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.

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 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.