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 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. Discussion: 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.

PBDEs have been detected in liver, blood, milk and adipose tissues, occasionally at high concentrations, in both wildlife (for reviews see de Wit 2002;Law et al. 2003) and human tissues, including breast milk (Bradman et al. 2007;Petreas et al. 2003;Schecter et al. 2003;Sjödin et al. 2004;reviewed in Frederiksen et al. 2009). Toxicokinetics studies in rodents Hakk et al. 2002;Örn and Klasson-Wehler 1998;Sanders et al. 2006a;Staskal et al. 2006;von Meyerinck et al. 1990; reviewed in Darnerud et al. 2001;Hakk and Letcher 2003) demonstrated high absorption and slow elimination as well as accumulation in adipose tissue after a single oral dose of tetra-, penta-and hexaBDEs. Studies in fish showed an efficient absorbance of PBDEs, with a negative correlation with bromination degree (Burreau et al. 1997(Burreau et al. , 2004. BDE-209 has also been detected in bird's eggs, birds, fish and marine mammals (reviewed in Law et al. 2006) as well as human tissues (reviewed in Frederiksen et al. 2009) despite its poor absorption in the gastrointestinal tract, low solubility, high log octanol-water partition coefficient (K ow ) and molecular weight (Mörck et al. 2003). Ecotoxicological concern has arisen from the observation of very high concentrations of

BDE-209 in birds of prey in North-China. This observation is a sign of significant biomagnifications of BDE-209
in terrestrial food chains (Chen et al. 2007).
In in vivo toxicokinetics studies, OH-PBDEs were detected in liver, lung, plasma, feces and bile after oral administration of BDE-47 or BDE-99 to rats Hakk et al. 2002;Marsh et al. 2006;Örn and Klasson-Wehler 1998). OH-PBDEs have also been observed in plasma after intraperitonal administration of an equimolar mixture of environmentally relevant PBDEs to rats (Malmberg et al. 2005). Intravenous administration of BDE-47, BDE-99, BDE-100 or BDE-153 to mice revealed that hydroxylated metabolites were formed from all four PBDEs. BDE-99 was observed to be most readily metabolized by oxidation and oxidation/debromination, while debromination was not observed for the other PBDEs (Staskal et al. 2006). In contrast, metabolism of BDE-153 after oral administration is minimal (Qiu et al. 2007;Sanders et al. 2006b), which is suggested to be due to the absence of Br-atoms with 2 adjacent unsubstituted C-atoms. In support of this explanation, the presence of several OH-PBDEs was observed in feces after oral administration of BDE-154, in which a Br-atom with two unsubstituted adjacent C-atoms is present (Hakk et al. 2009). After oral administration of BDE-209 to rats, several methoxylated and acetylated metabolites were detected in bile and feces (Mörck et al. 2003). In addition, hydroxylated octa-and nonaBDEs were also detected in plasma and the liver after oral or intravenous administration of BDE-209 to rats (Sandholm et al. 2003;Riu et al. 2008). After subchronic low dose administration of DE-71 through the feed to rats, OH-PBDEs were identified in feces (Huwe et al. 2007). In mice, OH-PBDEs were observed in plasma after oral or subcutaneous exposure to DE-71 (Qiu et al. 2007).
Formation of OH-PBDEs from BDE-47 was also demonstrated using phenobarbital-induced rat liver microsomes (Hamers et al. 2008). Recently, the formation of OH-PBDEs was also investigated in human primary hepatocytes exposed to BDE-99 or BDE-209. These cells metabolized BDE-99 into OH-PBDEs while in contrast, OH-PBDEs were not detected after exposure to BDE-209 (Stapleton et al. 2009). Recently, in vitro biotransformation of parent, OH-and MeO-PBDEs in rainbow trout, chicken and rat microsomes suggested an additional metabolic pathway, i.e., formation of OH-PBDEs from MeO-PBDEs (Wan et al. 2009).

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A distribution study with radiolabeled PBDEs in mice showed that fetal uptake during gestation was relatively limited, while maternal transfer via breast milk resulted in transfer of approximately 20% of the administered dose to the offspring (Darnerud and Risberg 2006). Assuming similar toxicokinetics of PBDEs in humans during gestation and lactation, this suggests that exposure through lactation is also from a quantitative point of view an important exposure route for PBDEs as well as OH-PBDEs in humans (Lacorte and Ikonomou 2009). In fetal liver and placental tissue, CYP enzyme activity is present (Hakkola et al. 1998).
Placental transfer of hydroxylated polychlorinated biphenyls (OH-PCBs) has been demonstrated in experimental studies (Meerts et al. 2002). Although placental transfer of OH-PBDEs has not yet been proven, it is not unlikely (especially for lower-brominated PBDEs), due to the structural resemblance with OH-PCBs.
Therefore, the internal fetal exposure to OH-PBDEs may be due to fetal hydroxylation and/or placental transfer.