Gadolinium exposure disrupts iron homeostasis in cultured cells.
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 GdCl(3) 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.
National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, NC 27711, USA. ghio.andy@epa.gov
Andrew J
AJ
Ghio
Joleen M
JM
Soukup
Lisa A
LA
Dailey
Judy
J
Richards
Zhongping
Z
Deng
Jerrold L
JL
Abraham
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism*
D005682:Gadolinium; D007501:Iron
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