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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

  • Organ Toxicity and Mechanisms
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Abstract

Brominated flame retardants such as tetrabromobisphenol-A (TBBPA) may exert (developmental) neurotoxic effects. However, data on (neuro)toxicity of halogen-free flame retardants (HFFRs) are scarce. Recent in vitro studies indicated a high neurotoxic potential for some HFFRs, e.g., zinc stannate (ZS), whereas the neurotoxic potential of other HFFRs, such as aluminum diethylphosphinate (Alpi), appears low. However, the in vivo (neuro)toxicity of these compounds is largely unknown. We therefore investigated effects of neonatal exposure to TBBPA, Alpi or ZS on synaptic plasticity in mouse hippocampus. Male C57bl/6 mice received a single oral dose of 211 µmol/kg bw TBBPA, Alpi or ZS on postnatal day (PND) 10. On PND 17–19, effects on hippocampal synaptic plasticity were investigated using ex vivo extracellular field recordings. Additionally, we measured levels of postsynaptic proteins involved in long-term potentiation (LTP) as well as flame retardant concentrations in brain, muscle and liver tissues. All three flame retardants induced minor, but insignificant, effects on LTP. Additionally, TBBPA induced a minor decrease in post-tetanic potentiation. Despite these minor effects, expression of selected synaptic proteins involved in LTP was not affected. The flame retardants could not be measured in significant amounts in the brains, suggesting low bioavailability and/or rapid elimination/metabolism. We therefore conclude that a single neonatal exposure on PND 10 to TBBPA, Alpi or ZS does affect neurodevelopment and synaptic plasticity only to a small extent in mice. Additional data, in particular on persistence, bioaccumulation and (in vivo) toxicity, following prolonged (developmental) exposure are required for further (human) risk assessment.

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Abbreviations

ACSF:

Artificial cerebrospinal fluid

Alpi:

Aluminum diethylphosphinate

BFR:

Brominated flame retardant

CaMK-II:

Calcium-/calmodulin-dependent protein kinase-II

fEPSPs:

Field excitatory postsynaptic potentials

GAP-43:

Growth-associated protein-43

HFFR:

Halogen-free flame retardant

IO:

Input–output

ISI:

Inter-stimulus interval

LTP:

Long-term potentiation

nACh:

Nicotinic acetylcholine

NMDA:

N-methyl-d-aspartate

PND:

Postnatal day

PPF:

Paired-pulse facilitation

PPR:

Paired-pulse ratio

PSD 95:

Postsynaptic density 95

PTP:

Post-tetanic potentiation

TBBPA:

Tetrabromobisphenol-A

ZS:

Zinc stannate

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Acknowledgments

We acknowledge Petra Krystek (Philips Innovation Services, Eindhoven, The Netherlands) for the metal analysis, the Department of Organismal Biology at Uppsala University Sweden for protein expression analysis. This work was supported by a grant from the European Union (ENFIRO; grant agreement FP7-ENV-2008-1-226563) and the Faculty of Veterinary Medicine of Utrecht University.

Conflict of interest

The authors declare they have no competing financial interests.

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Authors and Affiliations

  1. Neurotoxicology Research Group, Toxicology Division, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, 3508 TD, Utrecht, The Netherlands

    Hester S. Hendriks, Milou M. L. Dingemans & Remco H. S. Westerink

  2. Master’s Programme in Neuroscience and Cognition, Utrecht University, 3508 TC, Utrecht, The Netherlands

    Lucas A. E. Koolen

  3. Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden

    Henrik Viberg & Iwa Lee

  4. Institute for Environmental Studies (IVM), VU University, Amsterdam, The Netherlands

    Pim E. G. Leonards

  5. Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    Geert M. J. Ramakers

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  1. Hester S. Hendriks
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  2. Lucas A. E. Koolen
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  3. Milou M. L. Dingemans
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  6. Pim E. G. Leonards
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  8. Remco H. S. Westerink
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Corresponding author

Correspondence to Remco H. S. Westerink.

Additional information

Hester S. Hendriks and Lucas A. E. Koolen have contributed equally to this study.

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Hendriks, H.S., Koolen, L.A.E., Dingemans, M.M.L. et al. 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. Arch Toxicol 89, 2345–2354 (2015). https://doi.org/10.1007/s00204-014-1366-8

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