Neonatal Exposure to Brominated Flame Retardant BDE-47 Reduces Long-Term Potentiation and Postsynaptic Protein Levels in Mouse Hippocampus

Abstract

BackgroundIncreasing environmental levels of brominated flame retardants raise concern about possible adverse effects, particularly through early developmental exposure.ObjectiveThe objective of this research was to investigate neurodevelopmental mechanisms underlying previously observed behavioral impairments observed after neonatal exposure to polybrominated diphenyl ethers (PBDEs).MethodsC57Bl/6 mice received a single oral dose of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) on postnatal day (PND) 10 (i.e., during the brain growth spurt). On PND17–19, effects on synaptic plasticity, levels of postsynaptic proteins involved in long-term potentiation (LTP), and vesicular release mechanisms were studied ex vivo. We investigated possible acute in vitro effects of BDE-47 on vesicular catecholamine release and intracellular Ca2+ in rat pheochromocytoma (PC12) cells.ResultsField-excitatory postsynaptic potential (f-EPSP) recordings in the hippocampal CA1 area demonstrated reduced LTP after exposure to 6.8 mg (14 μmol)/kg body weight (bw) BDE-47, whereas paired-pulse facilitation was not affected. Western blotting of proteins in the postsynaptic, triton-insoluble fraction of hippocampal tissue revealed a reduction of glutamate receptor subunits NR2B and GluR1 and autophosphorylated-active Ca2+/calmodulin-dependent protein kinase II (αCaMKII), whereas other proteins tested appeared unaffected. Amperometric recordings in chromaffin cells from mice exposed to 68 mg (140 μmol)/kg bw BDE-47 did not reveal changes in catecholamine release parameters. Modest effects on vesicular release and intracellular Ca2+ in PC12 cells were seen following acute exposure to 20 μM BDE-47. The combined results suggest a post-synaptic mechanism in vivo.ConclusionEarly neonatal exposure to a single high dose of BDE-47 causes a reduction of LTP together with changes in postsynaptic proteins involved in synaptic plasticity in the mouse hippocampus.

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…Somewhat in contrast with these findings, Dingemans et al (2007) reported that increased vesicular catecholamine release in PC-12 cells. The release of the neuropeptide vasopressin from hypothalamic preparations (tissue punches from the supraoptic and paraventricular nuclei) was shown to be inhibited by DE-71, BDE-47 and BDE-77 at micromolar concentrations (Coburn et al 2007).…”

“…Micromolar concentrations of BDE-99 were reported to increase Ca ++ concentrations in rat astrocytes, PC-12 cells and human macrophages Smolnikar et al 2001 (abstract)]. Similarly, BDE-47 (20 uM) was reported to increase [Ca ++ ] in PC-12 cells (Dingemans et al 2007). In contrast, DE-71 (30 uM) did not cause any Ca ++ elevation in cerebellar granule cells (Reistad et al 2006), and octaBDE (10-40 uM) did not alter Ca ++ levels in mouse thymocytes (Sandal et al 2004).…”

“…glutamate receptor subunits NR2B and GluR1, and autophosphorylated-active alpha Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)] at PND 17-19 (Dingemans et al 2007). A decrease of CaMKII, in addition to decreases in the levels of brain derived neurotrophic factor (BDNF) and of Gap-43 (neuromodulin) were also found on PND 10 in mice exposed to BDE-209 on PND 3 (Viberg et al 2007b).…”

Acute exposure to DE‐71: Effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae

“…Several studies have shown structural and functional alterations in the brains of PBDE-exposed animals. Brain changes have also been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, and synaptic plasticity [7,11,12]. Cellular and molecular mechanisms affected include neuronal viability (via apoptosis and oxidative stress), neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium homeostasis, and intracellular signaling pathways [9].…”

Determination of environmentally relevant exposure concentrations of polybrominated diphenyl ethers for in vitro toxicological studies

“…In general, previous studies of PBDEs in vitro have incorporated micromolar (lM) levels in the culture media, although several reports have used nanomolar (nM) levels (Barber et al, 2006;Cantón et al, 2006;Dingemans et al, 2007Dingemans et al, , 2008Fery et al, 2009;Giordano et al, 2008Giordano et al, , 2009He et al, 2008aHe et al, ,b, 2009Hu et al, 2007;Madia et al, 2004;Mercado-Feliciano and Bigsby, 2008;Peters et al, 2004Peters et al, , 2006Stavenes Andersen et al, 2009;Song et al, 2009;Stapleton et al, 2009;Tagliaferri et al, 2010;Zhang et al, 2007). None of these studies measured the cellular PBDE concentrations but it is assumed that the concentrations used may not be environmentally relevant because they are much higher than the picomolar (pM) or lower levels typically found in environmental water or body fluids (Frederiksen et al, 2009;Gill et al, 2004;Streets et al, 2006;Wu et al, 2008).…”