Abstract
Iron oxide nanoparticles are used in various industrial fields, as a tool in biomedicine as well as in food colorants, and can therefore reach human metabolism via oral uptake or injection. However, their effects on the human body, especially the liver as one of the first target organs is still under elucidation. Here, we studied the influence of different representative iron oxide materials on xenobiotic metabolism of HepaRG cells. These included four iron oxide nanoparticles, one commercially available yellow food pigment (E172), and non-particulate ionic control FeSO4. The nanoparticles had different chemical and crystalline structures and differed in size and shape and were used at a concentration of 50 µg Fe/mL. We found that various CYP enzymes were downregulated by some but not all iron oxide nanoparticles, with the Fe3O4-particle, both γ-Fe2O3-particles, and FeSO4 exhibiting the strongest effects, the yellow food pigment E172 showing a minor effect and an α-Fe2O3 nanoparticle leading to almost no inhibition of phase I machinery. The downregulation was seen at the mRNA, protein expression, and activity levels. Thereby, no dependency on the size or chemical structure was found. This underlines the difficulty of the grouping of nanomaterials regarding their physiological impact, suggesting that every iron oxide nanoparticle species needs to be evaluated in a case-by-case approach.
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Acknowledgements
We would like to thank Lisa Klusmann for her kind assistance with the AAS measurements, Lisa Gödtke for her help with the sample acquisition of CYP-activity and quantity measurements, and Markus König for technical assistance with CYP activity measurements.
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This work was supported by the German Federal Institute for Risk Assessment (Project 1323-102) and in part by the Robert-Bosch Foundation (Stuttgart, Germany).
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LV, AB, LB, and HS were responsible for the conceptualization of the present study. LV and KY acquired the gene expression data, LV, VS, and LB conducted the MTT assay. The sp-ICP-MS data was acquired and evaluated by JV, KL and LV. LV prepared the samples for CYP-quantity and activity-measurements, they were measured by OP and HH (quantity) and UH (activity). MP and LV did the MagPix measurements. LV created the first draft. All authors have given approval to the final version of the manuscript.
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The authors declare the following competing financial interest(s): Oliver Pötz is shareholder of SIGNATOPE GmbH. SIGNATOPE offers assay development and service using MS-based immunoassay technology. Apart from that, the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Voss, L., Yilmaz, K., Burkard, L. et al. Impact of iron oxide nanoparticles on xenobiotic metabolism in HepaRG cells. Arch Toxicol 94, 4023–4035 (2020). https://doi.org/10.1007/s00204-020-02904-1
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DOI: https://doi.org/10.1007/s00204-020-02904-1