Hippocampal proteomic analysis reveals the disturbance of synaptogenesis and neurotransmission induced by developmental exposure to organophosphate flame retardant triphenyl phosphate.
Hippocampal proteomic analysis reveals the disturbance of synaptogenesis and neurotransmission induced by developmental exposure to organophosphate flame retardant triphenyl phosphate.
复制标题
DOI：
10.1016/j.jhazmat.2020.124111
复制
发表时间：
2020-09
影响因子：
13.6
通讯作者：
X. Zhong;Yuejin E. Yu;Can Wang;Qicheng Zhu;Jingwei Wu;Weijian Ke;D. Ji;C. Niu;Xifei Yang;Yanhong Wei
中科院分区：
文献类型：
--
作者：
X. Zhong;Yuejin E. Yu;Can Wang;Qicheng Zhu;Jingwei Wu;Weijian Ke;D. Ji;C. Niu;Xifei Yang;Yanhong Wei
随着有机磷阻燃剂（OPFRs）的广泛应用，其所带来的环境和健康风险日益引起人们的关注。磷酸三苯酯（TPHP）是溴化阻燃剂和卤化opfr的流行替代品。神经发育毒性是TPHP的主要不良反应，而生物标志物和作用模式尚未阐明。在本研究中，小鼠从出生后第10天（P10）至P70天口服0.5、5和50 mg/kg的TPHP。行为测试显示学习和记忆能力受损。对暴露于0.5或50 mg/kg TPHP的海马进行蛋白质组学分析，鉴定出531种差异表达蛋白，这些蛋白主要参与轴突引导、突触功能、神经递质转运、胞外分泌和能量代谢。免疫印迹和免疫荧光分析显示，暴露于TPHP降低了海马神经元突触中TUBB3和SYP的蛋白水平。TPHP暴露还以剂量依赖的方式下调神经递质受体（包括grin、Htr1α和adra1 α）的基因表达。此外，由突触囊泡蛋白STX1A和SYT1控制的钙依赖性突触胞吐在tpp处理的海马中被抑制。我们的研究结果表明，TPHP暴露通过干扰突触发生和神经传递导致异常的学习和记忆行为。
With the spread of organophosphorus flame retardants (OPFRs), the environmental and health risks they induce are attracting attention. Triphenyl phosphate (TPHP) is a popular alternative to brominated flame retardant and halogenated OPFRs. Neurodevelopmental toxicity is TPHP’s primary adverse effect, whereas the biomarkers and the modes of action have yet to be elucidated. In the present study, 0.5, 5, and 50 mg/kg of TPHP were orally administered to mice from postnatal day 10 (P10) to P70. The behavioral tests showed a compromised learning and memory capability. Proteomic analysis of the hippocampus exposed to 0.5 or 50 mg/kg of TPHP identified 531 differentially expressed proteins that were mainly involved in axon guidance, synaptic function, neurotransmitter transport, exocytosis, and energy metabolism. Immunoblot and immunofluorescence analysis showed that exposure to TPHP reduced the protein levels of TUBB3 and SYP in the synapses of hippocampal neurons. TPHP exposure also downregulated the gene expression of neurotransmitter receptors includingGrins,Htr1α, andAdra1αin a dose-dependent fashion. Moreover, the calcium-dependent synaptic exocytosis governed by synaptic vesicle proteins STX1A and SYT1 was inhibited in the TPHP-treated hippocampus. Our results reveal that TPHP exposure causes abnormal learning and memory behaviors by disturbing synaptogenesis and neurotransmission.