2005 Progress Report: Environmental Factors in the Etiology of Autism; Analytic Biomakers (xenobiotic) Core

EPA Grant Number: R829388C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R829388
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism
Center Director: Pessah, Isaac N.
Title: Environmental Factors in the Etiology of Autism; Analytic Biomakers (xenobiotic) Core
Investigators: Hammock, Bruce , Dettmer, Katja , German, Bruce , Green, Peter , Lango, Jozsef
Institution: University of California - Davis
EPA Project Officer: Hahn, Intaek
Project Period: September 30, 2001 through September 29, 2002
Project Period Covered by this Report: September 30, 2004 through September 29, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text |  Recipients Lists
Research Category: Health , Health Effects , Children's Health

Objective:

To provide state-of-the-art analytical support to CCEH research projects. To develop new methodologies for sensitive and quantitative analyses of key biomarkers (e.g., oxylipids, tryptophan metabolites, opioid peptides) and xenobiotic markers in human and animal samples.

Progress Summary:

Researchers in the Analytical Core have developed an impressive array of analytical platforms for analyzing small molecular weight metabolites and xenobiotics to trypic fragments and intact proteins. The Core has also developed radioimmunoassay for PBDEs, non-coplanar PCBs, and new generation pesticides such as fipronil.

Metal Analyses. Dr. Green has completed multi-element metals analysis on over 300 CHARGE whole blood samples using 250 µL aliquots. The 2-5 year old children in the study showed great variations in total Hg concentrations (~100-fold range), a moderate variation of Pb (~10-fold), and relatively narrow variation in the levels of about two-dozen other elements. The Core tested standards from New York State that include two lower levels of 1.7 and 3.1µg/dL Pb and there was excellent agreement with our Core results, especially at lower levels. Several children were flagged for Hg levels above the US EPA safe guideline concentration of 5.8 ppb, and Center Administration was alerted. Letters were sent to the parents of these participants indicating the findings, an explanation, and recommendations. A fact sheet giving steps to reduce mercury exposure was included.

Hg analysis in mouse tissues has been performed in support of Project 3. Using instrumentation at the UC Davis Interdisciplinary Center for Plasma Mass Spectrometry, we developed a method for Hg analysis in hair as well as other elements. Using the typical growth rate of 1 cm/month, this technique can provide temporal resolution of Hg arrival in the scalp, and using Laser Ablation does not require sample cleaning, extraction, or digestion. We are developing a method for the trace analysis of methyl-Hg and ethyl-Hg in blood and possibly hair and other relevant samples using chromatography coupled to ICP-MS.

Nutritional and structural lipids in serum samples. CHARGE samples that included autistic children, siblings, typically developing children, and MR/DD children were analyzed by the Lipomics lipid metabolomics platform. Sample quality was found to be acceptable; the variations in lipid composition within the samples were within ranges of previously measured populations of humans. Strikingly, even in preliminary analysis of this small dataset, differences in the lipid profiles of children with autism and unaffected siblings were detected. Data analysis should be complete by early 2006.

Metabolomic analysis of urine. We have developed an LC-MS/MS method for profiling urinary peptides to explore the opioid excess theory in autism. This hypothesis proposes that autism could be the consequence of the action of exogenous peptides derived from an incomplete breakdown of gluten and casein. The opioid peptides gliadinomorphin, derived from wheat gliadin, and β-caseomorphin, derived from bovine casein, were used as lead compounds. A set of 77 urine samples have been analyzed, but neuropeptides above the detection limit were not found. Thus, the opioid peptide excess theory was not validated with this sample set.

Metabolomic analysis of plasma. Another important class of metabolites that might provide novel insights into the underlying mechanisms of autism are oxidized lipids derived from the arachidonic acid and linoleic acid cascades, which are recognized as mediators of inflammatory and proliferative responses. This might be important in the case of ASD, since children with autism often manifest mild to moderate degrees of gastrointestinal inflammation. We have developed a novel LC/MS/MS-based method to routinely measure about 40 metabolites of arachidonate and linoleate metabolism emanating from COX, LOX, and cytochrome P450-dependent metabolism. CHARGE plasma samples from autistic and control children are currently being analyzed for oxylipids.


Journal Articles on this Report : 18 Displayed | Download in RIS Format

Other subproject views: All 20 publications 19 publications in selected types All 18 journal articles
Other center views: All 146 publications 134 publications in selected types All 133 journal articles
Type Citation Sub Project Document Sources
Journal Article Aronov PA, Dettmer K, Hammock BD, Christiansen JA, Cornel AJ. Development of a HPLC/tandem-MS method for the analysis of the larvicides methoprene, hydroprene, and kinoprene at trace levels using Diels-Alder derivatization. Journal of Agricultural and Food Chemistry 2005;53(9):3306-3312. R829388 (2006)
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  • Journal Article Davis BB, Thompson DA, Howard LL, Morisseau C, Hammock BD, Weiss RH. Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 2002;99(4):2222-2227. R829388 (2006)
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  • Journal Article Dey A, Williams RS, Pollock DM, Stepp DW, Newman JW, Hammock BD, Imig JD. Altered kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria. Obesity Research 2004;12(8):1278-1289. R829388 (2006)
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  • Journal Article Fang X, Weintraub NL, Oltman CL, Stoll LL, Kaduce TL, Harmon S, Dellsperger KC, Morisseau C, Hammock BD, Spector AA. Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide. American Journal of Physiology-Heart and Circulatory Physiology 2002;283(6):H2306-H2314. R829388 (2006)
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  • Journal Article Fang X, Weintraub NL, McCaw RB, Hu S, Harmon SD, Rice JB, Hammock BD, Spector AA. Effect of soluble epoxide hydrolase inhibition on epoxyeicosatrienoic acid metabolism in human blood vessels. American Journal of Physiology-Heart and Circulatory Physiology 2004;287(6):H2412-H2420. R829388 (2006)
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  • Journal Article Fleming EJ, Mack EE, Green PG, Nelson DC. Mercury methylation from unexpected sources: molybdate-inhibited freshwater sediments and an iron-reducing bacterium. Applied and Environmental Microbiology 2006;72(1):457-464. R829388 (Final)
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  • Journal Article German JB, Watkins SM, Fay LB. Metabolomics in practice: emerging knowledge to guide future dietetic advice toward individualized health. Journal of the American Dietetic Association 2005;105(9):1425-1432. R829388 (2006)
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  • Journal Article Gibney MJ, Walsh M, Brennan L, Roche HM, German B, van Ommen B. Metabolomics in human nutrition: opportunities and challenges. American Journal of Clinical Nutrition 2005;82(3):497-503. R829388 (2006)
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  • Journal Article Huang H, Stok JE, Stoutamire DW, Gee SJ, Hammock BD. Development of optically pure pyrethroid-like fluorescent substrates for carboxylesterases. Chemical Research in Toxicology 2005;18(3):516-527. R829388 (Final)
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  • Journal Article Inceoglu B, Lango J, Pessah IN, Hammock BD. Three structurally related, highly potent, peptides from the venom of Parabuthus transvaalicus possess divergent biological activity. Toxicon 2005;45(6):727-733. R829388 (Final)
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  • Journal Article Kim I-H, Morisseau C, Watanabe T, Hammock BD. Design, synthesis, and biological activity of 1,3-disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility. Journal of Medicinal Chemistry 2004;47(8):2110-2122. R829388 (2006)
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  • Journal Article Kim I-H, Heirtzler FR, Morisseau C, Nishi K, Tsai H-J, Hammock BD. Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility. Journal of Medicinal Chemistry 2005;48(10):3621-3629. R829388 (2006)
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  • Journal Article Newman JW, Watanabe T, Hammock BD. The simultaneous quantification of cytochrome P450 dependent linoleate and arachidonate metabolites in urine by HPLC-MS/MS. Journal of Lipid Research 2002;43(9):1563-1578. R829388 (2006)
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  • Journal Article Newman JW, Morisseau C, Harris TR, Hammock BD. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proceedings of the National Academy of Sciences of the United States of America 2003;100(4):1558-1563. R829388 (2006)
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  • Journal Article Newman JW, Morisseau C, Hammock BD. Epoxide hydrolases: their roles and interactions with lipid metabolism. Progress in Lipid Research 2005;44(1):1-51. R829388 (2006)
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  • Journal Article Smith KR, Pinkerton KE, Watanabe T, Pedersen TL, Ma SJ, Hammock BD. Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor. Proceedings of the National Academy of Sciences of the United States of America 2005;102(6):2186-2191. R829388 (2006)
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  • Journal Article Viswanathan S, Hammock BD, Newman JW, Meerarani P, Toborek M, Hennig B. Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells. Journal of the American College of Nutrition 2003;22(6):502-510. R829388 (2006)
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  • Journal Article Zhao X, Yamamoto T, Newman JW, Kim I-H, Watanabe T, Hammock BD, Stewart J, Pollock JS, Pollock DM, Imig JD. Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. Journal of the American Society of Nephrology 2004;15(5):1244-1253. R829388 (2006)
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  • Supplemental Keywords:

    Mass spectrometry, biomarkers of autism,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, ENVIRONMENTAL MANAGEMENT, Toxicology, Health Risk Assessment, Chemistry, Epidemiology, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Disease & Cumulative Effects, Physical Processes, Children's Health, genetic susceptability, Biology, Risk Assessment, chemical exposure, neurotoxic, xenobiotics, biomarkers, gene-environment interaction, neurodevelopment, pesticides, exposure, halogenated aromatics, children, neurobehavioral, neurodevelopmental, neurotoxicity, etiology, susceptibility, human exposure, neurobehavioral effects, autism, biological markers, mechanisms, exposure assessment, neurological development, biomarker, synergistic interactions, mercurials

    Progress and Final Reports:

    Original Abstract
  • Final

  • Main Center Abstract and Reports:

    R829388    CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R829388C001 Environmental Factors in the Etiology of Autism; Analytic Biomakers (xenobiotic) Core
    R829388C002 Environmental Factors in the Etiology of Autism; Cell Activation/Signaling Core
    R829388C003 Environmental Factors in the Etiology of Autism; Molecular Biomakers Core
    R829388C004 Environmental Factors in the Etiology of Autism; Childhood Autism Risks from Genetics and the Environment (The CHARGE Study)
    R829388C005 Environmental Factors in the Etiology of Autism; Animal Models of Autism
    R829388C006 Environmental Factors in the Etiology of Autism; Molecular and Cellular Mechanisms of Autism