title: 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.
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. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
authors.affiliation: Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli "Federico II", via D. Montesano 49, I-80131 Naples, Italy. rsantama@unina.it
authors.forename: Rita
authors.initials: R
authors.lastname: Santamaria
authors.forename: Filomena
authors.initials: F
authors.lastname: Fiorito
authors.forename: Carlo
authors.initials: C
authors.lastname: Irace
authors.forename: Luisa
authors.initials: L
authors.lastname: De Martino
authors.forename: Carmen
authors.initials: C
authors.lastname: Maffettone
authors.forename: Giovanna Elvira
authors.initials: GE
authors.lastname: Granato
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Pascale
authors.forename: Valentina
authors.initials: V
authors.lastname: Iovane
authors.forename: Ugo
authors.initials: U
authors.lastname: Pagnini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Colonna
mesh_terms: D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D005293:Ferritins; D007501:Iron; D035925:Iron-Regulatory Proteins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D000099236:Solute Carrier Family 11, Member 2