郝小吉¹,
尚小娜^1,3,
于海华²,
么建萍²,
韩璐²,
刘晓晖¹,
李亚晨¹,
邵静¹
1. 大连医科大学公共卫生学院, 大连市血液病重点实验室, 辽宁省造血干细胞移植医学中心, 辽宁省造血干细胞移植临床转化医学研究重点实验室, 大连 116044;
2. 大连市妇幼保健院, 大连 116033;
3. 康龙化成(北京)新药技术股份有限公司, 北京 100176

作者简介: 郝小吉(1991-),男,硕士研究生,研究方向为劳动卫生与环境卫生学,E-mail:849246840@qq.com.

基金项目: 国家自然科学基金(81773389，81273031)；大连医科大学教学改革研究项目(DYLX16053)


中图分类号: X171.5

Effect of Hexabromocyclododecane (HBCD) on the Expressions of Deiodinases 2 and 3 in the Human Neuroglioma H4 Cells and Neuroblastoma SK-N-AS Cells

Hao Xiaoji¹,
Shang Xiaona^1,3,
Yu Haihua²,
Yao Jianping²,
Han Lu²,
Liu Xiaohui¹,
Li Yachen¹,
Shao Jing¹
1. School of Public Health, Dalian Medical University, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian 116044, China;
2. Maternal and Child Care Service Centre of Dalian, Dalian 116033, China;
3. Pharmaron Beijing Co., Ltd. (China), Beijing 100176, China

CLC number: X171.5

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摘要:六溴环十二烷(hexabromocyclododecane, HBCD)与多溴联苯醚(polybrominated diethyl ethers, PBDEs)复合污染体系，对人类健康尤其神经系统所造成的潜在危害及其机制一直是笔者课题组的研究方向。HBCD是广泛使用的溴化阻燃剂，与PBDEs一样，会通过干扰内分泌系统、影响甲状腺激素分泌及损伤神经系统，对生物体产生发育神经毒性。作为系列研究之一，本研究以H4人脑神经胶质瘤细胞和SK-N-AS人神经母细胞瘤细胞为体外生物模型，通过观察HBCD对H4细胞Ⅱ型脱碘酶(Dio2)和SK-N-AS细胞Ⅲ型脱碘酶(Dio3)表达的调控，初步探讨了HBCD对神经系统局部甲状腺激素水平的潜在影响。H4细胞和SK-N-AS细胞分别暴露于0、1、3和9 μmol·L^-1 HBCD 24 h后，采用MTT法检测细胞活力，Western Blot和RT-PCR法分别分析Dio2和Dio3蛋白和基因的表达，酶联免疫吸附测定(ELISA)法检测H4细胞脑源性神经细胞营养因子(BDNF)的分泌。结果表明，HBCD以剂量依赖方式降低H4细胞和SK-N-AS细胞生存率，引起H4细胞Dio2蛋白和基因表达下调，而致SK-N-AS细胞Dio3蛋白和基因表达上调。此外，HBCD还降低H4细胞BDNF的分泌。这表明，HBCD很可能通过影响神经和胶质细胞脱碘酶的表达，影响脑局部甲状腺激素水平，从而引起神经系统损伤及发育神经毒性。
关键词: 六溴环十二烷/
H4细胞/
SK-N-AS细胞/
神经毒性/
脱碘酶

Abstract:Being one of the chemicals in the complex of persistent organic pollutants, hexabromocyclododecane (HBCD), as a widely used brominated flame retardant, has been known to cause disturbance in the endocrine system, in particular, the thyroid hormone system, which may underlie its neurotoxicity and developmental neurotoxicity. This current study used the human H4 neuroglioma cells and human SK-N-AS neuroblastoma cells as the in vitro models, to investigate the effects of HBCD on the type 2 iodothyroninedeiodinase (Dio2) expression in the H4 cells and the type 3 iodothyroninedeiodinase (Dio3) expression in the SK-N-AS cells. Briefly, the H4 and SK-N-AS cells were separately exposed to HBCD for 24 h, and the cell viability was examined by the methyl-thiazolyl-tetrazolium (MTT) method; the levels of Dio2 and Dio3 protein and mRNA expression were quantitated by the Western Blot and the qRT-PCR, respectively; in addition, the secretion of brain-derived neurotrophic factor (BDNF) was examined by the ELISA in the H4 cells. The data showed that HBCD led to a loss of cell viability in both cell types in a dose-dependent manner; HBCD caused the reduction of both Dio2 protein and mRNA expressions in the H4 cells, and the elevation in the Dio3 protein and mRNA expressions in the SK-N-AS cells; moreover, HBCD also reduced the secretion of BDNF in the H4 cells as detected in the culture medium. Our data suggest that HBCD is likely to modulate the local level of thyroid hormones (in particular T3) in the brain by affecting the expression of deiodinated enzymes in the neurons and the glia, thereby resulting in the HBCD-mediated neurotoxicity and developmental neurotoxicity.
Key words:hexabromocyclododecane (HBCD)/
human neuroblastoma cells (SK-N-AS)/
human neuroglioma cells (H4)/
neurotoxicity/
deiodinase.