Nanostructured materials have been suggested to be used as a source of dietary zinc for livestock animals. In this study, we assessed the cytotoxicity of newly synthesized nanostructured zinc carbonate hydroxide (ZnCH) Zn5(CO3)(OH)6microflakes. Cytotoxicity of the microflakes was assessed against murine L929 cell line and rat mature erythrocytes. Viability, motility, cell death pathways, implication of Ca2+, reactive oxygen species and reactive nitrogen species (RNS) signaling, caspases, and alterations of cell membranes following exposure of L929 cells to the microflakes were assessed. To assess hemocompatibility of the Zn-containing microflakes, osmotic fragility and hemolysis assays were performed, as well as multiple eryptosis parameters were evaluated. Our findings indicate a dose-response cytotoxicity of ZnCH microflakes against L929 cells with no toxicity observed for low concentrations (10 mg l-1and below). At high concentrations (25 mg l-1and above), ZnCH microflakes promoted nitrosyl stress, Ca2+- and caspase-dependent apoptosis, and altered lipid order of cell membranes in a dose-dependent manner, evidenced by up to 7-fold elevation of RNS-dependent fluorescence, 2.9-fold enhancement of Fura 2-dependent fluorescence, over 20-fold elevation of caspases-dependent fluorescence (caspase-3, caspase-8, and caspase-9), and up to 4.4-fold increase in the ratiometric index of the NR12S probe. Surprisingly, toxicity to enucleated mature erythrocytes was found to be lower compared to L929 cells. ZnCH microflakes induced eryptosis associated with oxidative stress, nitrosyl stress, Ca2+signaling and recruitment of caspases at 25-50-100 mg l-1. Eryptosis assays were found to be more sensitive than evaluation of hemolysis. Zn5(CO3)(OH)6microflakes show no cytotoxicity at low concentrations indicating their potential as a source of zinc for livestock animals.

BIOCEV 1st Faculty of Medicine Charles University Průmyslová 595 25250 Vestec Czech Republic

Department of Biochemistry 5 N Karazin Kharkiv National University 4 Svobody sq 61022 Kharkiv Ukraine

Department of Cryobiochemistry Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23 Pereyaslavskaya st 61015 Kharkiv Ukraine

Department of Microbiology Virology and Immunology West Kazakhstan Marat Ospanov Medical University 68 Maresyev st 030012 Aktobe Kazakhstan

Department of Nanostructured Materials Institute for Scintillation Materials of the National Academy of Sciences of Ukraine 60 Nauky ave 61072 Kharkiv Ukraine

Institute for Single Crystals National Academy of Sciences of Ukraine 60 Nauky ave 61072 Kharkiv Ukraine

Institute of Health National University of Water and Environmental Engineering 11 Soborna st 33028 Rivne Ukraine

Medical Biochemistry Department Nevsehir Haci Bektas Veli University 2000 Evler Mah Zübeyde Hanım Cad 50300 Nevşehir Turkey

Research Institute of Experimental and Clinical Medicine Kharkiv National Medical University 4 Nauky ave 61022 Kharkiv Ukraine

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