Zinc oxide nanoparticles exhibit cytotoxicity and genotoxicity through oxidative stress responses in human lung fibroblasts and <em>Drosophila melanogaster</em>

Abstract

Background Although zinc oxide nanoparticles (ZnO NPs) have been widely used, there has been an increasing number of reports on the toxicity of ZnO NPs. However, study on the underlying mechanisms under in vivo conditions is insufficient. Methods In this study, we investigated the toxicological profiles of ZnO NPs in MRC5 human lung fibroblasts in vitro and in an in vivo model using the fruit fly Drosophila melanogaster . A comprehensive study was conducted to evaluate the uptake, cytotoxicity, reactive oxygen species (ROS) formation, gene expression profiling and genotoxicity induced by ZnO NPs. Results For in vitro toxicity, the results showed that there was a significant release of extracellular lactate dehydrogenase and decreased cell viability in ZnO NP-treated MRC5 lung cells, indicating cellular damage and cytotoxicity. Generation of ROS was observed to be related to significant expression of DNA Damage Inducible Transcript ( DDIT3 ) and endoplasmic reticulum (ER) to nucleus signaling 1 ( ERN1 ) genes, which are ER stress-related genes. Oxidative stress induced DNA damage was further verified by a significant release of DNA oxidation product, 8-hydroxydeoxyguanosine (8-OHdG), as well as by the Comet assay. For the in vivo study using the fruit fly D. melanogaster as a model, significant toxicity was observed in F1 progenies upon ingestion of ZnO NPs. ZnO NPs induced significant decrease in the egg-to-adult viability of the flies. We further showed that the decreased viability is closely associated with ROS induction by ZnO NPs. Removal of one copy of the D. melanogaster Nrf2 alleles further decreased the ZnO NPs-induced lethality due to increased production of ROS, indicating that nuclear factor E2-related factor 2 (Nrf2) plays important role in ZnO NPs-mediated ROS production. Conclusion The present study suggests that ZnO NPs induced significant oxidative stress-related cytotoxicity and genotoxicity in human lung fibroblasts in vitro and in D. melanogaster in vivo. More extensive studies would be needed to verify the safety issues related to increased usage of ZnO NPs by consumers.

Population Effects of Calcium Phosphate Nanoparticles in Drosophila melanogaster: The Effects of Phase Composition, Crystallinity, and the Pathway of Formation

“…27 Chronic cold exposure can shift the sex ratio toward a male-biased extreme, 28 whereas spiroplasma endosymbionts, the maternally inherited micro-organisms that infect arthropod species including Drosophila and act as reproductive manipulators by killing exclusively sons of infected mothers may be a factor involved in this variation. 29 Genotoxic effects have been observed in Drosophila dosed with inorganic nanoparticles, 30–32 but they are improbable to occur with CPs, especially at the low concentration in media of 0.3 wt % used in this study. Even more elevated calcium levels would have been expected to produce a more systemic, cell signaling effect rather than a genotypic one.…”

Nanoparticles in Daily Life: Applications, Toxicity and Regulations

“…The cytotoxicity and genotoxicity potential of ZnONPs has been shown both in vitro and in vivo. 24,25 In further studies, ZnONPs have reduced cell viability in dose-dependent and time-dependent manner. 26 ZnONPs are suspected of increasing the expression of the metallothionein gene, which is considered a biomarker in metal-induced toxicity.…”

Toxicological characterization of ZnO nanoparticles in malignant and non‐malignant cells

“…[Heinlaan et al, 2008;Ma et al, 2009;Kao et al, 2012]. It was reported that dissolved Zn21 ions even caused more toxicity to cells than the nanoparticle portion [Ng et al, 2017]. Yet, Moos et al [2010] found that although ZnO-NPs released zinc ions in an aqueous state, the concentrations were not able to induce toxic effects.…”