Tributyltin induces apoptotic signaling in hepatocytes through pathways involving the endoplasmic reticulum and mitochondria

Journal Article · Sun Jul 01 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.03.028· OSTI ID:20976972

Grondin, Melanie ^[1]; Marion, Michel ^[1]; Denizeau, Francine ^[1]; Averill-Bates, Diana A ^[2]

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1. Departement de Chimie, Centre de Recherche en Toxicologie de l'environnement (TOXEN), Universite du Quebec a Montreal, CP 8888, Succursale Centre-Ville, Montreal, Quebec, H3C 3P8 (Canada)
2. Departement des Sciences Biologiques, Centre de Recherche en Toxicologie de l'environnement (TOXEN), Universite du Quebec a Montreal, Montreal, Quebec (Canada)

Tri-n-butyltin is a widespread environmental toxicant, which accumulates in the liver. This study investigates whether tri-n-butyltin induces pro-apoptotic signaling in rat liver hepatocytes through pathways involving the endoplasmic reticulum and mitochondria. Tri-n-butyltin activated the endoplasmic reticulum pathway of apoptosis, which was demonstrated by the activation of the protease calpain, its translocation to the plasma membrane, followed by cleavage of the calpain substrates, cytoskeletal protein vinculin, and caspase-12. Caspase-12 is localized to the cytoplasmic side of the endoplasmic reticulum and is involved in apoptosis mediated by the endoplasmic reticulum. Tri-n-butyltin also caused translocation of the pro-apoptotic proteins Bax and Bad from the cytosol to mitochondria, as well as changes in mitochondrial membrane permeability, events which can activate the mitochondrial death pathway. Tri-n-butyltin induced downstream apoptotic events in rat hepatocytes at the nuclear level, detected by chromatin condensation and by confocal microscopy using acridine orange. We investigated whether the tri-n-butyltin-induced pro-apoptotic events in hepatocytes could be linked to perturbation of intracellular calcium homeostasis, using confocal microscopy. Tri-n-butyltin caused changes in intracellular calcium distribution, which were similar to those induced by thapsigargin. Calcium was released from a subcellular compartment, which is likely to be the endoplasmic reticulum, into the cytosol. Cytosolic acidification, which is known to trigger apoptosis, also occurred and involved the Cl{sup -}/HCO{sub 3} {sup -} exchanger. Pro-apoptotic events in hepatocytes were inhibited by the calcium chelator, Bapta-AM, and by a calpain inhibitor, which suggests that changes in intracellular calcium homeostasis are involved in tri-n-butyltin-induced apoptotic signaling in rat hepatocytes.

• OSTI ID: 20976972
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 222; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACIDIFICATION
ACRIDINE ORANGE
APOPTOSIS
CALCIUM
CELL MEMBRANES
CHROMATIN
CYANIDES
ENDOPLASMIC RETICULUM
HOMEOSTASIS
LIVER
LIVER CELLS
MITOCHONDRIA
ORGANIC FLUORINE COMPOUNDS
PERMEABILITY
PVC
RATS
TRANSLOCATION