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.
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.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Tan
authors.initials: T
authors.lastname: Li
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wang
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Pan
authors.forename: Lihong
authors.initials: L
authors.lastname: Xu
authors.forename: Zhengui
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005411:Flame Retardants / Q000378:metabolism / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000378:metabolism / Q000633:toxicity*; D006900:Hydroxylation; D051379:Mice; D008815:Mice, Inbred Strains; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020933:Neurotrophin 3 / Q000378:metabolism*; D061251:Primary Cell Culture; D015398:Signal Transduction
chemical_list: D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D020933:Neurotrophin 3; C511295:2,2',4,4'-tetrabromodiphenyl ether; D048054:Mitogen-Activated Protein Kinase 7
keywords: PBDE; adult neurogenesis; apoptosis; neuronal differentiation; neurotoxicity; proliferation
references.citation: Environ Health Perspect. 2010 Apr;118(4):572-8
references.pmid: 20368126
references.citation: J Occup Environ Med. 2005 Mar;47(3):199-211
references.pmid: 15761315
references.citation: Toxicol Appl Pharmacol. 2008 Oct 15;232(2):161-8
references.pmid: 18656495
references.citation: Neurotoxicology. 2007 Nov;28(6):1047-67
references.pmid: 17904639
references.citation: Nature. 1997 Apr 3;386(6624):493-5
references.pmid: 9087407
references.citation: Cell. 2008 Feb 22;132(4):645-60
references.pmid: 18295581
references.citation: Dev Neurobiol. 2010 Apr;70(5):339-49
references.pmid: 20186714
references.citation: Neurotoxicology. 2009 Jan;30(1):10-5
references.pmid: 19022289
references.citation: Environ Health. 2011 Jan 05;10(1):1
references.pmid: 21205326
references.citation: Toxicol Lett. 2008 Feb 15;176(3):230-8
references.pmid: 18248924
references.citation: Toxicol Sci. 2010 Dec;118(2):635-42
references.pmid: 20861069
references.citation: Nat Neurosci. 2007 Aug;10(8):1003-11
references.pmid: 17603480
references.citation: Ecotoxicology. 2010 Apr;19(4):623-34
references.pmid: 19882349
references.citation: Int J Hyg Environ Health. 2009 Mar;212(2):109-34
references.pmid: 18554980
references.citation: J Neurosci. 2012 Mar 21;32(12):4118-32
references.pmid: 22442076
references.citation: Environ Health Perspect. 2008 May;116(5):637-43
references.pmid: 18470311
references.citation: Neurobiol Dis. 2010 Jul;39(1):73-84
references.pmid: 20114075
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19170-5
references.pmid: 17135354
references.citation: Environ Health Perspect. 2005 Dec;113(12):1689-92
references.pmid: 16330348
references.citation: Chemosphere. 2009 Jul;76(4):542-8
references.pmid: 19349061
references.citation: Environ Health Perspect. 2003 Jul;111(9):1249-52
references.pmid: 12842781
references.citation: Nat Neurosci. 1999 Mar;2(3):266-70
references.pmid: 10195220
references.citation: Chemosphere. 2002 Feb;46(5):583-624
references.pmid: 11999784
references.citation: Toxicol Sci. 2010 Mar;114(1):124-32
references.pmid: 19969594
references.citation: Physiol Behav. 2010 Jun 1;100(3):245-9
references.pmid: 20100501
references.citation: PLoS One. 2013 Apr 22;8(4):e61948
references.pmid: 23630619
references.citation: Environ Mol Mutagen. 2012 Oct;53(8):589-98
references.pmid: 22930557
references.citation: Environ Health Perspect. 2004 May;112(6):654-8
references.pmid: 15121506
references.citation: Toxicol In Vitro. 2010 Feb;24(1):116-22
references.pmid: 19720130
references.citation: J Biol Chem. 2012 Jul 6;287(28):23306-17
references.pmid: 22645146
references.citation: Drug Chem Toxicol. 2011 Apr;34(2):213-9
references.pmid: 21314472
references.citation: J Neurosci. 1995 Aug;15(8):5765-78
references.pmid: 7643217
references.citation: Environ Health Perspect. 2011 Jul;119(7):900-7
references.pmid: 21245014
references.citation: Toxicol Sci. 2013 Mar;132(1):196-210
references.pmid: 23288049
references.citation: Neurotoxicology. 2012 Jan;33(1):8-15
references.pmid: 22079442
references.citation: Toxicology. 2011 Oct 28;289(1):59-65
references.pmid: 21820030
references.citation: Environ Health Perspect. 2004 Jul;112(10):1085-91
references.pmid: 15238282
references.citation: Toxicol Sci. 2005 Jun;85(2):952-62
references.pmid: 15772365
references.citation: Toxicol In Vitro. 2011 Dec;25(8):1509-15
references.pmid: 21704695
references.citation: Environ Health Perspect. 2003 Nov;111(14):1723-9
references.pmid: 14594622
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9697-702
references.pmid: 16766652
references.citation: Toxicol Sci. 2008 Jan;101(1):81-90
references.pmid: 17916640
references.citation: Neuron. 2011 May 26;70(4):687-702
references.pmid: 21609825
references.citation: Microsc Res Tech. 2003 Jan 1;60(1):70-5
references.pmid: 12500263
references.citation: Toxicol Sci. 2003 Nov;76(1):112-20
references.pmid: 12915714
references.citation: Neurotoxicology. 2011 Jan;32(1):9-24
references.pmid: 21182867
references.citation: Mar Pollut Bull. 2011;63(5-12):179-88
references.pmid: 21439595
references.citation: J Neurosci. 2012 May 9;32(19):6444-55
references.pmid: 22573667
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8532-7
references.pmid: 12826611
references.citation: J Biol Chem. 2013 Jan 25;288(4):2623-31
references.pmid: 23223235
references.citation: Toxicol Sci. 2002 May;67(1):98-103
references.pmid: 11961221
references.citation: J Toxicol Sci. 2012;37(2):223-33
references.pmid: 22467012
references.citation: Cell Cycle. 2003 Jul-Aug;2(4):339-45
references.pmid: 12851486
references.citation: PLoS One. 2009;4(4):e5204
references.pmid: 19365559
references.citation: Oncogene. 2007 May 14;26(22):3100-12
references.pmid: 17496909
references.citation: Hum Mol Genet. 2012 Jun 1;21(11):2399-411
references.pmid: 22343140
references.citation: Toxicol Appl Pharmacol. 2010 May 15;245(1):1-8
references.pmid: 20171977
references.citation: Chemosphere. 2008 Aug;72(10):1602-1606
references.pmid: 18508108
references.citation: Environ Health Perspect. 2010 May;118(5):712-9
references.pmid: 20056561
references.citation: Neurotoxicology. 2008 Jan;29(1):124-9
references.pmid: 18054389
references.citation: EMBO J. 1997 Dec 1;16(23):7054-66
references.pmid: 9384584
references.citation: PLoS One. 2012;7(11):e49622
references.pmid: 23185386
references.citation: Acta Biomed. 2008 Dec;79(3):172-83
references.pmid: 19260376
references.citation: Toxicol Sci. 2012 Jun;127(2):496-507
references.pmid: 22387749
references.citation: Biochem Biophys Res Commun. 1995 Aug 15;213(2):715-24
references.pmid: 7646528
references.citation: PLoS One. 2012;7(11):e50455
references.pmid: 23189204
references.citation: Environ Health Perspect. 2009 Jan;117(1):93-8
references.pmid: 19165393
references.citation: Rev Environ Health. 2009 Jul-Sep;24(3):157-229
references.pmid: 19891120