Grant Number:
Principal Investigator:
Lu, Quan
Institution:
Harvard School of Public Health
Most Recent Award Year:
2018
Lifestage of Participants:
Exposure:
Prenatal; Infant (0-1 year); Youth (1-18 years)
Assessment:
Youth (1-18 years)
Exposures:
Metals:
Lead
Health Outcomes:
Neurological/Cognitive Outcomes:
Neurodevelopmental outcomes
Genes or Other DNA Products Studied:
Variants in secreted phosphoprotein 1 (SPP1) and associated pathway genes
Abstract:
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.
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Related NIEHS-Funded Study Populations
Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT)
Principal Investigator:
Hu, Howard; Peterson, Karen; Hernandez-Avila, Mauricio; Tellez-Rojo, Martha Maria
| Study Population Page Study Population c49
Institution:
University of Michigan
Location:
Mexico City, Mexico
Number of Participants::
1,653
Brief Description::
This is a group of three sequentially-enrolled, on-going, epidemiologic birth cohort studies in Mexico City with an original aim to investigate the impact of lead on child development. The research aims have since expanded to include a wide range health outcomes and environmental, nutritional, behavioral, genetic, and epigenetic risk factors. More than 1,600 mother-child pairs enrolled in the study beginning in 1994, some of whom have been followed for over two decades.