ToxTracker Reporter Cell Lines as a Tool for Mechanism-Based (Geno)Toxicity Screening of Nanoparticles—Metals, Oxides and Quantum Dots

Abstract

The increased use of nanoparticles (NPs) requires efficient testing of their potential toxic effects. A promising approach is to use reporter cell lines to quickly assess the activation of cellular stress response pathways. This study aimed to use the ToxTracker reporter cell lines to investigate (geno)toxicity of various metal- or metal oxide NPs and draw general conclusions on NP-induced effects, in combination with our previous findings. The NPs tested in this study (n = 18) also included quantum dots (QDs) in different sizes. The results showed a large variation in cytotoxicity of the NPs tested. Furthermore, whereas many induced oxidative stress only few activated reporters related to DNA damage. NPs of manganese (Mn and Mn3O4) induced the most remarkable ToxTracker response with activation of reporters for oxidative stress, DNA damage, protein unfolding and p53-related stress. The QDs (CdTe) were highly toxic showing clearly size-dependent effects and calculations suggest surface area as the most relevant dose metric. Of all NPs investigated in this and previous studies the following induce the DNA damage reporter; CuO, Co, CoO, CdTe QDs, Mn, Mn3O4, V2O5, and welding NPs. We suggest that these NPs are of particular concern when considering genotoxicity induced by metal- and metal oxide NPs.

Cytotoxic effects of manganese oxide nanoparticles in combination with microbial components on intestinal epithelial cells

“…Environmental exposure to MnO NPs can occur as a result of occupational exposure in manganese ore processing, the metallurgy industry, metalworking, welding, and various potential biomedical applications [20][21][22]39 . MnO NP have been shown to cause impairment of dopaminergic neurons and induce inflammation in the brain, increase in oxidative stress and apoptosis in alveolar epithelial cells, and increase oxidative stress and DNA damage in mouse embryonic stem cells, human breast cancer epithelial cells, and human fibrosarcoma epithelial cells [39][40][41][42] . However, few studies have evaluated at the effects of MnO NP toxicity on intestinal epithelial cells, even though the primary route of exposure would be oral or ingestion.…”

From Basic Research to New Tools and Challenges for the Genotoxicity Testing of Nanomaterials

“…This issue contains mostly data from in vitro studies. In addition to classical cell lines such as hamster and human fibroblasts [ 1 , 2 ] or human lung cells [ 3 , 4 ], new models have been also used for investigating nanomaterials genotoxicity: ToxTracker reporter cell lines [ 5 ], human amniotic cells [ 6 ] and 3D HepG2 spheroids [ 7 ]. In this issue, three papers also deal with in vivo studies: on the plant Allium cepa [ 8 ], on the tadpoles of Xenopus laevis [ 9 ] and on rats [ 10 ].…”

“…Concerning the role of the physico-chemical characteristics, it was reported that the surface area is one of the dose metrics showing a better correlation with the genotoxicity of quantum dots [ 5 ], while the metal/coating agent ratio is a key parameter for the toxicity observed with the commercially available AgNPs formulation Argovit™ [ 8 ]. Similarly, the thermal reduction of graphene oxides generates a material that was no longer genotoxic at low concentrations [ 9 ].…”

“…In contrast, the type of synthesis used for producing tungstene particles did not significantly affect the toxicity [ 4 ]. The impact of size was investigated on the toxic responses either using two protocols of dispersion with TiO 2 nanoparticles leading to different size distribution [ 1 ] or by testing similar nanomaterials with different primary sizes [ 5 ]. Such results are integrated into a “safe by design” approach by investigating solutions to decrease the genotoxicity of the nanomaterials through specific coatings, production processes or treatments as examples.…”

“…A high throughput methodology applied to the comet assay has been used in the European project NanoReg [ 3 ]. ToxTracker reporter cell lines [ 5 ] can be also a way to quickly assess the activation of cellular stress response pathways.…”