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Effects of flame retardants on the nervous system and in neurodevelopment

 

 

Principle investigator: Milou Dingemans, Ph.D.
 
Project leader: R.H.S. Westerink, Ph.D.
Project description:
 
The aim of this project is to provide insight into the mechanisms of adverse effects of flame retardants, in particular the brominated diphenyl ethers (BDEs), on the nervous system and in neurodevelopment. These results can be used to provide a basis for predicting the possible neurotoxic potential of different BDE-congeners (structure-activity relationship).
 
Methods:
The effects of flame retardants on exocytosis (amperometry), Ca2+-signaling (fluorescence imaging), gene expression (molecular biology) and plasticity (paired pulse facilitation/long term potentiation) are assessed in neuronal cell lines, neuroendocrine chromaffin cells, dopaminergic neurons and brain slices.
 
Background:
The general human population is chronically exposed to flame retardants. These chemicals are used in electronic circuitry and housing, textiles and plastics to reduce fire risks. Although the use of several congeners is now restricted, brominated flame retardants are still being found in practically every kind of environmental samples (water, sediments, fish, wildlife and humans). Moreover, hydroxylated metabolites of PBDEs have been detected to bio-accumulate in humans.
Previously, it has been shown that exposure to brominated flame retardants causes neurobehavioral effects in mice (impaired spontaneous behaviour, hyperactivity, impairment of learning and memory) and also in vitro effects have been detected (accumulation in neuronal and glial cells, dioxin-like behaviour). Because of the continuous exposure of the human population to brominated flame retardants, also during rapid brain development, it is important to assess possible neurotoxic effects of these chemicals.
 
Recent publications:
- Dingemans MML, van den Berg M and Westerink RHS. Neurotoxicity of PBDEs: Dingemans et al. respond. Environmental Health Perspectives 119, a331-a332 (2011).
- Dingemans, M.M.L., van den Berg, M. and Westerink, R.H.S. (2011). Neurotoxicity of brominated flame retardants: (in-)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Environmental Health Perspectives 119, 900-907.
- Dingemans, M.M.L. (2010). Neurotoxicity of PBDEs and metabolites: concern for the developing brain? ISBN 978-90-393-5290-8. Awarded by the Netherlands Society for Toxicology with the ‘Joep van den Bercken Prize‘ for the best PhD thesis of the year in the field of Toxicology.
- Dingemans, M.M.L., Heusinkveld, H.J., van den Berg, M., Bergman, A., Westerink, R.H.S. (2010). Bromination pattern of hydroxylated metabolites of BDE-47 affects their potency to release calcium from intracellular stores in PC12 cells. Environmental Health Perspectives 118, 519-525.
- Dingemans, M.M.L., van den Berg, M., Bergman, A., Westerink, R.H.S. (2010). Calcium-related processes involved in the inhibition of depolarization-evoked calcium increase by hydroxylated PBDEs in PC12 cells. Toxicological Sciences 114, 302-309.
- Dingemans, M.M.L., Heusinkveld, H.J., de Groot, A., Bergman, Å., van den Berg, M., Westerink, R.H.S. (2009). Hexabromocyclododecane inhibits depolarization-induced increase in intracellular calcium levels and neurotransmitter release in PC12 cells. Toxicological Sciences 107, 490-497.
- Dingemans, M.M.L., de Groot, A., van Kleef, R.G.D.M., Bergman, Å., van den Berg, M., Vijverberg, H.P.M., Westerink, R.H.S (2008). Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells. Environmental Health Perspectives 116, 637-643.
- Dingemans, M.M.L., Ramakers, G.M.J., Gardoni, F., van Kleef, R.G.D.M., Bergman, Å., Di Luca, M., van den Berg, M., Westerink, R.H.S., Vijverberg, H.P.M. (2007). Neonatal exposure to brominated flame retardant BDE-47 reduces long-term potentiation and postsynaptic protein levels in mouse hippocampus. Environmental Health Perspectives, 115, 865-870.
 
Collaborations:
- Prof. E. Fritsche, Institut für umweltmedizinische Forschung, Heinrich-Heine-Universität Düsseldorf, Germany
- Dr. G.M.J. Ramakers, Rudolf Magnus Institute, University Medical Centre Utrecht