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
| Autor: | Tan Li, Wenbin Wang, Lihong Xu, Zhengui Xia, Yung Wei Pan |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
endocrine system
Cell Survival Primary Cell Culture Subventricular zone Poison control Mice Inbred Strains Biology Hydroxylation Toxicology Mice Polybrominated diphenyl ethers Neural Stem Cells Neurotrophin 3 Halogenated Diphenyl Ethers medicine Animals Progenitor cell Cells Cultured Mitogen-Activated Protein Kinase 7 reproductive and urinary physiology Cell Proliferation Flame Retardants Neurogenesis Oligodendrocyte differentiation Neurotoxicity Brain Cell Differentiation medicine.disease Neural stem cell Cell biology medicine.anatomical_structure Immunology Signal Transduction Research Article |
| Zdroj: | Toxicological Sciences. 134:111-124 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kft083 |
| Popis: | 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 7.5μM inhibited proliferation at 2.5–5μM while suppressing neuronal and oligodendrocyte differentiation at submicromolar concentrations (≤ 1μM). 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. |
| Databáze: | OpenAIRE |
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