2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs iron homeostasis by modulating iron-related proteins expression and increasing the labile iron pool in mammalian cells

• Published in: Biochimica et biophysica acta Vol. 1813; no. 5; pp. 704 - 712
• Main Authors: Santamaria, Rita, Fiorito, Filomena, Irace, Carlo, De Martino, Luisa, Maffettone, Carmen, Granato, Giovanna Elvira, Di Pascale, Antonio, Iovane, Valentina, Pagnini, Ugo, Colonna, Alfredo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2011
• Subjects: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Animals; Blotting, Western; Cation Transport Proteins - metabolism; Cattle; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Ferritins - genetics; Ferritins - metabolism; Gene Expression Regulation - drug effects; Homeostasis - drug effects; Iron - metabolism; Iron regulatory proteins; Iron-Regulatory Proteins - genetics; Iron-Regulatory Proteins - metabolism; Iron-related proteins; Labile iron pool; Mammals - metabolism; Polychlorinated Dibenzodioxins - toxicity; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Labile iron pool; Iron metabolism; MDBK; 2-ME; TCDD; Iron regulatory proteins; TfR-1; MTT; 2,3,7,8-Tetrachlorodibenzo-p-dioxin; DMT-1; IRPs; LIP; SIH; CA-AM; IRE; Iron-related proteins
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2011.02.003

Cellular iron metabolism is essentially controlled by the binding of cytosolic iron regulatory proteins (IRP1 or IRP2) to iron-responsive elements (IREs) located on mRNAs coding for proteins involved in iron acquisition, utilization and storage. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent toxins of current interest that occurs as poisonous chemical in the environment. TCDD exposure has been reported to induce a broad spectrum of toxic and biological responses, including significant changes in gene expression for heme and iron metabolism associated with liver injury. Here, we have investigated the molecular effects of TCDD on the iron metabolism providing the first evidence that administration of the toxin TCDD to mammalian cells affects the maintenance of iron homeostasis. We found that exposure of Madin–Darby Bovine Kidney cell to TCDD caused a divergent modulation of IRP1 and IRP2 RNA-binding capacity. Interestingly, we observed a concomitant IRP1 down-regulation and IRP2 up-regulation thus determining a marked enhancement of transferrin receptor 1 (TfR-1) expression and a biphasic response in ferritin content. The changed ferritin content coupled to TfR-1 induction after TCDD exposure impairs the cellular iron homeostasis, ultimately leading to significant changes in the labile iron pool (LIP) extent. Since important iron requirement changes occur during the regulation of cell growth, it is not surprising that the dioxin-dependent iron metabolism dysregulation herein described may be linked to cell-fate decision, supporting the hypothesis of a central connection among exposure to dioxins and the regulation of critical cellular processes. ►TCDD affects the maintenance of iron homeostasis. ►TCDD causes an opposite modulation of the iron regulatory proteins activity. ►TCDD determines an increase of TfR-1 expression and a decrease of ferritin content. ►TCDD causes an enlargement of the intracellular free iron pool. ►IRP2 becomes the effector of cellular iron homeostasis when TCDD exposure is prolonged.