A unified in silico model based on perturbation theory for assessing the genotoxicity of metal oxide nanoparticles.

Nanomaterials (NMs) are an ever-increasing field of interest, due to their wide range of applications in science and technology. However, despite providing solutions to many societal problems and challenges, NMs are associated with adverse effects with potential severe damages towards biological species and their ecosystems. Particularly, it has been confirmed that NMs may induce serious genotoxic effects on various biological targets. Given the difficulties of experimental assays for estimating the genotoxicity of many NMs on diverse biological targets, development of alternative methodologies is crucial to establish their level of safety. In silico modelling approaches, such as Quantitative Structure-Toxicity Relationships (QSTR), are now considered a promising solution for such purpose. In this work, a perturbation theory machine learning (PTML) based QSTR approach is proposed for predicting the genotoxicity of metal oxide NMs under various experimental assay conditions. The application of such perturbation approach to 6084 NM-NM pair cases, set up from 78 unique NMs, afforded a final PTML-QSTR model with an accuracy better than 96% for both training and test sets. This model was then used to predict the genotoxicity of some NMs not included in the modelling dataset. The results for this independent data set were in excellent agreement with the experimental ones. Overall, that thus suggests that the derived PTML-QSTR model is a reliable in silico tool to rapidly and cost-efficiently assess the genotoxicity of metal oxide NMs. Finally, and most importantly, the model provides important insights regarding the mechanism of the genotoxicity triggered by these NMs.