SPP1; OXIDATIVE STRESS; AND LEAD TOXICITY

PROJECT SUMMARYSPP1, Oxidative Stress, and Lead ToxicityExposure to lead (Pb), a pervasive environmental toxicant, at the early stages of braindevelopment has long-lasting effects on neurocognitive function. However, the molecularmechanisms underlying the unique susceptibility of early brain development to Pb remain poorlyunderstood. As the progenitor cells in the central nervous system, neural stem cells (NSCs) playan essential role in shaping the developing brain. We performed global transcriptional profilingand identified genes whose expression is significantly altered by Pb treatment in neural stemcells. Most of the Pb-upregulated genes are targets of NRF2?the master transcriptional factorfor the oxidative stress response, including SPP1 (secreted phosphoprotein 1). SPP1 is knownto be neuroprotective, and consistent with this, we demonstrated that addition of recombinantSPP1 protein reduces the inhibitory effect of Pb on NSC growth. Using data from existinggenome-wide association studies of an environmental epidemiological cohort, we furthershowed that a genetic variant in the promoter region of SPP1 significantly associates withimproved cognitive development in children. Based on these studies, we hypothesize thatNRF2-mediated SPP1 upregulation functions as a self-protective response to reduce Pbexposure-induced injury in neural stem cells. We further hypothesize that failure orcompromised ability to upregulate SPP1 in response to Pb exposure contributes to neural stemcell dysfunction and consequently the impairment of early brain development. To test thesehypotheses, we propose a highly integrative project that combines molecular mechanisticstudies in cultured neural stem cells, in vivo mouse models, and human genetic epidemiology inchildren exposed to Pb. Aim 1 will investigate the mechanisms thorough which SPP1upregulation protects against Pb toxicity in neural stem cells. Aim 2 will investigate the role ofSPP1 in mediating the effect of Pb on neurodevelopment in mice. Aim 3 will determine thefunctional association of SPP1 variants with neurodevelopment in children exposed to Pb.Results from this study will establish SPP1 upregulation as a critical mechanism linking Pbexposure with neural stem cell function and neurodevelopment in children, and may identifySPP1 as a novel target for preventative and therapeutic interventions against detrimentalneurodevelopment effects of Pb exposure in children.