Immunotoxicity of zinc oxide nanoparticles with different size and electrostatic charge

Abstract

While zinc oxide (ZnO) nanoparticles (NPs) have been recognized to have promising applications in biomedicine, their immunotoxicity has been inconsistent and even contradictory. To address this issue, we investigated whether ZnO NPs with different size (20 or 100 nm) and electrostatic charge (positive or negative) would cause immunotoxicity in vitro and in vivo, and explored their underlying molecular mechanism. Using Raw 264.7 cell line, we examined the immunotoxicity mechanism of ZnO NPs as cell viability. We found that in a cell viability assay, ZnO NPs with different size and charge could induce differential cytotoxicity to Raw 264.7 cells. Specifically, the positively charged ZnO NPs exerted higher cytotoxicity than the negatively charged ones. Next, to gauge systemic immunotoxicity, we assessed immune responses of C57BL/6 mice after oral administration of 750 mg/kg/day dose of ZnO NPs for 2 weeks. In parallel, ZnO NPs did not alter the cell-mediated immune response in mice but suppressed innate immunity such as natural killer cell activity. The CD4 + /CD8 + ratio, a marker for matured T-cells was slightly reduced, which implies the alteration of immune status induced by ZnO NPs. Accordingly, nitric oxide production from splenocyte culture supernatant in ZnO NP-fed mice was lower than control. Consistently, serum levels of pro/anti-inflammatory (interleukin [IL]-1β, tumor necrosis factor-α, and IL-10) and T helper-1 cytokines (interferon-γ and IL-12p70) in ZnO NP-fed mice were significantly suppressed. Collectively, our results indicate that different sized and charged ZnO NPs would cause in vitro and in vivo immunotoxicity, of which nature is an immunosuppression.

The Toxicity Phenomenon and the Related Occurrence in Metal and Metal Oxide Nanoparticles: A Brief Review From the Biomedical Perspective

“…It was believed that the positively charged NPs induce more toxicity and it can affect the cellular uptake and intracellular location (Asati et al, 2010;De Angelis et al, 2013). Kim et al (2014) also proved the higher cytotoxicity of positively charged ZnO NPs in comparison to the negatively charged ones. In addition, genotoxicity and DNA damage was seen in ZnO treated MRC5 lung cells along with the high secretion of extracellular LDH and reduction in cell viability (Ng et al, 2017).…”

“… Thevenot et al (2008) demonstrated that negative charged COOH treated TiO 2 NPs had not an impact on the cell viability because they can easily be absorbed into the cells without any membrane binding. In fact, the positively charged particles are more toxic and the variance surface charge determines the cellular uptake, the positively charged ZnO NPs show increased toxicity values compared to negatively charged NPs ( Kim et al, 2014 ).…”

Dietary ZnO nanoparticles alters intestinal microbiota and inflammation response in weaned piglets

“…It has been reported that Nano-ZnO differed from ordinary ZnO due to its unique chemical and physical properties, including the effect of volume, surface, quantum size and macro quantum tunnel [ 5 ], in addition, Nano-ZnO only partly dissolved in gastric fluid in vivo [ 6 ], and showed a limited solubility in neutral environments [ 7 ]. Thus, Nano-ZnO is likely absorbed as the intact particulate form and as zinc ions [ 8 ]. Studies about Nano-ZnO application mainly focused on the hazards or toxicity in a dose- and time-dependent manner, which was probably caused by reactive oxygen species, oxidant injury or excitation of inflammation [ 9 ].…”

<p>Effect of commercial and green synthesized ZnO NPs in murine model of chloroquine-induced pruritus</p>

“…However, CQ-induced pruritus is also mediated by increased production of NO (linked to cGMP) 41. In in vivo studies, ZnO NPs have been reported to reduce NO level 36,41. Here, the reduction in scratching intensity could be attributed to the ZnO NPs’ NO lowering property.…”

“…ZnO NPs have successfully been synthesized using various plant extracts as reducing agents 35. Yet, toxicities and bio-hazards of ZnO NPs are conflicting 36…”