Cell death and impairment of glucose-stimulated insulin secretion induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in the β-cell line INS-1E

• Published in: Toxicology and applied pharmacology 2007-05, Vol.220 (3), p.333-340
• Main Authors: Piaggi, Simona, Novelli, Michela, Martino, Luisa, Masini, Matilde, Raggi, Chiara, Orciuolo, Enrico, Masiello, Pellegrino, Casini, Alessandro, De Tata, Vincenzo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium - metabolism; Cell Death - drug effects; Cell Line; Cell Nucleus - drug effects; Cell Nucleus - ultrastructure; Cell Survival - drug effects; Chemical and industrial products toxicology. Toxic occupational diseases; Cytosol - drug effects; Cytosol - metabolism; Diabetes; Diabetes. Impaired glucose tolerance; Dioxin; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Environmental Pollutants - toxicity; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - pharmacology; INS-1 cells; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Medical sciences; Microscopy, Electron; Polychlorinated Dibenzodioxins - toxicity; Toxicology; Vacuoles - drug effects; Vacuoles - ultrastructure; Various organic compounds
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.01.017

The aim of this research was to characterize 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) toxicity on the insulin-secreting β-cell line INS-1E. A sharp decline of cell survival (below 20%) was observed after 1 h exposure to TCDD concentrations between 12.5 and 25 nM. Ultrastructurally, β-cell death was characterized by extensive degranulation, appearance of autophagic vacuoles, and peripheral nuclear condensation. Cytotoxic concentrations of TCDD rapidly induced a dose-dependent increase in intracellular calcium concentration. Blocking calcium entry by EGTA significantly decreased TCDD cytotoxicity. TCDD was also able to rapidly induce mitochondrial depolarization. Interestingly, 1 h exposition of INS-1E cells to very low TCDD concentrations (0.05–1 nM) dramatically impaired glucose-stimulated but not KCl-stimulated insulin secretion. In conclusion, our results clearly show that TCDD exerts a direct β-cell cytotoxic effect at concentrations of 15–25 nM, but also markedly impairs glucose-stimulated insulin secretion at concentrations 20 times lower than these. On the basis of this latter observation we suggest that pancreatic β-cells could be considered a specific and sensitive target for dioxin toxicity.