NORTHWESTERN UNIVERSITY
Grant: $499,982 - National Institutes of Health - Sep. 27, 2009
75% voted satisfied - 25% voted not satisfied - 4 vote(s) cast
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Award Description: This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-ES-104: Identification of alterations in epigenetic marks related to environmental exposures. In the US, over one million people are occupationally exposed to pesticides. Pesticides, and their residuals, are pervasive in our environment. Our dependence upon pesticides is increasing. All pesticides sold in the U.S. passed US Environmental Protection Agency (EPA) tests for carcinogenicity. However, EPA evaluation of chemical carcinogenicity is primarily based on the detection of genotoxic/mutagenic events. Epigenetic alterations, an emerging hallmark of cancer, have not been considered in the EPA evaluation. The potential importance of pesticide-induced epigenetic alterations is supported by the fact that epidemiologic studies have repeatedly shown increased cancer risk with pesticide exposure. Emerging evidence suggests that promoter DNA methylation is affected by environmental exposures. Prior studies have shown that epigenetic information, including DNA methylation, contained in blood cell DNA represents a valuable predictive marker of cancer risk. Blood is a conduit between the external environment and human tissues, and as such constitutes a seminal target tissue to evaluate the effects of environmental toxicants on human health. We recently linked exposure to organophosphate pesticides (OPs), the most commonly used insecticides in the U.S, to increased promoter methylation of several tumor suppressor genes in blood DNA. We further confirmed this finding in vitro, using human blood cells treated with OPs. Taken together, we hypothesize that exposure to pesticides can induce promoter DNA methylation changes in blood cell DNA, and that this will provide currently unknown mechanistic insights into the association between pesticide exposure and cancer risk. We propose to study whether OP exposure alters gene promoter DNA methylation patterns in both human subjects and OP-treated in-vitro cell lines. We will first conduct a genome-wide screening in a subset of population with the highest and lowest OP expsoure and cell lines and then validate the findings using gene-specific approach in an independent replication population and different dose of OP treated cell lines. The investigations proposed in the current study will take advantage of an existing NIEHS-funded cross-sectional study, which is nested in AHS, that examines OP exposure and neurological disorders in 700 AHS participants. Thus, we will have well-defined OP exposure data, DNA from blood samples, and comprehensive data for confounding and modifying effect evaluation. Further, we have an established in-vitro system for evaluating epigenetic effects of pesticides. This is the first study to examine the effect of pesticides exposures on epigenome-wide gene promoter DNA methylation in both human and in-vitro settings. The provide direct evidence on the effect of each pesticide on DNA methylation and whether there is a dose-response relationship. The in-vitro data will to some extent guarantee in minimizing the chance findings in human sample duo to other factors. This study will have high public health significance due to the widespread pesticide use in the US and worldwide. These are novel and innovative experiments, as similar studies assessing alterations in DNA methylation after pesticide treatment of human cell lines have not been done. A major strength is the study population of farmers with well-characterized exposure assessment. This high quality and completeness of data on pesticide use would be difficult to achieve in a general population cohort. Another major strength is that this study is guaranteed to be completed in a timely manner, since the DNA is ready for analysis, and other data, are readily available also.
Project Description: As defined in the Award Description field
Jobs Summary: American Recovery and Reinvestment Act funds have significantly aided the research mission of Northwestern University by providing salary compensation for individuals directly involved in research, both at Northwestern and at consortium institutions, as well as at the vendor organizations who provide goods and services in support of that mission. Northwestern has employed a standard methodology for determining jobs created or retained, based on guidance presented by OMB. Jobs are reported in aggregate for the grant, comprised of calculated figures for hourly and salaried employees at Northwestern plus the reported jobs created or retained by subrecipients. The number of Northwestern hourly employees will be calculated as the number of hours charged to the grant divided by the standard hours in a full-time schedule for the period. The number of Northwestern salaried employees will be calculated based on the paid effort charged to the ARRA grant divided by the total salary. There are currently no jobs created or retained by this ARRA funded project. (Total jobs reported: 0)
Project Status: Not Started
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