title: In VitroEffects of Lead on Gene Expression in Neural Stem Cells and Associations between Up-regulated Genes and Cognitive Scores in Children.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 ofSPP1(secreted phosphoprotein 1), which has known neuroprotective effects. We demonstrated thatSPP1is a novel direct NRF2 target gene. Single nucleotide polymorphisms (SNPs) (rs12641001) in the regulatory region ofSPP1exhibited a statistically significant association (p= 0.005) with the Cognitive Development Index (CDI).
  
  
  
  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.
authors: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors: Peter J
authors: PJ
authors: Wagner
authors: Hae-Ryung
authors: HR
authors: Park
authors: Zhaoxi
authors: Z
authors: Wang
authors: Rory
authors: R
authors: Kirchner
authors: Yongyue
authors: Y
authors: Wei
authors: Li
authors: L
authors: Su
authors: Kirstie
authors: K
authors: Stanfield
authors: Tomas R
authors: TR
authors: Guilarte
authors: Robert O
authors: RO
authors: Wright
authors: David C
authors: DC
authors: Christiani
authors: Quan
authors: Q
authors: Lu
mesh_terms: D002648:Child; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055106:Genome-Wide Association Study; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D007854:Lead / Q000633:toxicity*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D015386:Hazardous Substances; C506895:SPP1 protein, human; D053495:Osteopontin; D007854:Lead