Superfund Research Program
Genetic Mechanisms of Metal Neurotoxicity
Project Summary (2010-2014)
Lead (Pb), manganese (Mn) and arsenic (As) are common metal contaminants in the environment. They are of great public health concern because exposures to them impair neuronal functions, including adverse effects on neurodevelopment in children. Although epidemiological and animal studies have unequivocally established that these metals are neurotoxicants, the molecular mechanisms by which they impair neuronal functions remain poorly understood. Metal neurotoxicity is likely determined by intricate interactions between metals and their target cells. For instance, metals use cellular machinery to gain entry into target cells and to be transported to certain cellular sites; on the other hand, the target cells have intrinsic mechanisms to respond to metals and defend against metal toxicity. Critical to an ultimate mechanistic understanding of metal neurotoxicity, the researchers believe, is discovering the cellular genes and pathways involved in metal toxicity and in the cellular responses to these insults. Accordingly, this project is designed to identify and characterize genes and genetic networks that mediate the neurotoxicity of Pb, Mn, and As. Researchers use a novel genome-wide gene inactivation approach, together with a phenotype-based assay, to identify human genes whose inactivation alter neuronal susceptibility to metal exposure. They then employ powerful bioinformatics tools to expand the isolated genes in the screen into genetic pathways and identify comprehensive biological networks that affect metal neurotoxicity. These analyses are augmented by data mining of existing databases of metal toxicity. The researchers are establishing and characterizing the physiological mechanisms through which the isolated genes affect the ability of metal exposure to dysregulate neuronal functions/status including synaptogenesis and neurite morphology.