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Harvard School of Public Health

Superfund Research Program

Genetic Epidemiology of Neurodevelopmental Metal Toxicity

Project Leader: David C. Christiani
Co-Investigators: Robert O. Wright, Molly L. Kile (Oregon State University)
Grant Number: P42ES016454
Funding Period: 2010-2015
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2010-2014)

Metals such as manganese and arsenic are of increasing public health concern since recent data demonstrates their neurotoxicity to the developing brain. However, the role of genetic susceptibility to these toxic metals is unknown. Furthermore, while lead poisoning has been studied extensively, genetic susceptibility to its toxicity is not well understood. A systematic approach to studying gene-environment interaction would have immediate impact on the understanding of how metals induce toxicity and provide biological insight for potential treatment and prevention measures.

In this project, researchers assess data from three cohort studies of metals and neurodevelopment. One in a developing country-Bangladesh, where metal exposures are unusually high, one in Mexico, a middle income country where metal exposures are moderately high, and one in the United States, in Tar Creek, OK, where exposure are representative of a community near a US toxic waste site. Tar Creek is a Superfund Megasite and former metal mining community. The success in assembling these cohorts has laid the groundwork for further research in genetic susceptibility to metals. The three cohorts combined yield a sample of 2600 children with prospective data on metal exposure and repeated neurophenotype measures; sufficient power to discover and to validate genetic susceptibility genes/SNPs. Using a genome-wide approach, researchers discover susceptibility variants in a discovery phase, and then validate their findings in an independent sample of children while controlling for multiple comparisons.

Furthermore, researchers are integrating with Dr. Quan Lu (Genetic Mechanisms of Metal Neurotoxicity) to determine other biological pathways relevant to metal toxicity using state of the art siRNA technology to identify genes/pathways which prorriote/inhibit metal toxicity. This project represents perhaps the first large scale coordinated study of genetic susceptibility to metal toxicity and provides biological insight into the mechanisms by which metals produce toxicity.

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