Mechanisms underlying the effect of metal exposures on neurodevelopment

 

Disruption of neurodevelopment and cognitive function early in life due to environmental exposures can have lifelong impacts. The fetal period is a time of heightened vulnerability. Mechanism of early susceptibility is not fully understood, but may be explained, in part, by environmental impact on neural stem cells (NSCs). As the progenitor cells of the central nervous system, NSCs play an essential role in shaping the developing brain and disruption of this process by environmental exposure may lead to deficits later in life. Prenatal or postnatal exposure to environmental perturbation such as malnutrition, pollution, and heavy metals has been associated with low IQ and impaired neurobehavioral and cognitive functions. However, the molecular mechanisms by which environmental factors impact NSC function and early brain development remain poorly understood.

Common environmental metal contaminants such as arsenic (As), lead (Pb), cadmium (Cd), and manganese (Mn) are of great public health concern because of their adverse neurodevelopmental in children. However, despite overwhelming evidence from epidemiological as well as animal and cell-culture studies that show metals are a neurotoxicant, the molecular mechanisms by which metals impair neuronal functioning remain poorly defined. In addition, there are limited studies on the roles of metal mixtures in neurodevelopment that is relevant to real-world exposure.

Using state-of-the-art approaches as well as molecular mechanistic studies, Project 1 seeks to address a fundamental question in environmental metals research: What are the genetic pathways and mechanisms by which environmental metal exposure impairs neuronal function. Specifically, Project 1 is aimed:

1. To Identify human genes or microRNAs affecting neural susceptibility to metal/metal mixture using genome-wide genetic screens.
2. To identify critical genetic pathways and networks that contribute to metal neurotoxicity using bioinformatics analysis tools.
3. To validate the roles of identified targets on NSC function (proliferation, self-renewal, and/or differentiation) in the absence or presence of metal exposure.

From these studies, we expect to identify novel genes or microRNAs which may lead to increased susceptibility or resistance to metal exposure. In addition, comparing enriched pathways across multiple metals will give insights to discover the common genes/or pathways that are affected by different metals or identify unique signatures for each metal. Ultimately, this study will contribute to decipher the mechanisms of metal toxicity in neural stem cells and to identify novel therapeutic targets to prevent or reduce adverse neurodevelopmental outcomes in children exposed to metals.  

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