Selective beta-cell toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin on isolated pancreatic islets

摘要

An association between exposure to environmental pollutants and diabetes risk has been repeatedly shown by epidemiological studies. However, the biological basis of this association still need to be clarified. In this research we explored the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on isolated pancreatic islets. After 1, 6 and 24 h exposure of isolated islets to different concentrations (1 -50 nM) of TCDD we assayed: i) cell survival; ii) ultrastructure; iii) glucose-stimulated insulin secretion (GSIS); iv) expression of selected genes. A significant, dose-related increase of both necrosis and apoptosis was observed isolated rat islets after 24 h exposure to TCDD. The electron microscopic analysis revealed, at the same time point, the presence of several ultrastructural alterations (mitochondrial swelling, increased mitophagy, dilation of the endoplasmic reticulum) that, very interestingly, were exclusively observed in beta cells and not in other endocrine cells. Similar results were obtained in isolated human islets. GSIS was rapidly (1 h) and persistently (6 and 24 h) decreased by TCDD exposure even at the smallest concentration (1 nM). TCDD exposure significantly affected gene expression in isolated islets: Glut2, Gck, Bcl-xL, MafA, Pdxl FoxO1 and IRE1 gene expression was significantly decreased, whereas Puma, DP5, iNOS and Chop gene expression was significantly increased after 6 h exposure to TCDD. In conclusion, our results clearly indicated that pancreatic beta cells represent not only a sensitive but also a specific target of the toxic action of dioxin. (C) 2020 Elsevier Ltd. All rights reserved.