Citation

Li T, Wang W, Pan YW, Xu L, Xia Z. Toxicol. Sci. 2013; 134(1): 111-124.

Affiliation

Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.

Copyright

(Copyright © 2013, Oxford University Press)

DOI

10.1093/toxsci/kft083

PMID

23564643

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.

Language: en