Neurotoxicity of Brominated Flame Retardants: (In)direct Effects of Parent and Hydroxylated Polybrominated Diphenyl Ethers on the (Developing) Nervous System

BACKGROUND/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. DATA SYNTHESIS: 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 neuro-transmitter release. Cellular and molecular mechanisms include effects on neuronal viability (via apoptosis and oxidative stress), neuronal differentiation and migration, neuro-transmitter release/uptake, neuro-transmitter receptors and ion channels, calcium (Ca2+) homeo-stasis, and intracellular signaling pathways. DISCUSSION: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neuro-development, including binding to thyroid hormone receptors and transport proteins, disruption of Ca2+ homeo-stasis, and modulation of GABA and nicotinic acetylcholine receptor function. CONCLUSIONS: The increased hazard for developmental neuro-toxicity by hydroxylated (OH-) PBDEs compared with their parent congeners via direct neuro-toxicity 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) inter-actions between different environmental contaminants during exposure to mixtures, which may increase neuro-toxicity.