暴露是否会引起整体组蛋白修饰的改变，以及这些改变与血液毒性之间的关系。我们招募了来自中国广东省茂名市一家石化厂的 147 名低水平苯暴露工人和 122 名对照工人。苯暴露工人的内暴露标志物水平，即尿 S-苯巯基尿酸（SPMA），比对照组高 1.81 倍（P<0.001）。我们建立了 ELISA 方法来检测工人外周血淋巴细胞（PBLCs）中的特定组蛋白修饰。与对照组相比，苯暴露组的白细胞（WBC）、中性粒细胞、淋巴细胞和单核细胞计数均减少（均 P<0.05）。苯暴露组的全基因组三甲基化组蛋白 3 赖氨酸 4（H3K4me3）修饰增强（P<0.05），且与尿 SPMA 浓度呈正相关（β=0.103，P=0.045）和 DNA 损伤程度呈正相关（%尾 DNA：β=0.181，P=0.022），但与白细胞计数呈负相关（WBC：β=−0.038，P=0.023）。体外研究显示，在经对苯二酚处理的原代人淋巴细胞中，H3K4me3 标记在几个 DNA 损伤反应（DDR）基因的启动子中富集，包括 CRY1、ERCC2 和 TP53。特别是，H3K4me3 修饰与苯暴露工人 PBLCs 中 CRY1 的表达呈正相关。这些观察结果表明，H3K4me3 修饰可能介导了低剂量苯暴露时 DDR 基因的转录调控。
