Metal oxides and oxidative stress

The production of manufactured nanomaterials represents an indisputable scientific and technological breakthrough. However, while nanotechnologies can be both innovative solutions to major societal challenges (energy, health, environment) and a vector for global economic growth, we also need to consider the impact of nanoparticles' physico-chemical properties on the environment and on biological systems. In order to assess the hazards of nanoparticles in a reliable and reproducible way, screening approaches are needed. In particular, many research laboratories are beginning to develop test platforms to analyze bio-physical-chemical interactions at the nanomaterials/biology interface. Studying the effects and mechanisms involved enables a predictive toxicological approach. The use of in vitro high-throughput screening (HTS) methods, coupled with statistical analysis based on Combinatorics libraries, enables us to predict which nanomaterials may lead to the generation of pathologies or diseases. The results of in vivo tests on animals and on human cells or implanted cell lines are used to validate and improve the MCHD in vitro test system. Modeling, combined with an appropriate combination of in vitro and in vivo results, enables the structure-activity relationships of nanomaterials to be established in a robust way, and them to be classified according to toxicity risks. In this context, we have focused on the nanotoxicological analysis of particles based on metal oxides of the formula MxOy (M = Al, Ti, Co, Cr, Ce, Fe, Gd, Hf, La, Mn, Ni, Sb, Sn, Si,W, Y, Zn, Yb...) In this particular case, the oxidative stress created by certain oxides and/or the solubility of the nano-object are the main causes of toxicity. In particular, oxidative stress can generate various pathologies (aging, cancer, chronic inflammation, neurodegenerative diseases). There are three levels of cellular response to oxidative stress, in relation to which the activity of different nanoparticles has been classified: antioxidant defense, inflammation and cytoxicity. In particular, the analysis of published data has enabled us to establish a predictive paradigm in toxicology for assessing the risks posed by nanomaterials in this family of oxides. For oxidative stress in particular, it would appear that there is a good correlation between nano-object toxicity and the energetic position of its conduction band in relation to the redox potential of the _H+/H2 couple. In this set of analyses, nanoparticles of Nickel, Cobalt, Manganese and Chromium oxides are clearly toxic, as they generate significant oxidative stress. However, the main cause of the toxicity of Zinc and Copper oxide nanoparticles is associated with their high solubility, which leads to lysosomal disruption via the proton pump effect. Knowing the cause, the toxicity of ZnO can be greatly reduced by inserting iron into the structure, which greatly reduces the nano-object's solubility. Indeed, all in vitro (CHD) and in vivo (on mice and zebrafish) tests seem to show an absence of toxicity for iron substitution rates of 8%. On the other hand, the other oxides studied did not respond positively to all the in vitro (CHD) and in vivo toxicity tests, but showed little or no toxicity. Some of them are used as contrast agents in nuclear magnetic resonance imaging (magnetic iron oxides), in regenerative medicine to treat macular degeneration (cerium oxide), as luminescent probes (lanthanide oxides) or as hybrid therapeutic nanovectors for therasnostics (silica). The latter material, silica, is the focus of numerous research projects (in cosmetics and nanomedicine) and industrial developments. However, an analysis of the literature on silica toxicity seemed to show a disparity in the conclusions of studies carried out by different authors. That's why, in the following lecture, we take a closer look at silica toxicity.