Final Report: Genetic Susceptibility

EPA Grant Number: R834514C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R834514
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: University of Washington Center for Child Environmental Health Risks Research (2010)
Center Director: Faustman, Elaine
Title: Genetic Susceptibility
Investigators: Furlong, Clement
Institution: University of Washington
EPA Project Officer: Callan, Richard
Project Period: September 25, 2009 through September 24, 2015 (Extended to September 24, 2016)
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

The overall goal of the Genetic Susceptibility Research Project was to develop specific biomarkers of exposure to organophosphate (OP) compounds, and to use these biomarkers to explore gene-environment interactions related to genetic variability in the paraoxonase (PON1) gene, particularly with respect to OP exposures that occur during early development.

Summary/Accomplishments (Outputs/Outcomes):

Activities of the Genetic Susceptibility Research Project have contributed to a greater understanding of the role of gene–environment interactions for children’s susceptibility to OP insecticides. The project involves interactions with many other entities, including the Centers for Disease Control and Prevention (CDC), Environmental Protection Agency (EPA) Region 10, Agency for Toxic Substances and Disease Registry (ATSDR), the University of California Berkeley Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), Washington State Department of Health, Washington State Pesticide Incident and Reporting Panel (PIRT), other US government agencies, the United Kingdom (UK) Committee on Toxicity and several members of the UK Parliament. The overall goal of the Genetic Susceptibility Research Project is to develop specific biomarkers of exposure to OP compounds, and to use these biomarkers to explore gene–environment interactions related to genetic variability in the paraoxonase (PON1) gene, particularly with respect to OP exposures that occur during early development.

Highlights of the research include experiments characterizing PON1 status as a biomarker of sensitivity to chlorpyrifos (CP) and chlorpyrifos oxon (CPO) during gestation. The initial chronic dose-response studies in pregnant and non-pregnant mice demonstrated steep dose-response curves for inhibition of butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), with higher doses leading to weight loss and fetal abnormalities. PON1-/- mice were more sensitive than PON1+/+ mice to these effects of chronic CPO exposure. The PON1 status of the dam was also found to clearly influence CPO toxicity to the fetus. Microarray analysis of gene expression profile in fetal brains has been completed. Data analysis using approaches such as gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis is currently underway.

To evaluate the correlation between OP sensitivity and plasma PON1 status, PON1+/+, tgHuPON1Q192, and tgHuPON1R192 mice were exposed transdermally to diazinon-oxon (DZO). Four hours following the exposure, mice were sacrificed and tissues collected for cholinesterase (ChE) measurement. A positive, linear correlation was found between plasma PON1 activity and AChE level of both brain and diaphragm in all treated mice, indicating that plasma PON1 can serve as a susceptibility biomarker for DZO toxicity.

Conclusions:

One of the primary aims of this project in the previous funding period was to evaluate the effects of exposure to CPO during early postnatal development and to determine the role of the human PON1-Q192R polymorphism in modulating these effects, using multiple endpoints of OP toxicity. Assessment of all of the endpoints for these studies has been completed, and two manuscripts describing these results have been published in the last year. The first manuscript describes changes in gene expression patterns and brain AChE activity following repeated exposure of mice to CPO. The second manuscript describes the neurobehavioral assessment of mice following repeated CPO exposure during postnatal development. Findings indicate that neonatal CPO exposure is associated with wide-ranging effects on gene expression in the brain, and that PON1 status can modulate these effects, even when PON1 levels are low during early development.

Furthermore, the researcher’s development this year of mass spectrometric (MS) protocols for determining the percentage modification of biomarker proteins will provide a much more accurate determination of target protein inhibition. Currently, a baseline level of activity is required to establish a reasonable estimate of the percentage inhibition of an individual’s BChE. The MS protocols directly determine the percentage modification without the need for a baseline activity determination. The MS analysis of modified protein should be superior to analysis of urinary metabolites for estimating exposures, since it is not possible to know whether a metabolite was taken up directly from the environment or was generated in vivo.


Journal Articles on this Report : 29 Displayed | Download in RIS Format

Other subproject views: All 55 publications 37 publications in selected types All 36 journal articles
Other center views: All 507 publications 224 publications in selected types All 175 journal articles
Type Citation Sub Project Document Sources
Journal Article Cole TB, Jansen K, Park S, Li W-F, Furlong CE, Costa LG. The toxicity of mixtures of specific organophosphate compounds is modulated by paraoxonase 1 status. Advances in Experimental Medicine and Biology 2010;660:47-60. R834514 (2011)
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  • Journal Article Giordano G, Tait L, Furlong CE, Cole TB, Kavanagh TJ, Costa LG. Gender differences in brain susceptibility to oxidative stress are mediated by levels of paraoxonase-2 expression. Free Radical Biology and Medicine 2013;58:98-108. R834514 (2013)
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  • Journal Article Kim DS, Marsillach J, Furlong CE, Jarvik GP. Pharmacogenetics of paraoxonase activity: elucidating the role of high-density lipoprotein in disease. Pharmacogenomics 2013;14(12):1495-1515. R834514 (2013)
    R834514C004 (Final)
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  • Journal Article Marsillach J, Costa LG, Furlong CE. Protein adducts as biomarkers of exposure to organophosphorus compounds. Toxicology 2013;307:46-54. R834514 (2013)
    R834514C004 (Final)
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  • Journal Article Mehta AJ, Zanobetti A, Bind MA, Kloog I, Koutrakis P, Sparrow D, Vokonas PS, Schwartz JD. Long-term exposure to ambient fine particulate matter and renal function in older men: the Veterans Administration Normative Aging Study. Environmental Health Perspectives 2016;124(9):1353-1360. R834514C004 (Final)
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  • Journal Article Marsillach, J., E.J. Hsieh, R.J. Richter, M.J. Maccoss, and C.E. Furlong, Proteomic analysis of adducted butyrylcholinesterase for biomonitoring organophosphorus exposures. Chem Biol Interact, 2012. R834514C004 (Final)
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    Journal Article Kim, DS, Crosslin, DR, Auer, PL, Suzuki, SM, Marsillach, J, Burt, AA, Gordon, AS, Meschia, JF, Nalls, MA, Worrall, BB, Longstreth, WT, Jr., Gottesman, RF, Furlong, CE, Peters, U, Rich, SS, Nickerson, DA and Jarvik, GP. 2014. Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project. J Lipid Res. 55(6):1173-1178. 4031948. R834514C004 (Final)
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    Journal Article Guizzetti, M., N.H. Moore, G. Giordano, K.L. VanDeMark, and L.G. Costa, Ethanol inhibits neuritogenesis induced by astrocyte muscarinic receptors. Glia, 2010. 58(12):p. 1395-406. PMCID2925144. R834514C004 (Final)
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    Journal Article Suzuki SM, Stevens RC, Richter RJ, Cole TB, Park S, Otto TC, Cerasoli DM, Lenz DE, Furlong, CE. 2010. Engineering Human PON1 in an E. coli Expression System. Adv Exp Med Biol.;660:37–45. http://doi.org/10.1007/978-1-60761-350-3_5. PMID 20221869. R834514C004 (Final)
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    Journal Article Richter RJ, Jarvik GP, Furlong CE. 2010. Paraoxonase 1 (PON1) Status as a Risk Factor for Disease or Exposure. Adv Exp Med Biol 660:29-35. PMID 20221868. DOI 10.1007/978-1-60761-350-3_. NIHMSID #193805. R834514C004 (Final)
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    Journal Article Cole, TB, Fisher, JC, Burbacher, TM, Costa, LG and Furlong, CE. 2012. Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon. Neurotoxicol Teratol. 34(3):311-22. PMCID:PMC3367041. R834514C004 (Final)
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    Journal Article Kim, DS, Burt, AA, Ranchalis, JE, Richter, RJ, Marshall, JK, Nakayama, KS, Jarvik, ER, Eintracht, JF, Rosenthal, EA, Furlong, CE and Jarvik, GP. 2012. Dietary cholesterol increases paraoxonase 1 enzyme activity. J Lipid Res. 53(11):2450-8. PMCID:PMC3466014. R834514C004 (Final)
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    Journal Article Kim, DS, Burt, A, Ranchalis, J, Richter, RJ, Marshall, E, Rosenthal, E, Furlong, C and Jarvik, GP. 2012. Additional common polymorphisms in the PON gene cluster predict PON1 activity but not vascular disease. J Lipids 2012:476316. PMCID:PMC3364586. R834514C004 (Final)
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    Journal Article Costa, LG, Giordano, G, Cole, TB, Marsillach, J and Furlong, CE. 2013. Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity. Toxicology. 307(10):115-122. PMCID:PMC3516631. R834514C004 (Final)
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    Journal Article Kim, DS, Burt, AA, Crosslin, DR, Robertson, PD, Ranchalis, JE, Boyko, EJ, Nickerson, DA, Furlong, CE and Jarvik, GP. 2013. Novel common and rare genetic determinants of paraoxonase activity:FTO, SERPINA12, and ITGAL. J Lipid Res. 54(2):552-60. PMCID:PMC3588879. R834514C004 (Final)
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    Journal Article Marsillach, J, Hsieh, EJ, Richter, RJ, MacCoss, MJ, Furlong, CE. 2013. Proteomic analysis of adducted butyrylcholinesterase for biomonitoring organophosphorus exposures. Chem Biol Interact 203(1):85-90. R834514C004 (Final)
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    Journal Article Costa, LG, Tait, L, de Laat, R, Dao, K, Giordano, G, Pellacani, C, Cole, TB and Furlong, CE. 2013. Modulation of paraoxonase 2 (PON2) in mouse brain by the polyphenol quercetin:a mechanism of neuroprotection? Neurochem Res. 38(9):1809-18. 3735620. R834514C004 (Final)
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    Journal Article Costa, LG, de Laat, R, Dao, K, Pellacani, C, Cole, TB and Furlong, CE. 2013. Paraoxonase-2 (PON2) in brain and its potential role in neuroprotection. Neurotoxicology. 3942372. R834514C004 (Final)
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    Journal Article Cole, TB, Li, WF, Co, AL, Hay, AM, MacDonald, JW, Bammler, TK, Farin, FM, Costa, LG and Furlong, CE. 2014. Repeated Gestational Exposure of Mice to Chlorpyrifos Oxon is Associated with Paraoxonase 1 (PON1)-Modulated Effects in Maternal and Fetal Tissues. Toxicol Sci. R834514C004 (Final)
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    Journal Article Furlong CE, Marsillach J, Jarvik GP, Costa LG. 2016. Paraoxonases-1,-2 and-3:What are their functions? Chem Biol Interact. doi:10.1016/j.cbi.2016.05.036. PMID:27238723. R834514C004 (Final)
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    Journal Article Marsillach J, Costa LG, Furlong CE. 2016. Paraoxonase-1 and Early-Life Environmental Exposures. Ann Glob Health. 82(1):100-10. PMID:27325068; PMCID:PMC4916371. R834514C004 (Final)
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    Journal Article Garrick JM, Dao K, de Laat R, Elsworth J, Cole TB, Marsillach J, Furlong CE, Costa LG. 2016. Developmental expression of paraoxonase 2. Chem Biol Interact. pii:S0009-2797(16)30116-8. doi:10.1016/j.cbi.2016.04.001. PMID:27062895. R834514C004 (Final)
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    Journal Article Cole, T.B., J.C. Fisher, T.M. Burbacher, L.G. Costa, and C.E. Furlong, Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon. Neurotoxicol Teratol, 2012. 34(3):p. 311-322. R834514C004 (Final)
    R834798C003 (Final)
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    Journal Article Burton C, Marsillach J, Zhang YS, Zhao W, Zheng X. Bioanalysis. 2015;7(13):1667-73. doi:10.4155/bio.15.90. Epub 2015 Jul 7** Judit Marsillach selected as a finalist for the Young Investigator Award to identify and reward promising early career researchers in the community. R834514C004 (Final)
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    Journal Article Furlong, C.E., R.J. Richter, L.G. Costa, and G.P. Jarvik, Paraoxonase 1 (PON1) Status in Risk Assessment for Organophosphate Exposure and Pharmacokinetics, in Chapter 9:Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment. 2012, American Chemical Society:Available at:http://pubs.acs.org/doi/abs/10.1021/bk-2012-1099.ch009. p. 133-147. R834514C004 (Final)
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    Journal Article Costa, L.G., G. Giordano, and C.E. Furlong, Pharmacological and dietary modulators of paraxonase 1 (PON1) activity and expression:the hunt goes on. Biochem Pharmacol, 2011. 81(3):p. 337-344. PMCID3077125. R834514C004 (Final)
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    Journal Article Kim, D.S., A. Burt, J. Ranchalis, R.J. Richter, E. Marshall, E. Rosenthal, C. Furlong, and G.P. Jarvik, Additional common polymorphisms in the PON gene cluster predict PON1 activity but not vascular disease. J Lipids, 2012. 2012(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364586/pdf/JL2012-476316.pdf). R834514C004 (Final)
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    Journal Article Kim, D.S., A.A. Burt, J.E. Ranchalis, R.J. Richter, J.K. Marshall, K.S. Nakayama, E.R. Jarvik, J.F. Eintracht, E.A. Rosenthal, C.E. Furlong, and G.P. Jarvik, Dietary cholesterol increases paraoxonase 1 enzyme activity. J Lipid Res, 2012. 53(11):p. 2450-8. R834514C004 (Final)
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    Journal Article Asselbergs, F.W., Y. Guo, E.P. van Iperen, S. Sivapalaratnam, V. et al. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. Am J Hum Genet, 2012. 91(5):p. 823-38. R834514C004 (Final)
    R834798C005 (Final)
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    Supplemental Keywords:

    gene by environment, susceptibility factors, gender differences, paraoxonase 1, children's health, RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Biochemistry, Environmental Monitoring, Children's Health, Environmental Policy, Biology, Risk Assessment, pesticide exposure, age-related differences, pesticides, children's vulnerablity, biological markers, agricultural community

    Relevant Websites:

    CENTER FOR CHILD ENVIRONMENTAL HEALTH RISKS RESEARCH Exit

    Progress and Final Reports:

    Original Abstract
  • 2010
  • 2011 Progress Report
  • 2012
  • 2013 Progress Report
  • 2014
  • 2015 Progress Report

  • Main Center Abstract and Reports:

    R834514    University of Washington Center for Child Environmental Health Risks Research (2010)

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834514C001 Community-Based Participatory Research
    R834514C002 Pesticide Exposure Pathways
    R834514C003 Molecular Mechanisms
    R834514C004 Genetic Susceptibility