@article{ref1,
title="A Hydroxylated Metabolite of Flame-Retardant PBDE-47 Decreases the Survival, Proliferation and Neuronal Differentiation of Primary Cultured Adult Neural Stem Cells and Interferes with Signaling of ERK5 MAP Kinase and Neurotrophin 3",
journal="Toxicological sciences",
year="2013",
author="Li, Tan and Wang, Wenbin and Pan, Yung-Wei and Xu, Lihong and Xia, Zhengui",
volume="134",
number="1",
pages="111-124",
abstract="Polybrominated diphenyl ethers (PBDEs) are a group of organobromine compounds widely used as flame retardants. PBDE-47 is one of the most prominent PBDE congeners found in human tissues and it can be transformed into several metabolites including 6-OH-PBDE-47. Recent studies have shown that PBDE-47 is neurotoxic to animals and maybe humans. However, the basis for the neurotoxicity of PBDEs and their metabolites is unclear. For example, it is not known whether PBDEs affect adult neurogenesis, a process implicated in learning and memory as well as olfactory behavior. In this study, we examined the toxicity of PBDEs for primary adult neural stem/progenitor cells (aNSCs) isolated from the subventricular zone (SVZ) of adult mice. We discovered that 6-OH-PBDE-47, but not its parent compound PBDE-47, is cytotoxic for aNCSs using MTS metabolism and cell number as a measure of cytotoxicity. Interestingly, 6-OH-PBDE-47 induced apoptosis at concentrations above 7.5 μM, inhibited proliferation at 2.5-5 μM, while suppressing neuronal and oligodentrocyte differentiation at sub-micromolar concentrations (≤ 1 μM). The effect on proliferation was reversed upon removal of 6-OH-PBDE-47 and correlated with selective but reversible inhibition of ERK5 activation by mitogenic growth factors EGF and bFGF. 6-OH-PBDE-47 also inhibited the pro-neuronal differentiation effect of neurotrophin (NT) 3 as well as NT3 activation of ERK5. Together, these data show that 6-OH-PBDE-47 is more toxic than its parent compound for SVZ-derived aNSCs, and that it inhibits multiple aspects of adult neurogenesis. Furthermore, inhibition of ERK5 signaling may underlie the adverse effect of 6-OH-PBDE-47 on proliferation and neuronal differentiation. Our data suggest that exposure to PBDE-based flame retardants could cause neurotoxicity in the adult brain by interfering with adult neurogenesis.<p /><p>Language: en</p>",
language="en",
issn="1096-6080",
doi="10.1093/toxsci/kft083",
url="http://dx.doi.org/10.1093/toxsci/kft083"
}