Abstract
Toluene diisocyanate (TDI), a major intermediate agent used in the manufacturing industry, causes respiratory symptoms when exposed to the human body. In this study, we aimed to determine the molecular mechanism of TDI toxicity. To investigate the impact of TDI exposure on global gene expression, we performed transcriptomic analysis of human bronchial epithelial cells (BEAS-2B) after TDI treatment. Differentially expressed genes (DEGs) were sorted and used for clustering and network analysis. Among DEGs, dual-specificity phosphatase 6 (DUSP6) was one of the genes significantly changed by TDI exposure. To verify the expression level of DUSP6 and its effect on lung cells, the mRNA and protein levels of DUSP6 were analyzed. Our results showed that DUSP6 was dose-dependently upregulated by TDI treatment. Thereby, the phosphorylation of ERK1/2, one of the direct inhibitory targets of DUSP6, was decreased. TDI exposure also increased the mRNA level of p53 along with its protein and activity which trans-activates DUSP6. Since TRPA1 is known as a signal integrator activated by TDI, we analyzed the relevance of TRPA1 receptor in DUSP6 regulation. Our data revealed that up-regulation of DUSP6 mediated by TDI was blocked by a specific antagonist against TRPA1. TDI exposure attenuated the apoptotic response, which suggests that it promotes the survival of cancerous cells. In conclusion, our results suggest that TDI induces DUSP6 and p53, but attenuates ERK1/2 activity through TRPA1 receptor activation, leading to cytotoxicity.
Highlights
Toluene diisocyanate (TDI), a highly reactive aromatic compound, is mainly absorbed into the human body through the respiratory tract owing to its volatile properties [1]
Protein–protein interaction (PPI) was analyzed using genes significantly modulated by TDI treatment based on STRING and the Cytoscape database (Figure 2B,C)
To select the key factors that sensitively responded to TDI exposure, we re-analyzed them by increasing the confidence cut-off value to 0.7 (Figure 2C)
Summary
Toluene diisocyanate (TDI), a highly reactive aromatic compound, is mainly absorbed into the human body through the respiratory tract owing to its volatile properties [1]. TDI absorbed into the body causes inflammation in bronchial cells, thereby causing occupational asthma which leads to various respiratory symptoms such as bronchial irritation, bronchoconstriction, and hypersensitivity pneumonia [2,3,4,5,6,7,8,9,10]. TDI is a major intermediate agent in the synthesis of polyurethanes used in the manufacturing industry [14]. Polyurethane foam using TDI as a raw material is utilized in various industrial fields such as automobiles, furniture, and packing materials [5].
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