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In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Up-regulated Genes and Cognitive Scores in Children.

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  • Additional Information
    • Source:
      Publisher: National Institute of Environmental Health Sciences Country of Publication: United States NLM ID: 0330411 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-9924 (Electronic) Linking ISSN: 00916765 NLM ISO Abbreviation: Environ Health Perspect Subsets: MEDLINE
    • Publication Information:
      Original Publication: Research Triangle Park, N. C. National Institute of Environmental Health Sciences.
    • Subject Terms:
      Gene Expression Regulation/*drug effects ; Hazardous Substances/*toxicity ; Lead/*toxicity ; Neural Stem Cells/*drug effects; Child ; Chromatin Immunoprecipitation ; Gene Expression Profiling ; Genome-Wide Association Study ; Humans ; Neural Stem Cells/physiology ; Neuropsychological Tests ; Oligonucleotide Array Sequence Analysis ; Osteopontin ; Signal Transduction/drug effects ; Up-Regulation
    • Abstract:
      Background: Lead (Pb) adversely affects neurodevelopment in children. Neural stem cells (NSCs) play an essential role in shaping the developing brain, yet little is known about how Pb perturbs NSC functions and whether such perturbation contributes to impaired neurodevelopment.
      Objectives: We aimed to identify Pb-induced transcriptomic changes in NSCs and to link these changes to neurodevelopmental outcomes in children who were exposed to Pb.
      Methods: We performed RNA-seq-based transcriptomic profiling in human NSCs treated with 1 μM Pb. We used qRT-PCR, Western blotting, ELISA, and ChIP (chromatin immunoprecipitation) to characterize Pb-induced gene up-regulation. Through interrogation of a genome-wide association study, we examined the association of gene variants with neurodevelopment outcomes in the ELEMENT birth cohort.
      Results: We identified 19 genes with significantly altered expression, including many known targets of NRF2-the master transcriptional factor for the oxidative stress response. Pb induced the expression of SPP1 (secreted phosphoprotein 1), which has known neuroprotective effects. We demonstrated that SPP1 is a novel direct NRF2 target gene. Single nucleotide polymorphisms (SNPs) (rs12641001) in the regulatory region of SPP1 exhibited a statistically significant association ( p = 0.005) with the Cognitive Development Index (CDI).
      Conclusion: Our findings revealed that Pb induces an NRF2-dependent transcriptional response in neural stem cells and identified SPP1 up-regulation as a potential novel mechanism linking Pb exposure with neural stem cell function and neurodevelopment in children.
    • References:
      Toxicol Sci. 2012 Sep;129(1):108-25. (PMID: 22641619)
      Toxicol Sci. 2014 May;139(1):142-61. (PMID: 24519525)
      Nucleic Acids Res. 2012 Aug;40(15):7416-29. (PMID: 22581777)
      J Biol Chem. 2002 Aug 23;277(34):30730-7. (PMID: 12070177)
      Toxicol Sci. 2010 Jul;116(1):249-63. (PMID: 20375082)
      Environ Health Perspect. 2009 Jan;117(1):26-31. (PMID: 19165383)
      Hum Mol Genet. 2007 May 15;16(10):1188-200. (PMID: 17409198)
      J Biol Chem. 2003 Apr 4;278(14):12029-38. (PMID: 12556532)
      Pediatrics. 2009 Mar;123(3):e376-85. (PMID: 19254973)
      Am J Respir Cell Mol Biol. 2013 Aug;49(2):204-11. (PMID: 23672216)
      Bioinformatics. 2009 May 1;25(9):1105-11. (PMID: 19289445)
      Nucleic Acids Res. 2010 Sep;38(17):5718-34. (PMID: 20460467)
      Curr Chem Genomics. 2011;5:1-12. (PMID: 21643505)
      JAMA. 1994 Jul 27;272(4):284-91. (PMID: 8028141)
      Environ Health Perspect. 2004 Apr;112(5):548-52. (PMID: 15064159)
      Mol Cell Biochem. 2015 Dec;410(1-2):255-66. (PMID: 26346162)
      N Engl J Med. 2016 Mar 24;374(12):1101-3. (PMID: 26863114)
      Neuro Oncol. 2012 Nov;14 (11):1367-78. (PMID: 23074199)
      Toxicol Appl Pharmacol. 2013 Dec 15;273(3):551-60. (PMID: 24103449)
      Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1733-40. (PMID: 20595649)
      N Engl J Med. 1979 Mar 29;300(13):689-95. (PMID: 763299)
      PLoS One. 2013 Nov 19;8(11):e80558. (PMID: 24260418)
      Toxicol Sci. 2005 Aug;86(2):365-74. (PMID: 15788721)
      Toxicol Sci. 2008 Sep;105(1):119-33. (PMID: 18550602)
      Heredity (Edinb). 2005 Sep;95(3):221-7. (PMID: 16077740)
      J Neuroinflammation. 2014 Dec 03;11:197. (PMID: 25465048)
      Genome Biol. 2010;11(3):R25. (PMID: 20196867)
      Stroke. 2013 Nov;44(11):3189-94. (PMID: 24008574)
      J Cell Physiol. 2009 Oct;221(1):98-108. (PMID: 19475568)
      J Cereb Blood Flow Metab. 2005 Feb;25(2):217-25. (PMID: 15678124)
      Stem Cell Res Ther. 2015 May 22;6:99. (PMID: 25998490)
      Neurotoxicology. 2011 Mar;32(2):281-9. (PMID: 21192972)
      Sci Transl Med. 2012 Jan 18;4(117):117ra9. (PMID: 22261033)
      Exp Neurol. 2014 Nov;261:757-71. (PMID: 25151457)
      Pediatrics. 1997 Nov;100(5):856-62. (PMID: 9346987)
      Drug Metab Dispos. 2006 Jan;34(1):152-65. (PMID: 16243960)
      J Neurochem. 2008 Jun;105(5):1948-59. (PMID: 18284614)
      JAMA. 1996 Feb 7;275(5):363-9. (PMID: 8569015)
      Free Radic Biol Med. 2005 Feb 1;38(3):325-43. (PMID: 15629862)
      Genome Biol. 2007;8(10):R227. (PMID: 17961207)
      FEBS Lett. 1990 Feb 12;261(1):124-30. (PMID: 1689669)
      Lancet. 1987 May 30;1(8544):1221-6. (PMID: 2884367)
      Environ Health Perspect. 2011 May;119(5):615-21. (PMID: 21147602)
      N Engl J Med. 2003 Apr 17;348(16):1517-26. (PMID: 12700371)
      Neuroscience. 2007 Mar 30;145(3):1037-47. (PMID: 17276012)
      J Biol Chem. 2002 Jan 4;277(1):388-94. (PMID: 11687587)
      N Engl J Med. 1987 Apr 23;316(17):1037-43. (PMID: 3561456)
      Environ Health Perspect. 2008 Nov;116(11):1586-90. (PMID: 19057716)
      Alcohol Clin Exp Res. 2008 Feb;32(2):339-47. (PMID: 18162078)
      Neurosci Lett. 1992 Dec 14;148(1-2):27-30. (PMID: 1300499)
      Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901)
      Brain Res Brain Res Rev. 2005 Nov;49(3):529-54. (PMID: 16269318)
      Environ Res. 2008 Sep;108(1):15-20. (PMID: 18514186)
      Environ Health Perspect. 2016 May 1;124(5):A79. (PMID: 27136451)
      Environ Health Perspect. 1997 Sep;105(9):956-62. (PMID: 9410739)
      Annu Rev Pharmacol Toxicol. 2007;47:89-116. (PMID: 16968214)
      Toxicol Sci. 2012 May;127(1):277-95. (PMID: 22345308)
      J Biomed Mater Res B Appl Biomater. 2011 Aug;98 (2):300-7. (PMID: 21604367)
      Int J Dev Neurosci. 2012 Aug;30(5):359-62. (PMID: 22542685)
      Environ Health Perspect. 2006 Nov;114(11):1730-5. (PMID: 17107860)
      Lung Cancer. 2009 Jun;64(3):263-70. (PMID: 18996613)
      Arch Environ Health. 2002 Sep-Oct;57(5):482-8. (PMID: 12641193)
      Neurotoxicology. 2005 Jan;26(1):141-5. (PMID: 15527882)
      Neurotoxicology. 2004 Dec;25(6):1001-12. (PMID: 15474618)
      Nature. 2003 Dec 18;426(6968):789-96. (PMID: 14685227)
      Saf Health Work. 2013 Mar;4(1):1-11. (PMID: 23515885)
    • Grant Information:
      P30 ES000002 United States ES NIEHS NIH HHS; R01 ES022230 United States ES NIEHS NIH HHS; P30 ES023515 United States ES NIEHS NIH HHS; T32 HL007118 United States HL NHLBI NIH HHS; R01 ES015533 United States ES NIEHS NIH HHS; R01 ES006189 United States ES NIEHS NIH HHS; P42 ES016454 United States ES NIEHS NIH HHS; P30 ES009089 United States ES NIEHS NIH HHS
    • Accession Number:
      0 (Hazardous Substances)
      0 (SPP1 protein, human)
      106441-73-0 (Osteopontin)
      2P299V784P (Lead)
    • Publication Date:
      Date Created: 20160827 Date Completed: 20170803 Latest Revision: 20181113
    • Publication Date:
      20250114
    • Accession Number:
      PMC5381979
    • Accession Number:
      10.1289/EHP265
    • Accession Number:
      27562236