Iron diminishes the in vitro biological effect of vanadium

Mechanistic pathways underlying inflammatory injury following exposures to vanadium-containing compounds are not defined. We tested the postulate that the in vitro biological effect of vanadium results from its impact on iron homeostasis. Human bronchial epithelial (HBE) cells exposed to vanadyl sulfate (VOSO4) showed a time- and dose-dependent increase in vanadium relative to PBS. HBE cells exposed to VOSO4 and then exposed to ferric ammonium citrate (FAC) significantly increased intracellular iron import supporting an interaction between the two metals. Following exposure to VOSO4, there was an increase (336±73%) in RNA for divalent metal transporter 1 (DMT1), a major iron importer. With inclusion of VOSO4 in the incubation, vanadium could be measured in the nuclear and mitochondrial fractions and the supernatant. Non-heme iron in the nuclear and mitochondrial fractions were decreased immediately following VOSO4 exposure while there was an increased concentration of non-heme iron in the supernatant. Provision of excess iron inhibited changes in the concentration of this metal provoked by VOSO4 exposures. Using Amplex Red, VOSO4 was shown to significantly increase oxidant generation by HBE cells in a time- and dose-dependent manner. HBE cells pre-treated with FAC and then exposed to VOSO4 demonstrated a decreased generation of oxidants. Similarly, activation of the transcription factor NF-ĸB promoter and release of interleukin-6 and -8 were increased following VOSO4 exposure and these effects were diminished by pre-treatment with FAC. We conclude that an initiating event in biological effect after exposure to vanadyl sulfate is a loss of requisite cell iron. Schematic for changes following cell exposure to vanadyl sulfate. (A) Vanadyl cation displaces iron from intracellular cites. (B) The cell generates superoxide which can function as a ferri-reductant. (C) Iron importers and storage proteins are upregulated. (D) Protracted oxidant generation can impact inflammation. [Display omitted] •We tested the postulate that vanadium exposure would impact iron homeostasis.•Vanadyl sulfate decreased iron in the nuclei and mitochondria.•Provision of excess iron inhibited any loss of iron.•Inflammatory effects of vanadium were diminished by excess iron.•Loss of requisite cell iron after vanadium exposure initiates biological effect.