Inhibition of O-linked N-acetylglucosamine transferase activity in PC12 cells - A molecular mechanism of organophosphate flame retardants developmental neurotoxicity

doi:10.1016/j.bcp.2018.03.017

	Inhibition of O-linked N-acetylglucosamine transferase activity in PC12 cells - A molecular mechanism of organophosphate flame retardants developmental neurotoxicity
	Gu, Yuxin 1,2; Yang, Yu 1; Wan, Bin 1,2; Li, Minjie 3; Guo, Liang-Hong 1,2
刊名	BIOCHEMICAL PHARMACOLOGY
	2018-06-01
卷号	152 页码:21-33
关键词	Organophosphate flame retardants O-linked N-acetylglucosamine transferase Inhibition Developmental neurotoxicity Molecular docking
ISSN号	0006-2952
DOI	10.1016/j.bcp.2018.03.017
英文摘要	Organophosphate flame retardants (OPFRs), as alternatives of brominated flame retardants, can cause neuro-developmental effects similar to organophosphate pesticides. However, the molecular mechanisms underlying the toxicity remain elusive. O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) regulates numerous neural processes through the O-GlcNAcylation modification of nuclear and cytoplasmic proteins. In this study, we aimed to investigate the molecular mechanisms accounting for the developmental neurotoxicity of OPFRs by identifying potential targets of OPFRs and the attendant effects. Twelve OPFRs were evaluated for inhibition of OGT activity using an electrochemical biosensor. Their potency differed with substituent groups. The alkyl group substituted OPFRs had no inhibitory effect. Instead, the six OPFRs substituted with aromatic or chlorinated alkyl groups inhibited OGT activity significantly, with tri-m-cresyl phosphate (TCrP) being the strongest. The six OPFRs (0-100 mu M exposure) also inhibited OGT activity in PC12 cells and decreased protein O-GlcNAcylation level. Inhibition of OGT by OPFRs might be involved in the subsequent toxic effects, including intracellular reactive oxygen species (ROS), calcium level, as well as cell proliferation and autophagy. Molecular docking of the OGT/OPFR complexes provided rationales for the difference in their structure-dependent inhibition potency. Our findings may provide a new biological target of OPFRs in their neurotoxicological actions, which might be a major molecular mechanism of OPFRs developmental neurotoxicity.
资助项目	National Natural Science Foundation of China[21377142] ; National Natural Science Foundation of China[21577163] ; National Natural Science Foundation of China[21375143] ; National Natural Science Foundation of China[21477146] ; National Natural Science Foundation of China[21621064] ; National Natural Science Foundation of China[91543203] ; Chinese Academy of Sciences[XDB14040100] ; Chinese Academy of Sciences[QYZDJ-SSW-DQC020]
WOS关键词	GLCNAC TRANSFERASE ; PHOSPHATE TDCPP ; PLASTICIZERS ; GLYCOSYLATION ; GLCNACYLATION ; TOXICITY ; EXPOSURE ; COMPLEX ; NEURODEGENERATION ; PHOSPHORYLATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000433398700003
资助机构	National Natural Science Foundation of China ; Chinese Academy of Sciences
内容类型	期刊论文
源URL	[http://ir.ipe.ac.cn/handle/122111/24768]
专题	中国科学院过程工程研究所
通讯作者	Yang, Yu; Guo, Liang-Hong
作者单位	1.Chinese Acad Sci, Res Ctr Ecoenvironm Sci, State Key Lab Environm Chem & Ecotoxicol, POB 2871,18 Shuangqing Rd, Beijing 100085, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Inst Proc Engn, 1 North 2nd St, Beijing 100190, Peoples R China
推荐引用方式 GB/T 7714	Gu, Yuxin,Yang, Yu,Wan, Bin,et al. Inhibition of O-linked N-acetylglucosamine transferase activity in PC12 cells - A molecular mechanism of organophosphate flame retardants developmental neurotoxicity[J]. BIOCHEMICAL PHARMACOLOGY,2018,152:21-33.
APA	Gu, Yuxin,Yang, Yu,Wan, Bin,Li, Minjie,&Guo, Liang-Hong.(2018).Inhibition of O-linked N-acetylglucosamine transferase activity in PC12 cells - A molecular mechanism of organophosphate flame retardants developmental neurotoxicity.BIOCHEMICAL PHARMACOLOGY,152,21-33.
MLA	Gu, Yuxin,et al."Inhibition of O-linked N-acetylglucosamine transferase activity in PC12 cells - A molecular mechanism of organophosphate flame retardants developmental neurotoxicity".BIOCHEMICAL PHARMACOLOGY 152(2018):21-33.