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

• Peter J. Wagner ^[2] ; Hae-Ryung Park ^[2] ; Zhaoxi Wang ^[3] ; Rory Kirchner ^[4] ; Yongyue Wei ^[3] ; Li Su ^[3] ; Kirstie Stanfield ^[1] ; Tomas R. Guilarte ^[1] ; Robert O. Wright ^[5] ; David C. Christiani ^[6] ; Quan Lu ^[7]
  1. [1] Columbia University

     Columbia University

     Estados Unidos

     
  2. [2] 1 Department of Environmental Health,; 2 Program in Molecular and Integrative Physiological Sciences, and
  3. [3] 1 Department of Environmental Health,
  4. [4] 3 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  5. [5] 5 Department of Preventative Medicine, Mount Sinai School of Medicine, New York City, New York, USA
  6. [6] 2 Program in Molecular and Integrative Physiological Sciences, and
  7. [7] 1 Department of Environmental Health,; 2 Program in Molecular and Integrative Physiological Sciences, and; 6 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

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• Localización: Environmental health perspectives, ISSN 0091-6765, Vol. 125, Nº. 4, 2017, págs. 721-729
• Idioma: inglés
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  • 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 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).

    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.

    Wagner PJ, Park HR, Wang Z, Kirchner R, Wei Y, Su L, Stanfield K, Guilarte TR, Wright RO, Christiani DC, Lu Q. 2017. In vitro effects of lead on gene expression in neural stem cells and associations between up-regulated genes and cognitive scores in children. Environ Health Perspect 125:721–729; http://dx.doi.org/10.1289/EHP265