# SPP1, Oxidative Stress, and Lead Toxicity

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2021 · $554,785

## Abstract

PROJECT SUMMARY
SPP1, Oxidative Stress, and Lead Toxicity
Exposure to lead (Pb), a pervasive environmental toxicant, at the early stages of brain
development has long-lasting effects on neurocognitive function. However, the molecular
mechanisms underlying the unique susceptibility of early brain development to Pb remain poorly
understood. As the progenitor cells in the central nervous system, neural stem cells (NSCs) play
an essential role in shaping the developing brain. We performed global transcriptional profiling
and identified genes whose expression is significantly altered by Pb treatment in neural stem
cells. Most of the Pb-upregulated genes are targets of NRF2—the master transcriptional factor
for the oxidative stress response, including SPP1 (secreted phosphoprotein 1). SPP1 is known
to be neuroprotective, and consistent with this, we demonstrated that addition of recombinant
SPP1 protein reduces the inhibitory effect of Pb on NSC growth. Using data from existing
genome-wide association studies of an environmental epidemiological cohort, we further
showed that a genetic variant in the promoter region of SPP1 significantly associates with
improved cognitive development in children. Based on these studies, we hypothesize that
NRF2-mediated SPP1 upregulation functions as a self-protective response to reduce Pb
exposure-induced injury in neural stem cells. We further hypothesize that failure or
compromised ability to upregulate SPP1 in response to Pb exposure contributes to neural stem
cell dysfunction and consequently the impairment of early brain development. To test these
hypotheses, we propose a highly integrative project that combines molecular mechanistic
studies in cultured neural stem cells, in vivo mouse models, and human genetic epidemiology in
children exposed to Pb. Aim 1 will investigate the mechanisms thorough which SPP1
upregulation protects against Pb toxicity in neural stem cells. Aim 2 will investigate the role of
SPP1 in mediating the effect of Pb on neurodevelopment in mice. Aim 3 will determine the
functional association of SPP1 variants with neurodevelopment in children exposed to Pb.
Results from this study will establish SPP1 upregulation as a critical mechanism linking Pb
exposure with neural stem cell function and neurodevelopment in children, and may identify
SPP1 as a novel target for preventative and therapeutic interventions against detrimental
neurodevelopment effects of Pb exposure in children.

## Key facts

- **NIH application ID:** 10242681
- **Project number:** 5R01ES029097-04
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Quan Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $554,785
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242681

## Citation

> US National Institutes of Health, RePORTER application 10242681, SPP1, Oxidative Stress, and Lead Toxicity (5R01ES029097-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242681. Licensed CC0.

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