Immunotoxicity of silicon dioxide nanoparticles with different sizes and electrostatic charge

Abstract

Jae-Hyun Kim,1,* Cheol-Su Kim,1,* Rosa Mistica Coles Ignacio,2,* Dong-Heui Kim,2 Ma Easter Joy Sajo,2 Eun Ho Maeng,3 Xu-Feng Qi,4 Seong-Eun Park,5 Yu-Ri Kim,7 Meyoung-Kon Kim,7 Kyu-Jae Lee,2 Soo-Ki Kim1,5,6 1Department of Microbiology, 2Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju-si, Gangwon-do, Republic of Korea; 3Healthcare Laboratory, Medical Device Evaluation, Korea Testing and Research Institute, Wonju-si, Gangwon-do, Republic of Korea; 4Key Laboratory for Regenerative Medicine of Ministry of Education and Department of Developmental and Regenerative Biology, School of Life Science and Technology, Ji Nan University, Guangzhou, People’s Republic of China; 5Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju-si, Gangwon-do, Republic of Korea; 6Institute of Biomaterials, Yonsei University, Wonju Campus, Wonju-si, Gangwon-do, Republic of Korea; 7Department of Biochemistry and Molecular Biology, Medical School and College, Korea University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Silicon dioxide (SiO2) nanoparticles (NPs) have been widely used in the biomedical field, such as in drug delivery and gene therapy. However, little is known about the biological effects and potential hazards of SiO2. Herein, the colloidal SiO2 NPs with two different sizes (20 nm and 100 nm) and different charges (L-arginine modified: SiO2EN20[R], SiO2EN100[R]; and negative: SiO2EN20[-], SiO2EN100[-]) were orally administered (750 mg/kg/day) in female C57BL/6 mice for 14 days. Assessments of immunotoxicity include hematology profiling, reactive oxygen species generation and their antioxidant effect, stimulation assays for B- and T-lymphocytes, the activity of natural killer (NK) cells, and cytokine profiling. In vitro toxicity was also investigated in the RAW 264.7 cell line. When the cellularity of mouse spleen was evaluated, there was an overall decrease in the proliferation of B- and T-cells for all the groups fed with SiO2 NPs. Specifically, the SiO2EN20(-) NPs showed the most pronounced reduction. In addition, the nitric oxide production and NK cell activity in SiO2 NP-fed mice were significantly suppressed. Moreover, there was a decrease in the serum concentration of inflammatory cytokines such as interleukin (IL)-1Β, IL-12 (p70), IL-6, tumor necrosis factor-α, and interferon-γ. To elucidate the cytotoxicity mechanism of SiO2 in vivo, an in vitro study using the RAW 264.7 cell line was performed. Both the size and charge of SiO2 using murine macrophage RAW 264.7 cells decreased cell viability dose-dependently. Collectively, our data indicate that different sized and charged SiO2 NPs would cause differential immunotoxicity. Interestingly, the small-sized and negatively charged SiO2 NPs showed the most potent in vivo immunotoxicity by way of suppressing the proliferation of lymphocytes, depressing the killing activity of NK cells, and decreasing proinflammatory cytokine production, thus leading to immunosuppression. Keywords: silicon dioxide, nanoparticle, immunotoxicity, oxidative stress, cytokines, immunosuppression