2005 Progress Report: Environmental Factors in the Etiology of Autism; Molecular and Cellular Mechanisms of Autism

EPA Grant Number: R829388C006
Subproject: this is subproject number 006 , 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; Molecular and Cellular Mechanisms of Autism
Investigators: Pessah, Isaac N. , Goth, Samuel R. , Van de Water, Judith
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 , Children's Health , Health Effects

Objective:

To understand the molecular and cellular mechanism by which low levels of ethylmercury, PCBs, and PBDEs dysregulate dendritic cell and neuronal signaling. To understand genetic factors that impart susceptibility to immunotoxicants and developmental neurotoxicants.

Progress Summary:

During this funding period we completed several studies examining the molecular and cellular mechanism by which noncoplanar PCBs alter functions of micorsomal RyR complexes and related these changes to cellular neurotoxicity (Wong et al, 2001; Haak et al, 2001; Howard et al, 2003; Gafni et al. 2004; Pessah et al. 2006). A detailed structure-activity of pure congeners and metabolites necessary for enhancing RyR1 indicates the 2,3,6-Cl PCB configuration is most important for optimal recognition by the channel complex and/or critical for sensitizing its activation. The requirement for an intact major T cell immunophilin FKBP12-RyR1 complex was observed with each of 12 active PCB congeners indicating a common mechanism requiring an immunophilin-regulated Ca2+ release channel (Pessah et al. 2006). The SAR for activating RyR1 is consistent with those previously reported in several in vivo and in vitro studies, suggesting a common mechanism may contribute to the toxicity of non-coplanar PCBs. A practical application of the receptor-based screen developed here with RyR1 is that it provides a quantitative SAR that may be useful in predicting biological activity and risk of mixtures containing non-coplanar PCB congeners that have low or lack aryl hydrocarbon receptor (AhR) activity. Collaborations with Dr. Susan Schantz on changes in activity and expression of cerebellar RyR complexes resulting from developmental exposures to Aroclor 1254 and in vitro with the Fox River Mixture have been completed and published (Kostyniak et al, 2005; Roegge et al, 2005). These will serve as the basis for extended collaboration between UC Davis and University of Illinois Children’s Centers in the next project period.

Thimerosal does not produce detectable effects in C57BL/6 mice. We have examined the effects of neonatal exposure to thimerosal (THI; a form of ethyl mercury) on brain development and behavior in C57BL/6 mice. Briefly, we found significant dose-related elevations in brain mercury levels in the cerebrum and cerebellum of neonatal mice. Mercury accumulated in brain tissue over multiple injections in neonatal mice. However, when later measured in adult mice, mercury levels remained elevated only in the brain and only with the highest THI exposure (i.e., 5.0 mg/kg cumulative exposure). THI exposure failed to significantly delay or alter standard developmental markers (i.e., body weight, body length, eye and ear opening, and tooth eruption). In addition, there were no significant effects of THI exposure at the doses used in this study on motor performance, sensory reactivity, or complex social behaviors. Histological examination of a subset of brains from the THI-exposed groups also failed to demonstrate evidence of histopathology (e.g., cell loss in CA1 hippocampus, ectopic neurons) or gross morphological changes in brain appearance (e.g., size of hippocampus).

Transient nanomolar thimerosal exposure uncouples ATP-mediated calcium signaling and dysregulates IL-6 secretion in dendritic cells. Dendritic cells (DCs) are potent antigen-presenting cells that initiate primary immune responses at sites of infection and injury. Because DCs rely on changes in their intracellular redox state (Goth et al. 2005a) and Ca2+ signals for proper development and function, we tested the hypothesis that they represent a particularly sensitive target for thimerosal immunotoxicity (Goth et al. 2005b). Transcriptional and immunocytochemical analyses show murine myeloid immature and mature DC express inositol 1,4,5-trisphosphate (IP3R) and RyR calcium channels, known targets of THI. We found THI (100 nM for 5 min) shortens the ATP-mediated Ca2+ transient and produces a delayed rise in the Ca2+ baseline, an action directly mediated by RyR1 dysregulation. THI uncoupled RyR1-mediated negative regulation of purinergic signaling, and enhanced ATP-mediated Ca2+ responses. THI (100nM) also altered ATP-mediated DC IL-6 secretion, initially enhancing the rate of secretion but suppressing overall cytokine secretion. Arguably DCs are among the most sensitive mammalian cells to THI, with one mechanism involving the uncoupling of positive and negative regulation of Ca2+ signals contributed by RyR1.

Perinatal or lactational exposure to non-coplanar PCB decreases seizure threshold in rats. We have completed a detailed study that clearly shows how developmental exposure to low-level PCB 95 (0.6 and 1mg/kg/day) produces offspring that are significantly more susceptible to flurothyl- and PTZ-induced seizures. These effects have been correlated to electrophysiological changes in excitability in the hippocampal slice preparation with PCB concentrations as low as 10nM (manuscript in preparation). These finding are significant since >35% of autistic children suffer from seizure disorders, and deficiencies in GABA signaling within the CNS appear to be a major contributor to this co-morbidity.


Journal Articles on this Report : 21 Displayed | Download in RIS Format

Other subproject views: All 23 publications 21 publications in selected types All 21 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 Aleman M, Riehl J, Aldridge BM, Lecouteur RA, Stott JL, Pessah IN. Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia. Muscle & Nerve 2004;30(3):356-365. R829388 (2006)
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  • Journal Article Chen L, Esteve E, Sabatier J-M, Ronjat M, De Waard M, Allen PD, Pessah IN. Maurocalcine and peptide A stabilize distinct subconductance states of ryanodine receptor type 1, revealing a proportional gating mechanism. Journal of Biological Chemistry 2003;278(18):16095-16106. R829388 (2006)
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  • Journal Article Cherednichenko G, Zima AV, Feng W, Schaefer S, Blatter LA, Pessah IN. NADH oxidase activity of rat cardiac sarcoplasmic reticulum regulates calcium-induced calcium release. Circulation Research 2004;94(4):478-486. R829388 (2006)
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  • Journal Article Cherednichenko G, Hurne AM, Fessenden JD, Lee EH, Allen PD, Beam KG, Pessah IN. Conformational activation of Ca2+ entry by depolarization of skeletal myotubes. Proceedings of the National Academy of Sciences of the United States of America 2004;101(44):15793-15798. R829388 (2006)
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  • Journal Article Dietrich KN, Eskenazi B, Schantz S, Yolton K, Rauh VA, Johnson CB, Alkon A, Canfield RL, Pessah IN, Berman RF. Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environmental Health Perspectives 2005;113(10):1437-1446. R829388 (2006)
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  • Journal Article Feng W, Tu J, Yang T, Vernon PS, Allen PD, Worley PF, Pessah IN. Homer regulates gain of ryanodine receptor type 1 channel complex. Journal of Biological Chemistry 2002;277(47):44722-44730. R829388 (2006)
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  • Journal Article Gafni J, Wong PW, Pessah IN. Non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95) amplifies ionotropic glutamate receptor signaling in embryonic cerebellar granule neurons by a mechanism involving ryanodine receptors. Toxicological Sciences 2004;77(1):72-82. R829388 (2006)
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  • Journal Article Gao J, Voss AA, Pessah IN, Lauer FT, Penning TM, Burchiel SW. Ryanodine receptor-mediated rapid increase in intracellular calcium induced by 7,8-benzo(a)pyrene quinone in human and murine leukocytes. Toxicological Sciences 2005;87(2):419-426. R829388 (2006)
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  • Journal Article Goth SR, Chu RA, Pessah IN. Oxygen tension regulates the in vitro maturation of GM-CSF expanded murine bone marrow dendritic cells by modulating class II MHC expression. Journal of Immunological Methods 2006;308(1-2):179-191. R829388 (2006)
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  • Journal Article Goth SR, Chu RA, Gregg JP, Cherednichenko G, Pessah IN. Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal. Environmental Health Perspectives 2006;114(7):1083-1091. R829388 (2006)
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  • Journal Article Hansen ME, Pessah IN, Matsumura F. Heptachlor epoxide induces a non-capacitative type of Ca2+ entry and immediate early gene expression in mouse hepatoma cells. Toxicology 2006;220(2-3):218-231. R829388 (2006)
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  • Journal Article Howard AS, Fitzpatrick R, Pessah I, Kostyniak P, Lein PJ. Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicology and Applied Pharmacology 2003;190(1):72-86. R829388 (2006)
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  • Journal Article Hurne AM, O'Brien JJ, Wingrove D, Cherednichenko G, Allen PD, Beam KG, Pessah IN. Ryanodine receptor type 1 (RyR1) mutations C4958S and C4961S reveal excitation-coupled calcium entry (ECCE) is independent of sarcoplasmic reticulum store depletion. Journal of Biological Chemistry 2005;280(44):36994-37004. R829388 (2006)
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  • Journal Article Kim KH, Inan SY, Berman RF, Pessah IN. Excitatory and inhibitory synaptic transmission is differentially influenced by two ortho-substituted polychlorinated biphenyls in the hippocampal slice preparation. Toxicology and Applied Pharmacology 2009;237(2):168-177. R829388 (Final)
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  • Journal Article Kostyniak PJ, Hansen LG, Widholm JJ, Fitzpatrick RD, Olson JR, Helferich JL, Kim KH, Sable HJ, Seegal RF, Pessah IN, Schantz SL. Formulation and characterization of an experimental PCB mixture designed to mimic human exposure from contaminated fish. Toxicological Sciences 2005;88(2):400-411. R829388 (2006)
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  • Journal Article Paolini C, Fessenden JD, Pessah IN, Franzini-Armstrong C. Evidence for conformational coupling between two calcium channels. Proceedings of the National Academy of Sciences of the United States of America 2004;101(34):12748-12752. R829388 (Final)
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  • Journal Article Pessah IN, Hansen LG, Albertson TE, Garner CE, Ta TA, Do Z, Kim KH, Wong PW. Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1). Chemical Research in Toxicology 2006;19(1):92-101. R829388 (2006)
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  • Journal Article Roegge CS, Morris JR, Villareal S, Wang VC, Powers BE, Klintsova AY, Greenough WT, Pessah IN, Schantz SL. Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg. Neurotoxicology and Teratology 2006;28(1):74-85. R829388 (2006)
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  • Journal Article Ta TA, Feng W, Molinski TF, Pessah IN. Hydroxylated xestospongins block inositol-1,4,5-trisphosphate-induced Ca2+ release and sensitive Ca2+-induced Ca2+ release mediated by ryanodine receptors. Molecular Pharmacology 2006;69(2):532-538. R829388 (2006)
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  • Journal Article Voss AA, Lango J, Ernst-Russell M, Morin D, Pessah IN. Identification of hyperreactive cysteines within ryanodine receptor type 1 by mass spectrometry. Journal of Biological Chemistry 2004;279(33):34514-34520. R829388 (2006)
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  • Journal Article Ward CW, Feng W, Tu J, Pessah IN, Worley PK, Schneider MF. Homer protein increases activation of Ca2+ sparks in permeabilized skeletal muscle. Journal of Biological Chemistry 2004;279(7):5781-5787. R829388 (Final)
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  • Supplemental Keywords:

    mechanisms, dendritic cells, neuronal cell development, hippocampal excitability, seizures, mercury, PCBs, PBDEs,, RFA, Health, PHYSICAL ASPECTS, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Chemistry, 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, neurodevelopment, gene-environment interaction, pesticides, exposure, halogenated aromatics, neurobehavioral, neurodevelopmental, neurotoxicity, children, susceptibility, etiology, neurobehavioral effects, autism, mechanisms, biological markers, exposure assessment, neurological development, biomarker, synergistic interactions

    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