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2007 Progress Report: Integrating Innovative Biomarkers of Environmentally Induced Disease for Children in Agricultural Communities

EPA Grant Number: R832733
Title: Integrating Innovative Biomarkers of Environmentally Induced Disease for Children in Agricultural Communities
Investigators: Faustman, Elaine , Griffith, William C. , Yu, Xiaozhong
Institution: University of Washington - Seattle
EPA Project Officer: Callan, Richard
Project Period: October 1, 2005 through September 30, 2008
Project Period Covered by this Report: October 1, 2006 through September 30, 2007
Project Amount: $749,997
RFA: Early Indicators of Environmentally Induced Disease (2004)
Research Category: Biology/Life Sciences , Children's Health , Health Effects

Description:

Objective:

The purpose of this study is to develop an integrative tool for evaluating the importance of knowledge of genomic biomarkers of susceptibility and early response for establishing the exposure-effect-disease relationship in adults and children in agricultural and non-agricultural communities.

Progress Summary:

This study is coordinated with an ongoing community based participatory research study in the Yakima Valley (CBPR), a part of the EPA/NIEHS funded Children’s Health Risk Research Center (CHC). We are evaluating biomarkers of susceptibility (genotype for pesticide metabolism and oxidative protective pathways), biomarkers of early biological effect (gene expression responses in oxidative response and cell death), and biomarkers of effect (cholinesterase and clinical disease pathways). This study uses biorepository samples collected as part of the CHC-CBPR study.

Buccal cells (collected from the inner cheek) offer an attractive non-invasive alternative for of biospecimen collection. We have refined the collection techniques using soft oral brushes to produce a more applicable protocol for collecting specimens from children. In addition to their wide use for DNA analysis, the evaluation of buccal cell specimens have recently been shown to have high potential for RNA expression analysis, chromosomal analysis, genotoxicity analysis, and proteomic analysis. We have established an mRNA extraction protocol that produces high quality mRNA in sufficient quantity to be used for microarray-based gene expression analysis.

Using microarray data from a laboratory-based toxicological study of multiple doses measured at multiple time points we developed a GO-Quant methodology to provide functional interpretation of expression data for tens of thousands of genes (Yu et al., 2006). We used information from gene ontology databases and showed how information across multiple genes in biological pathways can be combined to provide a better understanding of toxicological modes of action. We have applied our methodology to show how quantitative metrics such as benchmark doses can be derived to improve toxicological interpretations of microarray data in terms of mode of action and biological pathway response, information critical to the development of risk assessment profiles.

Future Activities:

In the coming year, we will apply our optimized mRNA extraction protocol to isolate total mRNA from buccal cell samples collected as part of the CHC-CBPR and conduct microarray analysis. We will also isolate DNA from buffy coat specimens and conduct microarray-based SNP analysis. Paraoxonase (PON1) genotype and phenotype status is a biomarker of susceptibility for OP toxicity. We will use the PON1 status for the adults, AChE measurements, urinary OP metabolite concentrations, and the gene expression microarray data to inform our integrative framework tool. The early response portion of the tool designed to allow for incorporation of pathway-specific molecular response data into the exposure-effect-disease paradigm. We will use our GO-Quant methodology to provide quantitative analysis of the response pathways. These combined results will inform our integrative framework tool.


Journal Articles on this Report: 2 Displayed | Download in RIS Format

Other project views: All 6 publications 3 publications in selected types All 2 journal articles

Type Citation Project Document Sources
Journal Article Bekris LM, Shephard C, Janer M, Graham J, McNeney B, Shin J, Zarghami M, Griffith W, Farin F, Kavanagh TJ, Lernmark A. Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels. Experimental and Clinical Endocrinology & Diabetes 2007;115(4):221-228. R832733 (2007)
R831709 (2005)
  • Abstract from PubMed
    • Journal Article Yu X, Griffith WC, Hanspers K, Dillman III JF, Ong H, Vredevoogd MA, Faustman EM. A system-based approach to interpret dose-and time-dependent microarray data: quantitative integration of gene ontology analysis for risk assessment. Toxicological Sciences 2006;92(2):560-577. R832733 (2007)
    R831709 (2005)
    R831709 (2006)
    R831709C001 (2006)
  • Abstract from PubMed
  • Full-text: Oxford Journals
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  • Other: Oxford Journals PDF
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    • Supplemental Keywords:

    organophosphate pesticides, genomic biomarkers, children, neurodegenerative disease, , ENVIRONMENTAL MANAGEMENT, Scientific Discipline, Health, RFA, Risk Assessment, Health Risk Assessment, Children's Health, Biochemistry, exposure assessment, children's environmental health, assessment of exposure, susceptibility, agricultural community, pesticide exposure, biological markers, disease, children's vulnerablity

    Progress and Final Reports:
    2006 Progress Report
    Original Abstract

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    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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