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| Inhibition of O-linked N-acetylglucosamine transferase activity in PC12 cells - A molecular mechanism of organophosphate flame retardants developmental neurotoxicity | |
| Gu, Yuxin1,2; Yang, Yu1; Wan, Bin1,2; Li, Minjie3; Guo, Liang-Hong1,2 | |
| 2018-06-01 | |
| Source Publication | BIOCHEMICAL PHARMACOLOGY
 |
| ISSN | 0006-2952 |
| Volume | 152Pages:21-33 |
| Abstract | 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. |
| Keyword | Organophosphate flame retardants O-linked N-acetylglucosamine transferase Inhibition Developmental neurotoxicity Molecular docking |
| DOI | 10.1016/j.bcp.2018.03.017 |
| Language | 英语 |
| WOS Keyword | GLCNAC TRANSFERASE ; PHOSPHATE TDCPP ; PLASTICIZERS ; GLYCOSYLATION ; GLCNACYLATION ; TOXICITY ; EXPOSURE ; COMPLEX ; NEURODEGENERATION ; PHOSPHORYLATION |
| Funding Project | 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 Research Area | Pharmacology & Pharmacy |
| WOS Subject | Pharmacology & Pharmacy |
| Funding Organization | National Natural Science Foundation of China ; Chinese Academy of Sciences |
| WOS ID | WOS:000433398700003 |
| Publisher | PERGAMON-ELSEVIER SCIENCE LTD |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.ipe.ac.cn/handle/122111/24769 |
| Collection | 中国科学院过程工程研究所 |
| Corresponding Author | Yang, Yu; Guo, Liang-Hong |
| Affiliation | 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 |
| Recommended Citation 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. |
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