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Tributyltin-induced Endoplasmic Reticulum Stress and Its Ca(2+)-mediated Mechanism

Tributyltin-induced Endoplasmic Reticulum Stress and Its Ca(2+)-mediated Mechanism

Midori Isomura, Yaichiro Kotake, Kyoichi Masuda, Masatsugu Miyara, Katsuhiro Okuda, Shigeyoshi Samizo, Seigo Sanoh, Toru Hosoi, Koichiro Ozawa, Shigeru Ohta

Toxicol Appl Pharmacol. 2013 Oct 1;272(1):137-46.

PMID: 23743301

Abstract:

Organotin compounds, especially tributyltin chloride (TBT), have been widely used in antifouling paints for marine vessels, but exhibit various toxicities in mammals. The endoplasmic reticulum (ER) is a multifunctional organelle that controls post-translational modification and intracellular Ca(2+) signaling. When the capacity of the quality control system of ER is exceeded under stress including ER Ca(2+) homeostasis disruption, ER functions are impaired and unfolded proteins are accumulated in ER lumen, which is called ER stress. Here, we examined whether TBT causes ER stress in human neuroblastoma SH-SY5Y cells. We found that 700nM TBT induced ER stress markers such as CHOP, GRP78, spliced XBP1 mRNA and phosphorylated eIF2α. TBT also decreased the cell viability both concentration- and time-dependently. Dibutyltin and monobutyltin did not induce ER stress markers. We hypothesized that TBT induces ER stress via Ca(2+) depletion, and to test this idea, we examined the effect of TBT on intracellular Ca(2+) concentration using fura-2 AM, a Ca(2+) fluorescent probe. TBT increased intracellular Ca(2+) concentration in a TBT-concentration-dependent manner, and Ca(2+) increase in 700nM TBT was mainly blocked by 50μM dantrolene, a ryanodine receptor antagonist (about 70% inhibition). Dantrolene also partially but significantly inhibited TBT-induced GRP78 expression and cell death. These results suggest that TBT increases intracellular Ca(2+) concentration by releasing Ca(2+) from ER, thereby causing ER stress.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP2179922	Tributyltin cyanide		2179-92-2	Price

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