In vitro and in vivo models for assessing developmentally important mechanisms, biochemical markers and processes in neonatal neurotoxicity of environmental pollutants

Time period:

1 January 2008 – 31 December 2009

Project leader:

Henrik Viberg

Funder:

Formas

Type of award:

Unclassified

Total funding:

2,100,000 SEK

There is a need for in vitro models of developmental neurotoxicity, focusing on mechanistic biomarkers. In a neonatal animal model we have shown that perturbation of the developing brain by environmental chemicals, e.g. pesticides and brominated flame retardants, can cause irreversible functional deficits in adult animals. In a pilot study we have seen that neonatal exposure to chemicals can affect the level of proteins associated with neurite growth and synaptogenesis during the period of rapid brain development. The present project aims to develop a neuronal cell culture test system by characterizing important proteins related to processes of maturation of axon and dendritic outgrowth, establishment of neural connections and development of the cholinergic system, to serve as markers of developmental neurotoxicity. This in vitro system will correlate to the living developing neonatal brain, due to the fact that primary neuronal cultures assume a biochemical phenotype more similar to that observed in vivo compared to PC12 cells, which are the most commonly studied cells. The proposed in vitro method will decrease the number of animals in developmental neurotoxicity research and provide a valid high through-put screening method for neurotoxicants. In addition, this test system will give further understanding about basic neurotoxic mechanisms and will provide an improvement of predictions of harmful effects of chemicals on late gestational foetuses, newborns and children.