Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71

Abstract

Recent studies have identified exposure to polybrominated diphenyl ethers (PBDEs) as a risk factor for deficits in cognitive functioning seen in children as well as adults. Additionally, similar alterations in learning and memory have also been observed in animal models of PBDE exposure. However, given these findings, the molecular alterations that may underlie these neurobehavioral endpoints have not been identified. As the frontal cortex is involved in modulating several cognitive functions, the purpose of our study was to investigate the possible changes to the GABAergic and glutamatergic neurotransmitter systems located in the frontal cortex following exposure to the PBDE mixture, DE-71. Primary cultured neurons isolated from the frontal cortex showed a dose-dependent reduction in neurons as well as neurite outgrowth. Furthermore, evaluation of DE-71 neurotoxicity in the frontal cortex using an in vivo model showed alterations to specific proteins involved in mediating GABA and glutamate neurotransmission, including GAD67, vGAT, vGlut, and GABA(A) 2α receptor subunit. Interestingly, these alterations appeared to be preferential for the GABA and glutamate systems located in the frontal cortex. These findings identify specific targets of PBDE neurotoxicity and provide a possible molecular mechanism for PBDE-mediated neurobehavioral deficits that arise from the frontal cortex.

BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms

“…Specifically, our data demonstrate that BDE 47 and BDE 49 inhibit the early 379 stages of axonal growth in primary cultures of perinatal rat hippocampal neurons. These data 380 extend previous reports demonstrating that commercial PBDE mixture, DE-71, decreases 381 neurite length in primary mouse cortical cultures (Bradner et al, 2013), and that BDE-47 inhibits 382 neurite outgrowth in human embryonic stem cell-derived neurons (Behl et al, 2015), and 383 decreases the length of axons of motor neurons in larval zebrafish (Chen et al, 2012). In our 384 model, exposure to BDE-47 or BDE-49 significantly inhibits axonal growth at concentrations that 385 have no effect on cell viability, indicating that decreased axonal growth is not due to 386 compromised cell viability.…”

A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

“…They reported decreased levels of the NMDA receptor subunits NR 1 and NR 2 B and of their mRNAs in the hippocampus, which was accompanied by decreased performance in the Morris water maze. In contrast, in young adult mice, a 30 day treatment with DE-71 did not alter NR 2 B levels, but increased expression of vesicular glutamate transporter (Bradner et al 2013b). In another study in rats, prenatal exposure to BDE-99 was shown to increase the activity of the glutamate-nitric oxide-cGMP pathway, as assessed by microdialysis (Llansola et al 2007), possibly as a result of an effect on calmodulin (see below).…”

“…Alterations in some components of the GABAergic system (e.g. decreases of the GABA-A 2α receptor subunit and the GABA synthesizing enzyme GAD67) have been reported in the cerebral cortex of young adult mice following a 30 day exposure to DE-71 (Bradner et al 2013b). …”

Prenatal and postnatal polybrominated diphenyl ether (PBDE) exposure and measures of inattention and impulsivity in children

“…Other biologic mechanisms for neurotoxicity include inducing neuronal apoptosis through oxidative stress, reducing cell migration and differentiation into neurons and oligodendrocytes, interfering with signal transduction, and altering the cholinergic system and neurotransmitter release and function (Costa et al, 2014; Costa and Giordano, 2007; Dingemans et al, 2011; Schreiber et al, 2010). PBDEs may also affect GABAergic and glutamatergic neurotransmitter systems in the frontal cortex (Bradner et al, 2013). Since GABA is a major neurotransmitter in the brain, an imbalance could disrupt the excitation-inhibition neuronal activity and result in deficits in cognitive processes as well as over excitation, hyperactivity, and impulsivity behaviors.…”