曾柳丹^1,2,
马慧敏^1,,,
张干¹,
于志强¹,
盛国英¹,
傅家谟¹
1. 中国科学院广州地球化学研究所 有机地球化学国家重点实验室和广东省环境资源利用与保护重点实验室, 广州 510640;
2. 中国科学院研究生院, 北京 100049

作者简介: 曾柳丹(1989-),女,硕士研究生,研究方向为环境污染物与表观遗传学,E-mail:zengliudan@gig.ac.cn.

通讯作者: 马慧敏,mahuimin@gig.ac.cn ;

基金项目: 国家青年基金(NSFC-21007072)
有机地球化学国家重点实验室开放基金(SKLOG2015A02)
广东省环境资源利用与保护重点实验室开放运行费(2014B03031060)


中图分类号: X171.5

Cl-BDE-208 and BDE-209 Induce LINE-1 Gene Hypomethylation and ESR1 Gene Hypermethylation

Zeng Liudan^1,2,
Ma Huimin^1,,,
Zhang Gan¹,
Yu Zhiqiang¹,
Sheng Guoying¹,
Fu Jiamo¹
1. State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China;
2. Graduate School of the Chinese Academy of Science, Beijing 100049, China

Corresponding author: Ma Huimin,mahuimin@gig.ac.cn ;

CLC number: X171.5

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摘要:十溴联苯醚(BDE-209)是使用最多的一种多溴阻燃剂，由于具有高亲脂性和低挥发性，容易蓄积在生物体内，在人体血清、母乳、肝脏等组织中均有检出；其环境脱溴产物九溴一氯联苯醚(Cl-BDE-208)也在血清样品和环境样品中被频频检出，而目前对这种化合物的毒理学研究，特别是对人体早期健康效应的研究较少。为了评估Cl-BDE-208和BDE-209的早期健康效应，以人乳腺癌细胞MCF-7为模型，环境相关浓度(0.375~3 μmol·L^-1)为暴露浓度，检测Cl-BDE-208和BDE-209对重复序列LINE-1、全基因组DNA甲基化(GDM)和雌激素受体基因(包括ESR1和ESR2)甲基化水平的改变。结果表明，Cl-BDE-208和BDE-209都可能通过降低DNA甲基化转移酶(DNMTs)活性而诱导了LINE-1和GDM的低甲基化，8-羟基脱氧鸟苷(8-OHdG)水平的升高可能参与了BDE-209引起的低甲基化过程；同时通过促进雌激素受体α(ESR1)基因的高甲基化而显著下调了ESR1基因的表达，而对雌激素受体β(ESR2)基因甲基化水平并没有显著影响。Cl-BDE-208和BDE-209都可能通过改变DNA甲基化水平而影响人体的早期健康效应，同时ESR1基因的高甲基化可能是Cl-BDE-208和BDE-209引起内分泌毒性的机制之一。
关键词: Cl-BDE-208/
BDE-209/
DNA甲基化/
LINE-1/
ESR1/
环境相关浓度

Abstract:Decabromodiphenyl ether (BDE-209) is the mostly used compound of polybrominated flame retardants. The high lipid solubility and low vapor pressure contribute to their bioaccumulation. BDE-209 has been detected in human blood, milk, and liver tissues. Monochloro-nonabromo diphenyl ethers (Cl-BDE-208), the environmental metabolite of BDE-209 is also found in human tissues, but the information of Cl-BDE-208 and BDE-209 toxicity is limited. The objective of this study is to investigate whether environmental relative concentrations BDE-209 and Cl-BDE-208 (0.375-3 μmol·L^-1) could cause DNA methylation changes of several DNA methylation biomarkers in MCF-7 cells, including repetitive elements (LINE-1), global DNA methylation (GDM) and estrogen receptor gene (ESR1 and ESR2), and to explore the possible mechanism. Results showed that Cl-BDE-208 and BDE-209 down-regulated LINE-1 and global DNA methylation through DNMTs activity decrease, and 8-OHdG level increase may be involved in BDE-209-induced hypomethylation. More interesting, Cl-BDE-208 and BDE-209 inhibited ESR1 gene expression by promoting the DNA methylation in promoter area, while both compounds have no effects on ESR2 gene. Results suggested that Cl-BDE-208 and BDE-209 have the adverse health outcomes, and ESR1 gene hypermethylation may be the potential mechanism of endocrine toxicity of BDE-209.
Key words:Cl-BDE-208/
BDE-209/
DNA methylation/
LINE-1/
ESR1/
environmental relative concentrations.