期刊
TOXICOLOGICAL SCIENCES
卷 134, 期 1, 页码 111-124出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kft083
关键词
PBDE; neurotoxicity; adult neurogenesis; apoptosis; proliferation; neuronal differentiation
类别
资金
- National Institutes of Health [MH95840, T32HD007183, F31DC011216]
- China Scholarship Council [2011632117]
- National Institute of Child Health and Human Development [P30 HD02274]
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 possibly 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 and in 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 mu M inhibited proliferation at 2.5-5 mu M while suppressing neuronal and oligodendrocyte differentiation at submicromolar concentrations (<= 1 mu M). 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 proneuronal differentiation effect of neurotrophin 3 (NT3) and 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.
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