Validation of a human in vitro model for testing developmental neurotoxicity
Over the past few years it has become widely accepted that some substances can exert a negative impact on human neural development. Guidelines for testing substances for developmental neurotoxicity (DNT) in vivo exist but have ethical, time and cost issues and do not offer clearly defined endpoints. There is a world-wide effort to replace animal-based DNT experiments with predictive in vitro methods. Fritsche’s project proposes use of normal human neural progenitor cells (NHNP cells) as a human alternative for testing DNT. This model allows study of the effects of putative genotoxins at the genomic and proteomic level and also the fundamental processes that are key to brain development. The project will validate the use of NHNP cells as a model for DNT with known neurotoxic pesticides to define the sensitivity and power of the model. Substances from different mechanistic groups will be tested for their interference with normal NHNP cell development. . A variety of endpoints will be monitored including viability/ apoptosis, cell proliferation, differentiation and migration as well as substance specific endpoints like inhibition of acetylcholinesterase. The results of the effects of these chemicals on NHNP development will be associated with knowledge gained from animal and human studies. The most predictive assays will be used in second phase of the project to be undertaken by a second independent laboratory. Dr. Fritsche’s proposal should contribute to the validation of a human in vitro cell culture system as a new DNT test strategy. The model will be able to generate data in a human-based system that is powerful to perform risk assessments on a mechanistic data basis.
The other finalists were:
Dr Merja Korkalainen of the Finish National Public Health Institute (KTL) working on ‘Epigenetic mechanisms as a new target for environmental pollutants’
Dr Gareth Jenkins from Swansea University whose proposal was entitled: ‘Do non-linear dose responses exist for chronic low dose exposures to genotoxins?’