Nano-sized zinc oxide and silver, but not titanium dioxide, induce innate and adaptive immunity and antiviral response in differentiated THP-1 cells

Abstract

Nano-sized metal oxides are currently the most manufactured nanomaterials (NMs), and are increasingly used in consumer products. Recent exposure data reveal a genuine potential for adverse health outcomes for a vast array of NMs, however the underlying mechanisms are not fully understood. To elucidate size-related molecular effects, differentiated THP-1 cells were exposed to nano-sized materials (n-TiO n-ZnO and n-Ag), or their bulk-sized (b-ZnO and b-TiO) or ionic (i-Ag) counterparts, and genome-wide gene expression changes were studied at low-toxic concentrations (<15% cytotoxicity). TiO materials were nontoxic in MTT assay, inducing only minor transcriptional changes. ZnO and Ag elicited dose-dependent cytotoxicity, wherein ionic and particulate effects were synergistic with respect to n-ZnO-induced cytotoxicity. In gene expression analyzes, 6 h and 24 h samples formed two separate hierarchical clusters. N-ZnO and n-Ag shared only 3.1% and 24.6% differentially expressed genes (DEGs) when compared to corresponding control. All particles, except TiO, activated various metallothioneins. At 6 h, n-Zn, b-Zn and n-Ag induced various immunity related genes associating to pattern recognition (including toll-like receptor), macrophage maturation, inflammatory response (TNF and IL-1beta), chemotaxis (CXCL8) and leucocyte migration (CXCL2-3 and CXCL14). After 24 h exposure, especially n-Ag induced the expression of genes related to virus recognition and type I interferon responses. These results strongly suggest that in addition to ionic effects mediated by metallothioneins, n-Zn and n-Ag induce expression of genes involved in several innate and adaptive immunity associated pathways, which are known to play crucial role in immuno-regulation. This raises the concern of safe use of metal oxide and metal nanoparticle products, and their biological effects.

Mechanistic Similarities between 3D Human Bronchial Epithelium and Mice Lung, Exposed to Copper Oxide Nanoparticles, Support Non‐Animal Methods for Hazard Assessment

“…Gene set enrichment analysis based on the shared mouse and human DEG, reveal that these genes are signature genes of human bronchial epithelial cells and human/mouse bulk lung tissue ( Figure 2C, upper panel). The most significant biological processes represented by these shared genes are again consistent with known [11][12][13][14][15][16] pathobiological responses to metal oxide-based nanoparticles ( Figure 2C, lower panel). These were; response to organic substance (adj.…”

“…Since the biological functions represented by the shared differentially expressed gene-orthologue pairs have also been previously linked to toxicity of copper oxide nanoparticles, in in vitro and in vivo systems, [9,15,27,28] we performed correlation Figure 5. Identification of similarly activated/de-activated biological processes between shared mouse-human differentially expressed genes.…”

Differential influence ofStreptococcus mitison host response to metals in reconstructed human skin and oral mucosa

“…TiO 2 NP is also inert for THP-1 macrophages because it does not influence genes involved in modulating macrophage maturation, inflammatory responses, chemotaxis, and leukocyte migration. 78 In addition, TiO 2 cannot induce skin sensitization in LLNA in mice. 79 However TiO 2 NPs were found to act as an adjuvant when co-applied with the bacterial fragments LPS and peptidoglycan; 80 or co-applied with ovalbumin (OVA) 28 or toluene-2,4-diiscocyanate (TDI), 81 which significantly induced pulmonary sensitization in mice.…”

Mass Cytometry and Single‐Cell RNA‐seq Profiling of the Heterogeneity in Human Peripheral Blood Mononuclear Cells Interacting with Silver Nanoparticles

“…Thus, to understand the interactions of NPs with biological systems more comprehensively at a molecular level, the NP-induced transcriptional changes should be investigated. A variety of methods have been applied in monitoring the transcriptional cellular responses to NP exposure, such as microarray, [25] reverse-transcription polymerase chain reaction (RT-PCR), [26] and bulk RNA sequencing (RNA-seq). [27] Recent advancements in next-generation sequencing technology have enabled the analysis of single-cell transcriptome and cell-tocell variability in the genomic and transcriptomic effects of NPs, which are often masked in bulk RNA-seq.…”