Long-term exposure to endogenous levels of tributyltin decreases GluR2 expression and increases neuronal vulnerability to glutamate

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Organotins such as tributyltin are suspected of having multiple toxic effects in mammals, in addition to their endocrine-disrupting function. Endogenous organotin concentrations in human blood range from a few to a few hundred nM. In this review, we summarize recent findings on the mechanisms of toxicity of environmental organotins such as tributyltin (TBT) and triphenyltin (TPT) in mammals. TBT and TPT are potent inhibitors of mitochondrial ATP synthase, and a recent study suggests that TBT binds directly to ATP synthase. Organotins disturb steroid biosynthesis and degradation. TBT and TPT are dual agonists of retinoid X receptor (RXR) and peroxisome proliferator-activated receptor γ (PPARγ); they also induce the differentiation of adipocytes in vitro and in vivo, probably through PPARγ activation, suggesting that they may work as obesogens. Environmental organotins are also neurotoxic; they induce behavioral abnormality and are toxic to the developing central nervous system. In vitro studies have shown that organotins induce intracellular Ca 2 elevation and glutamate excitotoxicity. Recently, it was reported that endogenous levels of TBT decrease expression of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor subunit GluR2, leading to neuronal vulnerability. Most of the experimental studies have employed organotins at concentrations of µM order, and it remains important to clarify the molecular mechanisms of events induced by endogenous levels of environmental organotins.

Section: Glur2 Decrease By Endogenous Levels Of Organotinsmentioning

confidence: 99%

Molecular Mechanisms of Environmental Organotin Toxicity in Mammals

Kotake

2012

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“…[31][32][33] Long-term exposure to endogenous levels of tributyltin (TBT) decreases GluR2 expression in primary cortical neurons. 34) Furthermore, glutamate-induced Ca 2+ influx increased in TBT-treated neurons compared to that in control neurons, which increased neuronal susceptibility to glutamate excitotoxicity. 34) Moreover, perfluorooctane sulfonate (PFOS) decreases GluR2 expression and enhances neuronal vulnerability to excitotoxicity in vivo and in vitro.…”

Section: +mentioning

confidence: 97%

“…34) Furthermore, glutamate-induced Ca 2+ influx increased in TBT-treated neurons compared to that in control neurons, which increased neuronal susceptibility to glutamate excitotoxicity. 34) Moreover, perfluorooctane sulfonate (PFOS) decreases GluR2 expression and enhances neuronal vulnerability to excitotoxicity in vivo and in vitro. GluR2 expression in rat cerebral cortex was decreased by developmental exposure to PFOS, and neuronal death was induced by kainate (a glutamate analog) injection into PFOS-exposed rat.…”

Section: +mentioning

confidence: 97%

Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons

Ishida

Kotake

Sanoh

et al. 2017

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Lead is a persistent environmental pollutant and exposure to high environmental levels causes various deleterious toxicities, especially to the central nervous system (CNS). The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor that is devoid of the glutamate receptor 2 (GluR2) subunit is Ca 2 -permeable, which increases the neuronal vulnerability to excitotoxicity. We have previously reported that long-term exposure of rat cortical neurons to lead acetate induces decrease of GluR2 expression. However, it is not clarified whether lead-induced GluR2 decrease is involved in neurotoxicity. Therefore, we investigated the contribution of GluR2 non-containing AMPA receptor to lead-induced neurotoxic events. Although the expression of four AMPA receptor subunits (GluR1, GluR2, GluR3, and GluR4) was decreased by lead exposure, the decrease in GluR2 expression was remarkable among four subunits. Lead-induced neuronal cell death was rescued by three glutamate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a non-selective AMPA receptor blocker), MK-801 (N-methyl-D-aspartate (NMDA) receptor blocker), and 1-naphthyl acetyl spermine (NAS, a specific Ca 2 -permeable AMPA receptor blocker). Lead exposure activated extracellular signal-regulated protein kinase (ERK) 1/2, which was significantly ameliorated by CNQX. In addition, lead exposure activated p38 mitogen-activated protein kinase (MAPK p38), and protein kinase C (PKC), which was partially ameliorated by CNQX. Our findings indicate that Ca 2 -permeable AMPA receptors resulting from GluR2 decrease may be involved in lead-induced neurotoxicity.

“…[13][14][15] In particular, low-concentration TBT exposure decreased GluR2 expression and subsequently increased neuronal vulnerability to glutamate in primary cortical neurons. 16) However, additional research is needed to determine whether TBT exposure decreases GluR2 expression in mammalian brain. Thus, the aim of this study was to examine the effect of TBT on GluR2 expression in vivo.…”

Section: +mentioning

confidence: 99%

Prenatal Exposure to Tributyltin Decreases GluR2 Expression in the Mouse Brain

Ishida

Saiki

Umeda

et al. 2017

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Tributyltin (TBT), a common environmental contaminant, is widely used as an antifouling agent in paint. We previously reported that exposure of primary cortical neurons to TBT in vitro decreased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit glutamate receptor 2 (GluR2) expression and subsequently increased neuronal vulnerability to glutamate. Therefore, to identify whether GluR2 expression also decreases after TBT exposure in vivo, we evaluated the changes in GluR2 expression in the mouse brain after prenatal or postnatal exposure to 10 and 25 ppm TBT through pellet diets. Although the mean feed intake and body weight did not decrease in TBT-exposed mice compared with that in control mice, GluR2 expression in the cerebral cortex and hippocampus decreased after TBT exposure during the prenatal period. These results indicate that a decrease in neuronal GluR2 may be involved in TBT-induced neurotoxicity, especially during the fetal period.Key words tributyltin; glutamate receptor 2; developmental neurotoxicity Tributyltin (TBT), an organotin compound was widely employed as an antifouling agent in paints used for aquaculture nets and ships. Because of its irreversible effects on sexual abnormalities, known as imposex, in some female gastropods, 1) the use of TBT in paints is currently internationally restricted. Although the risk of acute environmental exposure to TBT has decreased, the issue of secondary exposure from contaminated sea food remains owing to its long-term environmental persistence and high bioaccumulation.2,3) Some studies indicated that TBT-induced endocrine disruption was caused by inhibition of aromatase enzymes, which catalyze the conversion of androgen to estrogen. 4,5) Conversely, other studies reported that TBT-induced endocrine disruption in gastropods was caused by retinoid X receptor (RXR) activation because 9-cis retinoic acid (a well-known RXR ligand) induces gastropod imposex and TBT is a potential agonist of RXR. 6,7)Ionotropic glutamate receptors, which are tetrameric ligandgated ion channels, are essential to brain functions, such as learning and memory, and for neuronal growth, maturation, and synaptic plasticity. However, over-activation of glutamate receptors increases cytosolic Ca 2+ , which triggers neuronal death. The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor is an ionotropic glutamate receptor and is composed of four subunits (GluR1 to GluR4). Its Ca 2+ permeability is dependent on the glutamate receptor 2 (GluR2) subunit.8) At steady state, most AMPA receptors contain GluR2 subunits in the cortical, hippocampal granule, and pyramidal neurons, 9) and are impermeable to Ca 2+. However, it is considered that decreases in neuronal GluR2 have been linked to neurotoxicity because neurons that contain GluR2-lacking AMPA receptors show high Ca 2+ permeability and vulnerability to excitotoxicity. 8)Organotin compounds, including TBT, are also known as neurotoxic compounds because they can permeate the blood-brain barrier (BB...