m6A Demethylase FTO Regulates Dopaminergic Neurotransmission Deficits Caused by Arsenite
| Autor: | Qizhong Qin, Qianghu Tang, Shuqun Cheng, Lina Zhang, Zhen Zou, Yinyin Xia, Xuejun Jiang, Xuefeng Wang, Xia Qin, Bo Lv, Baijie Tu, Chengzhi Chen, Xianqing Cao, Pan Meng, Kai Yang, Lulu Bai, Shaoyu Mu |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Adenosine Synaptic cleft Arsenites Cell Survival Dopamine Alpha-Ketoglutarate-Dependent Dioxygenase FTO Neurotransmission Toxicology PC12 Cells Synaptic Transmission FTO gene 03 medical and health sciences chemistry.chemical_compound Internal medicine Avoidance Learning medicine Animals Epigenetics Maze Learning Arsenite Cerebral Cortex Behavior Animal Dose-Response Relationship Drug biology Chemistry Dopaminergic Neurons Dopaminergic Rats Mice Inbred C57BL 030104 developmental biology Endocrinology biology.protein Demethylase Protein Modification Translational medicine.drug |
| Zdroj: | Toxicological Sciences. 165:431-446 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfy172 |
| Popis: | Arsenite exposure is known to increase the risk of neurological disorders via alteration of dopamine content, but the detailed molecular mechanisms remain largely unknown. In this study, using both dopaminergic neurons of the PC-12 cell line and C57BL/6J mice as in vitro and in vivo models, our results demonstrated that 6 months of arsenite exposure via drinking water caused significant learning and memory impairment, anxiety-like behavior and alterations in conditioned avoidance and escape responses in male adult mice. We also were the first to reveal that the reduction in dopamine content induced by arsenite mainly resulted from deficits in dopaminergic neurotransmission in the synaptic cleft. The reversible N6- methyladenosine (m6A) modification is a novel epigenetic marker with broad roles in fundamental biological processes. We further evaluated the effect of arsenite on the m6A modification and tested if regulation of the m6A modification by demethylase fat mass and obesity-associated (FTO) could affect dopaminergic neurotransmission. Our data demonstrated for the first time that arsenite remarkably increased m6A modification, and FTO possessed the ability to alleviate the deficits in dopaminergic neurotransmission in response to arsenite exposure. Our findings not only provide valuable insight into the molecular neurotoxic pathogenesis of arsenite exposure, but are also the first evidence that regulation of FTO may be considered as a novel strategy for the prevention of arsenite-associated neurological disorders. |
| Databáze: | OpenAIRE |
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