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Human relevant in-vitro models for developmental neurotoxicity testing

Human iPSC-derived neuronal cells (stained for β-III-Tubulin) after 21 days of differentiation
Oct 17 2017

JRC scientists have shown that human induced pluripotent stem cell-derived neurons are suitable non-animal models for testing neurotoxicity during brain development. The study revealed that long term exposure to the pesticide rotenone induces oxidative stress and can trigger neuronal cell death.

Exposure of developing organisms to chemicals may affect the development of the nervous system. In recent years, neurodevelopmental disorders in children have increased significantly. Therefore, the JRC's EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) is working with international partners to address the pressing need to implement reliable models to test potentially harmful effects of environmental chemicals and investigate mechanisms of developmental neurotoxicity (DNT) underlying chemical exposure.

Modern toxicity screening approaches are focused on reducing and replacing animal testing with alternative and human relevant models. In this context, human induced pluripotent stem cells (hiPSCs) represent important tools for toxicity screening because of their unique characteristics.

In a previous JRC study, hiPSC neuronal derivatives were used to assess the neurotoxic effects of rotenone - a broad-spectrum pesticide - after short-term exposure (24 hours). Rotenone induced the activation of the Nrf2 signalling pathway*, which regulates cellular response to oxidative stress. Oxidative stress is an important hallmark of various neurodegenerative diseases, including Parkinson's disease.

In this new study, JRC scientists investigated the effects of a prolonged rotenone exposure (14 days) on hiPSC-derived neural stem cells (NSCs) undergoing differentiation towards neurons and glia, assessing the expression and the activation of the Nrf2 pathway. Treatment with rotenone induced a progressive activation of Nrf2 signalling, together with an induction of astrocyte reactivity and neuronal cell death, in particular of dopaminergic neurons. Altogether these data indicate that hiPSC-neural models are relevant test systems for the evaluation of Nrf2 pathway activation upon induction of oxidative stress, allowing further understanding of the molecular mechanisms underlying exposure to developmental neurotoxicants.

It is believed that human stem cell derivatives could meet the need to improve current testing strategies to identify, characterise and prioritise chemicals for their potential to cause DNT.

*Signalling pathway describes a group of molecules in a cell that work together to control cell functions, such as cell division or cell death.

Read more in: Pistollato F, Canovas-Jorda D, Zagoura D, Bal-Price A: "Nrf2 pathway activation upon rotenone treatment in human iPSC-derived neural stem cells undergoing differentiation towards neurons and astrocytes", Neurochem Int. 108 (2017) 457-471. doi: 10.1016/j.neuint.2017.06.006


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