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A 3R systems biology strategy for human neurotoxicity hazard, risk and safety assessment (N3rvousSystem)

 
 
Principle investigator:
Harm Heusinkveld, Ph.D.
Project leaders:
Harm Heusinkveld, Ph.D.
Remco Westerink, Ph.D.

 

Project description:

The aim of this project is to develop an animal-free strategy to detect adverse neurophysiological effects resulting from chemical exposures.

 

Methods:
Effects of selected reference chemicals on neuronal function and calcium signaling will be investigated in human and mouse embryonic stem cell derived neurons using state of the art multi-electrode array recordings and single cell fluoresce microscopy, respectively, and combined with information on phosphoproteomics and pathway analysis. This in vitro data will be combined with information from the intact animal (specific neurobehavioral readouts and kinetic information collected at collaborating institutes) in a testing strategy for neurotoxicity hazard.

Background:
Humans are exposed to numerous chemicals via the environment. To prevent adverse health effects, risk and safety assessment are obligatory before chemicals are allowed on the market. Regulation regarding chemical legislation and exposure has been based on animal research for many years. Currently, there is societal and scientific incentive to (partly) replace animal research by human cellular assays. An integrated, system biology approach will reveal which combination of experiments and methods is best suited to predict human neurotoxicity, which is a clear societal and regulatory need. As such the N3rvousSystem project not only improves risk and safety assessment but also makes a strong contribution to the reduction and replacement of animal experiments.
 
Recent publications:
  • Heusinkveld HJ, Westerink RHS (2017). Comparison of different in vitro models for the assessment of pesticide-induced dopaminergic neurotoxicity. Toxicology in Vitro 45, 81-88.
  • Heusinkveld HJ, Wahle T, Campbell A, Westerink RHS, Tran L, Johnston H, Stone V, Casssee FR, Schins RP (2016). Neurodegenerative and neurological disorders by small inhaled particles. Neurotoxicology 56, 94-106.
  • Heusinkveld HJ, van Vliet AC, Nijssen PC, Westerink RHS (2016). In vitro neurotoxic hazard characterisation of dinitrophenolic herbicides. Toxicology Letters 252, 62-69.
  • Dingemans MML, Schutte MG, Wiersma DM, de Groot A, van Kleef RGDM, Wijnolts FM, Westerink RHS (2016). Chronic 14-day exposure to insecticides or methylmercury modulates neuronal activity in primary rat cortical cultures. Neurotoxicology 57, 194-202.
  • Meijer M, Brandsema JA, Nieuwenhuis D, Wijnolts FM, Dingemans MML, Westerink RHS (2015). Inhibition of voltage-gated calcium channels after subchronic and repeated exposure of PC12 cells to different classes of insecticides. Toxicological Sciences 147, 607-617.
  • Meijer M, Dingemans MML, van den Berg M, Westerink RHS (2014). Inhibition of voltage-gated calcium channels as common mode of action for (mixtures of) distinct classes of insecticides. Toxicological Sciences 141, 103-111.
  • de Groot MWGDM, Dingemans MML, Rus KH, de Groot A, Westerink RHS (2014).  Characterization of calcium responses and electrical activity in differentiating mouse neural progenitor cells in vitro. Toxicological Sciences 137, 428-435.
  • de Groot MWGDM, Westerink RHS, Dingemans MML (2013). Don't judge a neuron only by its cover: neuronal function in in vitro developmental neurotoxicity testing. Toxicological Sciences 132, 1-7.