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 |
| |
Authors: | Rita Santamaria Filomena FioritoCarlo Irace Luisa De MartinoCarmen Maffettone Giovanna Elvira GranatoAntonio Di Pascale Valentina IovaneUgo Pagnini Alfredo Colonna |
| |
Institution: | a Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli “Federico II”, via D. Montesano 49, I-80131 Naples, Italyb Dipartimento di Patologia e Sanità Animale, Università degli Studi di Napoli “Federico II”, via F. Delpino 1, I-80137 Naples, Italy |
| |
Abstract: | 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. |
| |
Keywords: | TCDD 2 3 7 8-tetrachlorodibenzo-p-dioxin IRPs iron regulatory proteins IRE iron-responsive element TfR-1 transferrin receptor 1 DMT-1 divalent metal transporter 1 MDBK Madin-Darby Bovine Kidney cells MTT 3-(4 5-dimethyl-2-thiazolyl)-2 5-diphenyl-2H-tetrazolium bromide LIP labile iron pool SIH salicylaldehyde isonicotinoyl hydrazone 2-ME 2-mercaptoethanol CA-AM calcein-acetomethoxy |
本文献已被 ScienceDirect 等数据库收录! |
|