Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system.
OBJECTIVE
Polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-) or methoxylated forms have been detected in humans. Because this raises concern about adverse effects on the developing brain, we reviewed the scientific literature on these mechanisms.


RESULTS
Many rodent studies reported behavioral changes after developmental, neonatal, or adult exposure to PBDEs, and other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects have been observed on synaptic plasticity and the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. In the brain, changes have been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability  (via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium (Ca²⁺) homeostasis, and intracellular signaling pathways.


CONCLUSIONS
Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neurodevelopment, including binding to thyroid hormone receptors and transport proteins, disruption of Ca²⁺ homeostasis, and modulation of GABA and nicotinic acetylcholine receptor function.


CONCLUSIONS
The increased hazard for developmental neurotoxicity by hydroxylated (OH-)PBDEs compared with their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into a) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; b) concentrations of parent and OH-PBDEs in the brain; and c) interactions between different environmental contaminants during exposure to mixtures, which may increase neurotoxicity.
Neurotoxicology Research Group, Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands. m.dingemans@uu.nl
Milou M L
MM
Dingemans
Martin
M
van den Berg
Remco H S
RH
Westerink
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000196:embryology; D004622:Embryo, Mammalian / Q000187:drug effects; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005411:Flame Retardants / Q000493:pharmacokinetics / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D006801:Humans; D006900:Hydroxylation; D051379:Mice; D009420:Nervous System / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000506:poisoning*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D018570:Risk Assessment
D004785:Environmental Pollutants; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D011078:Polychlorinated Biphenyls
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