Triphenyl phosphate permeates the blood brain barrier and induces neurotoxicity in mouse brain

• Published in: Chemosphere (Oxford) Vol. 252; p. 126470
• Main Authors: Liu, Xiaoshan, Zhao, Xiaolei, Wang, Yao, Hong, Jiabin, Shi, Ming, Pfaff, Donald, Guo, Lianxian, Tang, Huanwen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-08-2020
• Subjects: Metabolomics; Mice; Neurotoxicity; RNA-seq; Triphenyl phosphate; Metabolomics; Neurotoxicity; Mice; RNA-seq; Triphenyl phosphate
• ISSN: 0045-6535; 1879-1298
• DOI: 10.1016/j.chemosphere.2020.126470

Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored.
•TPP and its metabolite DPP can pass through the blood brain (BBB) barrier, cause neuronal apoptosis and neuroinflammation in mouse brain.•TPP could disturb lipid and amino acid metabolism, and change MAPK and FOXO pathways in mouse brain.
Major finding. TPP and its primary metabolite DPP can permeate the blood brain barrier and cause metabolomic and transcriptomic changes to mouse.