The effect of compounds on the developing brain is largely unknown. Therefore, there is a high need for testing the adverse effects of compound exposure on the development of the brain.
Short video about RIVM's activities researching in vitro neurotoxicity testing using stem cells
video
In vitro developmental neurotoxicity
Speaker: Dr. Ellen Hessel, scientific researcher developmental neurotoxicology
DR. ELLEN HESSEL: We are developing a model based on human embryonic stem cells and the model mimics a part of the brain development. The model is used to test the safety of compounds.
VISUAL: In vitro developmental neurotoxicity
VOICE OVER: Disruption of brain development may have enormous impact on future life and might result in disorders such as ADHD or mental retardation. It is known that genetic factors contribute to these disorders, but environmental factors, such as exposure to compounds, may also play a role.
DR. ELLEN HESSEL: The effect of compounds on the developing brain is largely unknown. Therefore, there is a high need for testing adverse effects on the brain development of compound exposure.
VOICE OVER: A testing strategy with in vitro and in silico methods based on the biology of human brain development will help to unravel the adverse effects of compounds on the developing brain.
DR. ELLEN HESSEL: RIVM is developing an in vitro method that mimics parts of the brain development. This model is based on human stem cells. Human embryonic stem cells and induced pluripotent stem cells from blood can be used. As a first step, these stem cells are differentiated into neural progenitor cells. These neural progenitor cells can be frozen or re-cultured and differentiated in a neuron-astrocyte network, within 10 days. This is a relatively short and robust protocol.
VOICE OVER: With this differentiation method the model can develop a functional neuronal network.
DR. ELLEN HESSEL: Characterisation of the model with gene and protein expression show that we have neurons and astrocytes within the model and the ratio of these cells differ during the 10-day differentiation period. After 3 days, we even have spontaneous electrical activity within the model. With this model we show that compounds affect neuronal differentiation and this is in line with in vivo data. This model can be an important component in a testing strategy for developmental neurotoxicity and to measure the effect of chemicals and pharmaceuticals on the developing brain. This method is human-relevant and animal-free and is based on mechanistic knowledge of human biology of brain development.
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Developmental neurotoxicity
Disruption of brain development may have an enormous impact on future life and might result in disorders such as ADHD or mental retardation. It Is known that genetic factors contribute to these disorders, but environmental factors, such as exposure to compounds, may also play a role.
Human stem cells
A testing strategy with in vitro and in silico methods, based on the biology of human brain development, will help to unravel the adverse effects of compounds on the developing brain. As part of this testing strategy, RIVM is developing an in vitro method that mimics parts of the brain development, the human neuroprogenitor test (hNTP). This method is based on human stem cells. Both human embryonic stem cells and induced pluripotent stem cells from blood can be used.
Effects on developing neurons and astrocytes
This hNTP model is a robust differentiation method that allows for studying the differentiation of neural progenitor cells into a cell culture containing excitatory neurons, inhibitory neurons and astrocytes. These cells together form a functional neuronal network showing spontaneous electrical activity. Effects of compounds on neuronal differentiation can be tested in this model using readouts such as gene- and protein expression. This model can measure the effect of chemicals and pharmaceuticals on the developing brain and can serve as a part of a testing strategy for developmental neurotoxicity.
Projects
Currently running
Key publications
| Neuronal differentiation pathways and compound-induced developmental neurotoxicity in the human neural progenitor cell test (hNPT) revealed by RNA-seq. | de Leeuw VC, van Oostrom CTM, Wackers PFK, Pennings JLA, Hodemaekers HM, Piersma AH, Hessel EVS | Chemosphere. 2022 Oct;304:135298 |
| An efficient neuron-astrocyte differentiation protocol from human embryonic stem cell-derived neural progenitors to assess chemical-induced developmental neurotoxicity. | de Leeuw, V.C., van Oostrom, C.T.M., Westerink, R.H.S., Piersma, A.H., Heusinkveld, H.J., Hessel E.V.S.Hessel, E.V.S. | Reproductive Toxicology 2020; 98:107–116 |
| Design and validation of an ontology-driven animal-free testing strategy for developmental neurotoxicity testing. | Hessel, E.V.S., Staal, Y.C.M., Piersma, A.H. | Toxicology and Applied Pharmacology 2018; 354:136–152 |