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Gadolinium exposure disrupts iron homeostasis in cultured cells

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Abstract

Human exposure to gadolinium-based contrast agents can be complicated by nephrogenic systemic fibrosis (NSF). Demonstration of significant quantities of insoluble gadolinium in the skin of NSF patients suggested transmetallation as a mechanism of toxicity of this injury. An alternative pathway for the biological effect of gadolinium is a disruption of iron homeostasis. We tested the postulate that cell exposure to gadolinium increases iron uptake to disrupt intracellular metal homeostasis and impact inflammatory events. Alveolar macrophages, THP1 cells, NHBE cells, and BEAS-2B cells all demonstrated a capacity to import gadolinium from both GdCl3 and Omniscan. All four cell types similarly imported iron following exposure to ferric ammonium citrate (FAC). Exposure of all cell types to gadolinium and iron resulted in increased iron import relative to cell concentrations following incubation with FAC alone. To analyze for further evidence of changes in iron homeostasis, cell ferritin concentration was determined. Relative to incubation with FAC alone, co-incubation of BEAS-2B cells with gadolinium and FAC resulted in significant increases in ferritin level. Finally, potential effects of gadolinium uptake and associated changes in iron homeostasis on the inflammatory response were evaluated by measuring IL-8. Co-incubation of BEAS-2B cells with both gadolinium and iron resulted in diminished release of IL-8 relative to levels of the cytokine following incubation with gadolinium alone. We conclude that gadolinium impacts cell iron homeostasis to change import and storage of the metal and biological effects of exposure.

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Abbreviations

BEGM:

Bronchial epithelial growth medium

FAC:

Ferric ammonium citrate

FCS:

Fetal calf serum

HBSS:

Hank’s balanced salt solution

ICPOES:

Inductively coupled plasma optical emission spectroscopy

IRP1:

Iron regulatory protein 1

KGM:

Keritinocyte growth medium

NSF:

Nephrogenic systemic fibrosis

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Authors and Affiliations

  1. National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, NC, 27711, USA

    Andrew J. Ghio, Joleen M. Soukup, Lisa A. Dailey & Judy Richards

  2. Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, NC, 27599, USA

    Zhongping Deng

  3. Department of Pathology, SUNY-Upstate Medical University, Syracuse, NY, 13210, USA

    Jerrold L. Abraham

  4. Human Studies Facility, USEPA, Campus Box 7315, 104 Mason Farm Road, Chapel Hill, NC, 27599-7315, USA

    Andrew J. Ghio

Authors
  1. Andrew J. Ghio
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  2. Joleen M. Soukup
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  3. Lisa A. Dailey
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  4. Judy Richards
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  5. Zhongping Deng
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Correspondence to Andrew J. Ghio.

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Ghio, A.J., Soukup, J.M., Dailey, L.A. et al. Gadolinium exposure disrupts iron homeostasis in cultured cells. J Biol Inorg Chem 16, 567–575 (2011). https://doi.org/10.1007/s00775-011-0757-z

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  • DOI: https://doi.org/10.1007/s00775-011-0757-z

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