Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition.

Keishi Ishida,Shigeru Ohta,Tomoko Takishita,Seigo Sanoh,Masatsugu Miyara,Yasunari Kanda,Kaori Aoki,Yaichiro Kotake,Tomoki Kimura,Shuichiro Sakamoto

doi:10.3390/ijms18081754

Abstract

Tributyltin (TBT), which has been widely used as an antifouling agent in paints, is a common environmental pollutant. Although the toxicity of high-dose TBT has been extensively reported, the effects of low concentrations of TBT are relatively less well studied. We have previously reported that low-concentration TBT decreases α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptor subunit 2 (GluR2) expression in cortical neurons and enhances neuronal vulnerability to glutamate. However, the mechanism of this TBT-induced GluR2 decrease remains unknown. Therefore, we examined the effects of TBT on the activity of transcription factors that control GluR2 expression. Exposure of primary cortical neurons to 20 nM TBT for 3 h to 9 days resulted in a decrease in GluR2 mRNA expression. Moreover, TBT inhibited the DNA binding activity of nuclear respiratory factor-1 (NRF-1), a transcription factor that positively regulates the GluR2. This result indicates that TBT inhibits the activity of NRF-1 and subsequently decreases GluR2 expression. In addition, 20 nM TBT decreased the expression of genes such as cytochrome c, cytochrome c oxidase (COX) 4, and COX 6c, which are downstream of NRF-1. Our results suggest that NRF-1 inhibition is an important molecular action of the neurotoxicity induced by low-concentration TBT.

Highlights

Organotin compounds, especially tributyltin chloride (TBT), have been widely used as biocides, agricultural fungicides, and antifouling agents in paints
We have previously reported that glutamate receptor subunit 2 (GluR2) protein and mRNA expression is decreased in rat primary cortical neurons following exposure to 20 nM TBT for 9 days [16]
To investigate the time-dependent effect of TBT exposure on GluR2 expression, rat cortical neurons were exposed to 20 nM TBT for various lengths of time, and protein and mRNA expression was measured

Summary

Introduction

Especially tributyltin chloride (TBT), have been widely used as biocides, agricultural fungicides, and antifouling agents in paints. Because of its widespread use as an antifouling agent on the hulls of ships, toxic levels of TBT have been released into water and are polluting marine environments. The use of TBT in paints is currently internationally regulated, the issue of secondary exposure from contaminated fish, solids, and water remains, owing to its high bioaccumulation and long-term environmental persistence [1,2]. Whalen et al have reported TBT concentrations between 10 and 100 nM in human blood [5]. The mechanisms of TBT-induced toxicity at high concentrations may be different from those at low concentrations that do not induce cell death. It is important to clarify the specific mechanisms of toxicity induced by low concentrations of TBT

Methods

Results

Conclusion