期刊
JOURNAL OF HAZARDOUS MATERIALS
卷 404, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jhazmat.2020.124111
关键词
Organophosphate flame retardant (OPFR); Triphenyl phosphate (TPHP); Neurotoxicity; Learning and memory; Proteomic profile
资金
- National Natural Science Foundation of China [21976216, 21906186]
- Guangdong Basic and Applied Basic Research Foundation [2019B151502019]
- Fundamental Research Funds for the Central Universities [19ykpy92]
TPHP exposure affects learning and memory behaviors by disturbing synaptogenesis and neurotransmission, as evidenced by reduced protein levels of TUBB3 and SYP in synapses, downregulated gene expression of neurotransmitter receptors, and inhibited synaptic exocytosis in the hippocampus.
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 including Grins, Htr1 alpha, and Adra1 alpha in 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.
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