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

Overview

Journal Environ Health Perspect

Date 2016 Aug 27

PMID 27562236

Citations 18

Authors

Peter J Wagner

Hae-Ryung Park

Zhaoxi Wang

Rory Kirchner

Yongyue Wei

Li Su

Kirstie Stanfield

Tomas R Guilarte

Robert O Wright

David C Christiani

Quan Lu

Affiliations

Soon will be listed here.

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 (secreted phosphoprotein 1), which has known neuroprotective effects. We demonstrated that is a novel direct NRF2 target gene. Single nucleotide polymorphisms (SNPs) (rs12641001) in the regulatory region of exhibited a statistically significant association ( = 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.

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