Prenatal Exposure to Tributyltin Decreases GluR2 Expression in the Mouse Brain

Ishida, Keishi; Saiki, Takashi; Umeda, Kanae; Miyara, Masatsugu; Sanoh, Seigo; Ohta, Shigeru; Kotake, Yaichiro

doi:10.1248/bpb.b17-00209

Cited by 5 publications

(1 citation statement)

References 25 publications

(33 reference statements)

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“…Exposure of rat cortical neurons to a low level (20 nM) of TBT decreased the expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptor subunit 2 ( GluR2 ), and increased neuronal vulnerability to glutamate without inducing neuronal death [ 16 ]. The GluR2 decrease was also observed in mammalian brain by prenatal exposure to TBT [ 19 ]. The Ca 2+ permeability of the AMPA receptor is dependent upon the GluR2 subunit, and GluR2 plays a role in blocking Ca 2+ influx into the cytoplasm at a steady state.…”

Section: Introductionmentioning

confidence: 99%

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

Ishida

Aoki

Takishita

et al. 2017

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

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

Ishida

Aoki

Takishita

et al. 2017

IJMS

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Tributyltin induces epigenetic changes and decreases the expression of nuclear respiratory factor-1

et al. 2018

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Tributyltin (TBT), a common organotin environmental pollutant, has been widely used as a component of marine antifouling paints. We previously reported that exposure to TBT inhibits the expression and DNA binding of nuclear respiratory factor-1 (NRF-1) and causes neurotoxicity. In the present study, we focused on the epigenetic effects of TBT and investigated whether TBT decreases NRF-1 expression via epigenetic modifications in SH-SY5Y human neuroblastoma cells. First, we found that exposure to 300 nM TBT decreases NRF-1 expression. We examined epigenetic changes induced by TBT, and showed that TBT causes hypermethylation of the NRF-1 promoter region, increases the amount of methyl-CpG-binding protein 2 (MeCP2) bound to the NRF-1 promoter, and alters the expression of DNA methyltransferases and ten-eleven translocation (TET) demethylation enzymes. These results suggest that epigenetic changes play an important role in regulation of NRF-1 expression. Next, we investigated effect of NRF-1 expression decrease on cells, and TBT reduces mitochondrial membrane potential and overexpression of NRF-1 rescued this reduction in membrane potential. Thus, we suggested that NRF-1 is important for maintaining mitochondrial membrane potential. Our study indicates that TBT causes epigenetic changes such as hypermethylation, which increases recruitment of MeCP2 to the NRF-1 promoter and probably lead to decreased of NRF-1 expression and mitochondrial membrane potential. Therefore, this research provides new evidence of the epigenetic action caused by organotin.

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Tributyltin Alters Calcium Levels, Mitochondrial Dynamics, and Activates Calpains Within Dorsal Root Ganglion Neurons

Fross

Mansel

McCormick

et al. 2021

Toxicological Sciences

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Tributyltin (TBT) remains a global health concern. The primary route of human exposure to TBT is either through ingestion or skin absorption, but TBT’s effects on the peripheral nervous system have still not been investigated. Therefore, we exposed in vitro sensory dorsal root ganglion (DRG) neurons to TBT at a concentration of 50-200nM, which is similar to the observed concentrations of TBT in human blood samples. We observed that TBT causes extensive axon degeneration and neuronal death in the DRG neurons. Furthermore, we discovered that TBT causes an increase in both cytosolic and mitochondrial calcium levels, disrupts mitochondrial dynamics, decreases neuronal ATP levels, and leads to the activation of calpains. Additional experiments demonstrated that inhibition of calpain activation prevented TBT-induced fragmentation of neuronal cytoskeletal proteins and neuronal cell death. Thus, we conclude that calpain activation is the key executioner of TBT-induced peripheral neurodegeneration.

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Prenatal Exposure to Tributyltin Decreases GluR2 Expression in the Mouse Brain

Cited by 5 publications

References 25 publications

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

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

Tributyltin induces epigenetic changes and decreases the expression of nuclear respiratory factor-1

Tributyltin Alters Calcium Levels, Mitochondrial Dynamics, and Activates Calpains Within Dorsal Root Ganglion Neurons

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