Towards an integrated risk assessment of micro- and nanoparticles: planarians as an alternative in vivo model to link particle characteristics and uptake dynamics to adverse outcomes

Abstract

Within our current world, micro- and nanoparticles form a potential threat to human and animal health. Diverse micro- and nanoparticles have already been found to induce neurotoxicity, often characterized by abnormal behavior or aberrant memory. However, the underlying mechanisms of particle-induced neurotoxicity are poorly understood, underscoring a critical gap in our knowledge with far-reaching consequences. Especially the diversity in micro- and nanoparticle types complicates the analysis of their potential health effects. More specifically, it is unknown how different particle characteristics determine cellular uptake and tissue localization, how this is linked with the elicited responses and how they can be correlated with detailed mechanistic insights. To obtain this comprehensive understanding, we need to link particle characteristics with particle uptake profiles and the observed adversed outcomes.

Here, we demonstrate the added value of planarians as an alternative in vivo model within the 3R principle for the toxicity assessment of micro- and nanoparticles, with a specific focus on neurodevelopmental toxicity. The freshwater planarian Schmidtea mediterranea is characterized by a high regenerative capacity, which is attributed to a large pool of pluripotent stem cells (neoblasts). Based on planarian behavior, regenerative success and underlying stem cell and neuronal responses, we investigate complex toxicological outcomes at different levels of biological organization and aim to identify specific adverse outcome pathways related to particle-induced neurotoxicity. In addition, we combine these observations with a detailled study of the physicochemical characteristics of the particles (e.g. composition, size, shape, charge, agglomeration behaviour …) and link this with information regarding their tissue, cellular and subcellular uptake behaviour. Together, this strategy allows an integrated risk assessment of micro- and nanoparticles, with a specific focus on neurodevelopmental toxicity.