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.

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 / Santamaria, Rita; Fiorito, Filomena; Irace, Carlo; DE MARTINO, Luisa; Maffettone, Carmen; Granato, GIOVANNA ELVIRA; DI PASCALE, Antonio; Iovane, Valentina; Pagnini, Ugo; Colonna, Alfredo. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH. - ISSN 0167-4889. - 1813:5(2011), pp. 704-712. [10.1016/j.bbamcr.2011.02.003]

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

SANTAMARIA, RITA;FIORITO, FILOMENA;IRACE, CARLO;DE MARTINO, LUISA;MAFFETTONE, CARMEN;GRANATO, GIOVANNA ELVIRA;DI PASCALE, ANTONIO;IOVANE, VALENTINA;PAGNINI, UGO;COLONNA, ALFREDO
2011

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.
2011
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 / Santamaria, Rita; Fiorito, Filomena; Irace, Carlo; DE MARTINO, Luisa; Maffettone, Carmen; Granato, GIOVANNA ELVIRA; DI PASCALE, Antonio; Iovane, Valentina; Pagnini, Ugo; Colonna, Alfredo. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH. - ISSN 0167-4889. - 1813:5(2011), pp. 704-712. [10.1016/j.bbamcr.2011.02.003]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/378507
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 28
  • ???jsp.display-item.citation.isi??? 28
social impact