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Developmental neurotoxicity and epigenetic changes in human model systems

Developmental neurotoxicity and epigenetic changes in human model systems

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BALMER, Nina Verena, 2013. Developmental neurotoxicity and epigenetic changes in human model systems [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Balmer2013Devel-24229, title={Developmental neurotoxicity and epigenetic changes in human model systems}, year={2013}, author={Balmer, Nina Verena}, address={Konstanz}, school={Universität Konstanz} }

Developmental neurotoxicity (DNT) is caused by exposure to toxicants during sensitive periods of neurodevelopment. It can lead to neurobehavioral alterations persisting long after removal of the original stimulus. Additionally, evidence has been accumulating that exposure to some compounds can influence susceptibility to and severity of psychiatric disorders in later life. Although there is increasing awareness for DNT in western countries, animal-based testing for DNT according to the OECD test guideline 426 has only been done for a few chemicals. The major concern about such animal studies is that they may not predict human health effects. Also human data on DNT from epidemiologic studies are limited, as cause-effect relationships are hard to identify in this field. Thus, there is an urgent need for human based in vitro test systems for DNT. In this study we have successfully established two new human-cell-based toxicological in vitro test systems to assess DNT.<br /><br />First, we established an assay using a human neuronal precursor cell line (LUHMES) that can be differentiated efficiently to fully mature neurons. In these cells, differentiation is naturally accompanied by neurite outgrowth. As disturbance of neurite outgrowth has been associated with DNT, we used fully automated analyses of neurite outgrowth as a functional read-out for this test system. In a second step, we established a test system to assess chemical’s effects on early patterning of the brain. This was done using human embryonic stem cells (hESC). To develop the test system, we first showed that hESC can be differentiated efficiently to neuroepithelial precursor cells. This differentiation process was investigated using expression levels of marker genes that specify the fate of the differentiating cells according to time and to region. Exposure scenarios have been tested and chemicals specifically interfering with distinct differentiation processes have been applied to validate the test system. We found that prolonged, but not short, exposure to the well-known DNT compound valproic acid altered neural differentiation in a similar manner as other inhibitors of histone deacetylases (HDACi). Moreover, exposure to HDACi altered histone methylation patterns at the promoters of deregulated marker genes. We finally investigated if the altered histone methylation pattern might represent the switch from altered histone acetylation to altered neural differentiation. We found that a transient increase in acetylation caused by HDACi can be associated with an accumulation of epigenetic alterations after chronic treatment. This in turn can lead to altered neural development as examined by massive whole genome transcriptome profiling.<br /><br />In summary, we developed two in vitro test systems which can be used to identify chemicals that potentially cause DNT. In the hESC based test system we identified a mechanism whereby chemicals can interfere with neurodevelopmental processes. Finally, we provide first evidence that epigenetic mechanisms could act as persistence sensors and therefore act as switch between innocuous short exposures to chemicals and adverse effects due to prolonged exposure. eng 2013-08-06T08:55:38Z 2013 Balmer, Nina Verena Developmental neurotoxicity and epigenetic changes in human model systems Balmer, Nina Verena terms-of-use

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