Transcriptome Profiling and Toxicity Following Long-Term, Low Dose Exposure of Human Lung Cells to Ni and NiO Nanoparticles—Comparison with NiCl2

Abstract

Production of nickel (Ni) and nickel oxide (NiO) nanoparticles (NPs) leads to a risk of exposure and subsequent health effects. Understanding the toxicological effects and underlying mechanisms using relevant in vitro methods is, therefore, needed. The aim of this study is to explore changes in gene expression using RNA sequencing following long term (six weeks) low dose (0.5 µg Ni/mL) exposure of human lung cells (BEAS-2B) to Ni and NiO NPs as well as soluble NiCl₂. Genotoxicity and cell transformation as well as cellular dose of Ni are also analyzed. Exposure to NiCl₂ resulted in the largest number of differentially expressed genes (197), despite limited uptake, suggesting a major role of extracellular receptors and downstream signaling. Gene expression changes for all Ni exposures included genes coding for calcium-binding proteins (<i>S100A14</i> and <i>S100A2</i>) as well as <i>TIMP3</i>, <i>CCND2</i>, <i>EPCAM</i>, <i>IL4R</i> and <i>DDIT4</i>. Several top enriched pathways for NiCl₂ were defined by upregulation of, e.g., interleukin-1A and -1B, as well as Vascular Endothelial Growth Factor A (<i>VEGFA</i>). All Ni exposures caused DNA strand breaks (comet assay), whereas no induction of micronuclei was observed. Taken together, this study provides an insight into Ni-induced toxicity and mechanisms occurring at lower and more realistic exposure levels.