Project 4 will test the hypothesis that CGG trinucleotide repeats in the FMRI gene, the most prevalent single gene disorder contributing to autism risk, influence susceptibility to non-dioxin-like (NDL) persistent organic pollutants (POPs) identified in Core 3 and pro-inflammatory cytokine profiles identified in Project 3 to predominate in plasma of women participating in the MARBLES study during pregnancy. A major advantage of the neurotypical and susceptible neuronal cell models to be used in our studies is that they originate from the same individual;thus, individual genetic background variation is excluded as a confounding variable.
The specific aims are:
Aim 1 : Produce isoautosomal iPSC-derived neuronal precursor cells (NPCs) possessing a normal FMRI gene and NPCs possessing an active FMRI CGG repeat expansion in the mid-premutation, high-premutation, and full-mutation (FXS) range.
Aim 2 : Identify morphological and functional differences between neuronal cultures with a normal FMRI active allele and neuronal cultures with an active FMRI CGG repeat expansion in the mid-premutation, high premutation, or full-mutation (FXS) range.
Aim 2. 1: Identify temporal differences the development of synchronized Ca^"^ oscillations, electrophysiological properties, mitochondrial bioenergetics and oxidative stress among genotypes.
Aim 2. 2: Determine how functional anomalies identified in Aim 2.1 influence Ca2+- dependent signaling pathways required for activity dependent dendritic growth, especially the CaMKl->CREB-->Wnt and P13K->AktTSC1/2mTOR signaling pathways.
Aim 3 : Define the spatiotemporal profile of neuropathological sequelae caused by exposures that mimic the gestational environment in mothers participating in the MARBLES study.
Aim 3. 1: Determine how exposures to individual congeners and complex mixtures that model the most abundant of PBDEs, PCBs, or perfluorinated compounds in maternal plasma alter the morphometric and functional outcomes measured in Aim 2. Identify critical windows of susceptibility among genotypes.
Aim 3. 2: Determine how exposures to cytokine/chemokine profiles identified in maternal plasma influence the morphometric and functional outcomes measured in Aim 2.
Aim 3. 3: Determine whether exposures tested in Aim 3.1 and/or Aim 3.2 differentially alter epigenetlc signatures of global and gene specific (F0XP3, MeCP2, Dnmt3a) methylation among genotypes.

Public Health Relevance

The isoautosomal neuronal models proposed will permit for the first time investigations of how a defined autism susceptibility gene influences susceptibility to environmental factors, e.g., neurotoxicants and cytokine profiles identified in the gestational environment of mothers at high risk for giving birth to an autistic child. Our approach also permits detailed analysis of the molecular and cellular mechanisms of gene X environment interactions promoting neurodevelopmental impairments relevant to autism.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Program Projects (P01)
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University of California Davis
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Fritsch, Erika B; Stegeman, John J; Goldstone, Jared V et al. (2015) Expression and function of ryanodine receptor related pathways in PCB tolerant Atlantic killifish (Fundulus heteroclitus) from New Bedford Harbor, MA, USA. Aquat Toxicol 159:156-66
Walker, Cheryl K; Krakowiak, Paula; Baker, Alice et al. (2015) Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Pediatr 169:154-62
Harrington, Rebecca A; Lee, Li-Ching; Crum, Rosa M et al. (2014) Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay. Pediatrics 133:e1241-8
Keil, Alexander P; Daniels, Julie L; Hertz-Picciotto, Irva (2014) Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Environ Health 13:3
Shelton, Janie F; Geraghty, Estella M; Tancredi, Daniel J et al. (2014) Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study. Environ Health Perspect 122:1103-9
Piras, I S; Haapanen, L; Napolioni, V et al. (2014) Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder. Brain Behav Immun 38:91-9
Cao, Zhengyu; Cui, Yanjun; Nguyen, Hai M et al. (2014) Nanomolar bifenthrin alters synchronous Ca2+ oscillations and cortical neuron development independent of sodium channel activity. Mol Pharmacol 85:630-9
Medici, Valentina; Shibata, Noreene M; Kharbanda, Kusum K et al. (2014) Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics 9:286-96
Akins, Roger S; Krakowiak, Paula; Angkustsiri, Kathleen et al. (2014) Utilization patterns of conventional and complementary/alternative treatments in children with autism spectrum disorders and developmental disabilities in a population-based study. J Dev Behav Pediatr 35:1-10
Pretto, Dalyir I; Kumar, Madhur; Cao, Zhengyu et al. (2014) Reduced excitatory amino acid transporter 1 and metabotropic glutamate receptor 5 expression in the cerebellum of fragile X mental retardation gene 1 premutation carriers with fragile X-associated tremor/ataxia syndrome. Neurobiol Aging 35:1189-97

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