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ENFIRO: Hazard characterization and assessment of the neurotoxic potential of alternative flame retardants

 

 
Principle investigator: Hester Hendriks, M.Sc.
Project leader: R.H.S. Westerink, Ph.D.
 
Project description:
 
The EU-funded ENFIRO project aims to study and quantify effects of alternative flame retardants (AFRs) on various processes related to nervous system function and development. These results can be used to assess the relation between potential effects and the chemical structure of AFRs (structure-activity relations).
 
Methods:
The potential cytotoxic effects of AFRs will be assessed in PC12 cells using a MTT assay. Amperometry and calcium-imaging techniques will be used to study which AFRs affect intracellular calcium homeostasis and basal or evoked neurotransmitter release in PC12 cells. The effects of those AFRs that are considered to have a low neurotoxic potential are used to measure effects on the functioning of nicotinic acetylcholine receptors expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Supposedly safe AFRs with the potential of large scale use will then be selected for assessing effects on synaptic plasticity in mouse hippocampal slices.
 
Details:
The wide application of flame retardants in our living environment and the increasing environmental burden of these compounds has raised toxicological and ecological concern. Therefore, brominated flame retardants (BFRs), including polybrominated diphenylethers (PBDEs), must be replaced by safe and less persistent alternatives. However, the toxic potential of the proposed (AFRs) is currently unknown.
Previous research identified the nervous system as being the most sensitive target organ for flame retardants. BFRs are reported to cause lasting neurobehavioral changes in rodents as well as alterations in synaptic plasticity in brain slices. On a cellular level, BFRs have been reported to alter calcium homeostasis and neurotransmitter release. It is therefore essential to assess the neurotoxic potential of AFRs before these compounds are globally used on a large scale.
 
 
 
Recent publications:
- Hendriks, H.S., Westerink, R.H.S. Neurotoxicity and risk assessment of brominated and alternative flame retardantsprotein levels in mice. Neurotoxicology and Teratology 52, 248-269 (2015).
- Hendriks, H.S., Koolen, L.A., Dingemans, M.M.L., Viberg, H., Lee, I., Leonards, P.E., Ramakers, G.M., Westerink, R.H.S. Effects of neonatal exposure to the flame retardant tetrabromobisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term potentiation and synaptic protein levels in mice. Archives of Toxicology 89, 2345-2354 (2015).
- Meijer, M., Hendriks, H.S., Heusinkveld, H.J., Langeveld, W.T., Westerink, R.H.S. Comparison of plate reader-based methods with fluorescence microscopy for measurements of intracellular calcium levels for the assessment of in vitro neurotoxicity. Neurotoxicology 45, 31-37 (2014).
- Hendriks, H.S., Meijer, M., Muilwijk, M., van den Berg, M., Westerink R.H.S. (2014). A comparison of the in vitro cyto- and neurotoxicity of brominated and halogen-free flame retardants: Prioritization in search for safe(r) alternatives. Archives of Toxicology 88, 857-869 (2014).
- Waaijers, S.L., Kong, D., Hendriks, H.S., de Wit, C.A., Cousins, I.T., Westerink R.H.S., Leonards, P.E., Kraak, M.H., Admiraal, W., de Voogt, P., Parsons, J.R. (2013). Persistence, bioaccumulation, and toxicity of halogen-free flame retardants. Reviews in Environmental Contaminations and Toxicology 222, 1-71.
- Hendriks, H.S., van Kleef, R.G.D.M., Westerink R.H.S. (2012). Modulation of human α4β2 nicotinic acetylcholine receptors by brominated and halogen-free flame retardants as a measure for in vitro neurotoxicity. Toxicology Letters 213, 266-274.
- Hendriks, H.S., van Kleef, R.G.D.M., van den Berg, M., Westerink R.H.S. (2012). Multiple novel modes of action involved in the in vitro neurotoxic effects of tetrabromobisphenol-A (TBBPA). Toxicological Sciences 128, 235-246.
- Hendriks, H.S., Antunes Fernandes, E.C., Bergman, A., van den Berg, M., Westerink R.H.S. (2010). PCB-47, PBDE-47 and 6-OH-PBDE-47 differentially modulate human GABAA and a4b2 nicotinic acetylcholine receptors. Toxicological Sciences  118, 635-642.
- Antunes Fernandes, E.C., Hendriks, H.S., van Kleef, R.G.D.M., van den Berg, M., Westerink R.H.S. (2010). Potentiation of the human GABAA receptor as a novel mode of action of lower-chlorinated non-dioxin-like PCBs. Environmental Science & Technology 448, 2864-2869.
- Antunes Fernandes, E.C., Hendriks, H.S. van Kleef, R.G.D.M., Reniers, A., Andersson, P.L., van den Berg, M., Westerink, R.H.S. (2010). Activation and potentiation of human GABAA receptors by non-dioxin-like-PCBs depends on chlorination pattern. Toxicological Sciences 118, 183-190.
 
Collaborations:
- Dr. H. Viberg, Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden
- Dr. G.M.J. Ramakers, Rudolf Magnus Institute, University Medical Centre Utrecht, Utrecht, The Netherlands
- ENFIRO partners