2017 Progress Report: The UC Davis Center for Children's Environmental Health and Disease Prevention

EPA Grant Number: R835432
Center: UC Davis Center for Children's Environmental Health and Disease Prevention
Center Director: Van de Water, Judith
Title: The UC Davis Center for Children's Environmental Health and Disease Prevention
Investigators: Van de Water, Judith , Ashwood, Paul , Bennett, Deborah H. , Hagerman, Paul , Hansen, Robin , Hertz-Picciotto, Irva , LaSalle, Janine M , Lein, Pamela J , Lin, Yanping , Pessah, Isaac N. , Puschner, Birgit , Schmidt, Rebecca , Sharp, Frank , Walker, Cheryl
Institution: University of California - Davis
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Period Covered by this Report: June 1, 2017 through May 31,2018
Project Amount: $3,827,820
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2012) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

  1. Leverage our existing studies and biobanks for specimens to expand our research and capitalize upon the Center's research findings to date. We will take advantage of our numerous resources from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, as well as the epidemiological and clinical studies involving prospective parents, pregnant women and children from the ongoing Markers of Autism Risk in Babies – Learning Early Signs (MARBLES) study, both of which grew out of previous years of Center for Children's Environmental Health (CCEH) funding.
  2. Build upon our novel findings of calcium dysregulation in cultured neurons and immune cells in the context of understanding the epigenetic effects and ramifications of toxicant exposure on gene pathways and immune function.
  3. Develop and apply new biomarkers of autism risk through analysis of gestational immune dysfunction, genetic susceptibility and environmental exposures to best characterize the potential health effects at various life stages and predict longer-term clinical and behavioral consequences.
  4. Train new investigators, including pre- and postdoctoral fellows and junior faculty, to address emerging issues in children's environmental health with cross-cutting technologies and integrated multidisciplinary approaches.
  5. Expand the successful Community Outreach and Translation Core to continue the active engagement of our autism spectrum disorder (ASD) families, as well as the California Department of Health Services and the broader cross-cultural community in the research process, and the translation and application of our research findings.

Progress Summary:

Project 1 (Epidemiology and Environment)

Most of this year was occupied with finalizing the exposome database for an Exposome-Wide Association Study (EWAS) in relation to autism diagnosis/phenotype. The final data set included (but was not limited to) variables in the domains of—

  • Demographics (age, race, parental education, etc.)
  • Child anthropometrics (birthweight, etc.)
  • Maternal metabolic conditions (diabetes, etc.)
  • Nutrition/nutrients (vitamins by time period)
  • Lifestyle (smoking, cannabinoid use, hot tubs)
  • Pregnancy variables (parity, inter-pregnancy interval, weight gain, gestational age, pregnancy intention, pre-eclampsia, delivery method)
  • Pesticides (home and garden use)
  • Pesticides (agricultural applications nearby, by time period)
  • Personal care products (including antibacterial soaps)
  • Residential history
  • Air pollutant exposures
  • UV exposure
  • Paints and solvents
  • Maternal medical exposures (medications by type of action, mental health conditions, acute illnesses)
  • Reproductive history of mother

Thousands of variables were assessed, cleaned and constructed. A complete set of codebooks and data dictionaries was also created, which documents how each variable was constructed and coded. Only cleaned variables were sent. Models for an exposome-wide analysis were fit to a total of 834 variables. The data analyzed included 778 cases of ASD and 508 typically developing (TD) controls.

An initial exposome-wide analysis was conducted by Dr. Marylyn Ritchie at the Pennsylvania State University and her postdoctoral trainee, Anurag Verma. These results were reviewed, and additional analyses were suggested. Based on preliminary work, an abstract ("Exposome-wide association study [EWAS] identifies link between pregnancy anxiety and various autism spectrum traits") was submitted and accepted at the American Society of Human Genetics for a platform (oral) presentation this coming October.

CNV Burden Pathway-Based Approach

  • After not seeing much signal in previous approaches, we tried to restrict the CNV burden analysis (deletion, duplication, total CNV burden) to copy number variations located in genes known to be associated with the nutrients (folic acid, iron and prenatal vitamin) and metabolic conditions (obesity, hypertension, diabetes as proxy for gestational diabetes and general neural development) of interest. The genes were chosen by performing a text search of KEGG pathways for each nutrient and selecting all genes involved in each pathway. The model would then be case/control status ~ nutrient or metabolic condition + CNV burden across genes that are members of a specific pathway relating to a nutrient or metabolic condition + interaction + covariates.
  • Overall, there were a total of 7,241 unique genes and 479,161 unique gene-pathway combinations. However, when we mapped the hotspot CNV regions to the genes of interest using 100 percent overlap criteria (i.e., the entire gene must be affected by the CNV region), we found that none of the pathways had a sample size of at least 50, and most had less than 15 total samples per pathway, which we did not feel was adequate to run regression reliably.

EWAS

  • We used an EWAS approach to run logistic regression on 874 demographic, maternal health, maternal lifestyle, chemical exposure, residential and other pregnancy variables from 1,286 participants (778 ASD, 508 TD), adjusting for covariates.
  • We used a multiphenotype approach to find associations between the top result from the EWAS approach, self-reported nervousness during pregnancy and clinical assessment (diagnostic) child measurement variables, also adjusting for covariates. In these models, self-reported nervousness was treated as the independent variable and the clinical assessment measures and child measurements were treated as the dependent variables.
  • We are currently investigating the results from the prior two analyses and looking into the correlation structure of the exposure dataset.

Polybrominated Diphenyl Ethers (PBDEs) and Early Child Development

This manuscript was not accepted, with the primary criticism being that the sample size was still too small. We therefore sent additional maternal samples corresponding to children who have newly been evaluated at age 3 years for their final diagnosis, as well as additional samples from the first trimester for mother-child dyads whose later gestational samples had previously been analyzed. This last batch was sent to the Environmental Chemistry laboratory of the State of California, where Drs. Petreas and Park conducted the PBDE determinations on the new batch, along with a subset of 20 from the previously analyzed samples. Because we would like to have the most statistically powerful and accurate analysis feasible, this summer Dr. Tancredi is investigating use of validation data to calibrate the results from the two laboratories and model approaches that will achieve the greatest validity.

Pyrethroid Pesticides and Early Child Development

Similar to the PBDE study, analyses of the pyrethroid pesticides in relation to child developmental outcomes were based on a relatively small sample. We therefore sent additional maternal urine samples to Emory University, which included more samples from the previously analyzed study group and urine from mothers of children who recently received their final diagnosis. These analyses are now in progress, and the original manuscript will be updated with those results.

Gene by Environment Interaction: Impacts of Prenatal Exposures on Gene Expression in Children at Ages 2-5

  1. Additional analyses of prenatal household pesticide exposures in the CHARGE Study and associations with RNAseq gene expression in the child's peripheral blood at ages 2-5 years were conducted by Dr. Dan Campbell, who transitioned this year to a new position at the Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University. Utilizing DESeq2, which allows for multivariate control of confounders and provides a more accurate identification of outliers than older software, we identified differentially expressed genes comparing those exposed versus not exposed to indoor pesticide applications in 6 or more months of pregnancy. Analyses were conducted overall and within diagnostic group, as well as within each sex and by age strata. An initial draft was circulated, and additional work is being done to synthesize the multiple analyses in order to confidently interpret the results.
  2. The analysis of RNAseq in relation to mothers' metabolic conditions was completed. Results indicated that the top differentially expressed genes in children with ASD included genes involved in neuronal signaling, cell cycle regulation, and immunity. Notable enriched KEGG pathways included chemokine signaling, glutamatergic and dopaminergic synapses, focal adhesion and cytokine-cytokine receptor interaction. A manuscript is undergoing further revision for submission.

Project 2 (Perinatal Epigenetic Signatures of Environmental Exposures)

The major objectives to date are to sequence and bioinformatically analyze MethylC-seq data from MARBLES, understand transcriptional regulation of FOXP3 through DNA methylation, and to determine the most effective current sequencing strategy for genomic DNA from MARBLES samples to identify structural variants once all MARBLES samples are obtained. Dr. LaSalle's laboratory has isolated DNA and prepared MethylC-seq libraries from 54 MARBLES cord blood samples, including 26 typical and 26 ASD. Whole-genome bisulfite sequencing (WGBS) and bioinformatics analyses were performed on all 52 samples. DNA methylation analysis of FOXP3, and a putative enhancer of FOXP3 was performed in sorted cord blood samples from the Ashwood Laboratory and DNA isolated from cell pellets of CHARGE sample ex vivo PBDE treatments from the Van de Water Laboratory. DNA from cord blood samples is undergoing whole genome sequencing on the Illumina X-ten at NovaGene.

Significant Results

  • A preliminary analysis of the first 22 samples analyzed by MethylC-seq reveal some regions of differential methylation between typical and ASD samples that will be explored in greater detail when sequencing of all samples is completed.
  • MethylC-seq analysis of sorted T regulatory cells reveals preliminary indication of global hypomethylation in addition to FOXP3 that may be useful in estimating the percentage of this cell population from whole cord blood MethylC-seq data.
  • MethylC-seq data from MARBLES placental samples were analyzed in univariate and multivariate models for associations with demographic, diagnostic and self-reported environmental factors. Pesticides were the strongest predictors of methylation. A manuscript is being drafted, and results were presented at the February 2016 Epigenomics Meeting in Puerto Rico.
  • MARBLES placenta MethylC-seq data were analyzed in univariate and multivariate models for associations with polychlorinated biphenyl (PCB) and PBDE levels measured by the Analytical Core. No significant associations were observed with PBDE congeners, but several significant associations were observed between placental DNA methylation and PCBs. PCB 175 was associated with a significantly higher proportion of the placental methylome in PMDs after FDR correction (= 0.01). After adjustment for PMD methylation, PCB 136 was significantly associated with higher HMD methylation (= 0.002).

Project 3 (Immune Environment Interactions and Neurodevelopment)

Significant Results

Working with Project 4, we completed studies screening the cytokine profiles derived from our studies of women whose blood was collected during pregnancy. The Van de Water Laboratory identified patterns of cytokines/chemokines that were associated with having a child with ASD + intellectual disability (ID) versus neurotypical and developmentally delayed children without ASD. In conjunction with the Lein Laboratory (through a shared graduate student) we determined the effects the ASD cytokine mix on cell viability, neuronal apoptosis, neurite outgrowth, neurite retraction and synaptogenesis in the human Lund human mesencephalic (LUHMES) neuronal cell line. We found that the cytokine profile associated with having a child with ASD + ID significantly modulated these endpoints in LUHMES cells. These data, which have significant implications for understanding the role of neuroimmune interactions in ASD, are currently in preparation for submission to a peer review journal.

The mammalian target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate growth and homeostasis in an organism. This key pathway regulates several major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes and neurodegeneration. Further, the mTOR pathways are required for normal T cell development, including T cell memory and effector function. Thus, in addition to the above study, we examined seven key genes in the mTOR signaling pathway for differences in expression between children with ASD and TD controls.

We found that performing a sex-specific analysis of the mTOR signaling pathway genes, both under a t-test and mixed regression analysis using PCR batch as a random factor and final diagnosis as a fixed factor, that five of the seven genes showed differential elevated expression in ASD versus TD in males, while no gene was differentially expressed in females. This suggests that we have elevated expression of the mTOR signaling genes in males but not females with ASD compared with TD controls. This suggests both sex and diagnostic differences in the mTOR signaling pathways, further supporting a differential response to the environment in key intracellular signaling components of immune cells from boys with ASD.

Project 4 (Calcium Signaling Defects in Autism)

Project 4 has continued to develop and use neuronal cell culture models from humans and mice with and without expression of FMR1 CGG expansion repeats, the most prevalent monogenic risk factor for ASDs and the cause of both FXS (full mutation) and the late onset degenerative disorder FXTAS. Studies that have been performed include single-cell and network electrophysiology, Ca2+ imaging, and measures of ROS, and mitochondrial function. Additional studies had investigated morphological endpoints related to activity-dependent dendritic growth using immunofluorescent labels targeting specific proteins of interest. Environmental compounds that are actively being studied include PCBs, PBDEs, bisphenol A, tetrabromobisphenol A and chlorpyrifos. New emerging halogenated organic compounds found as disinfectant byproducts have been shown for the first time to be neurotoxic and are potentially emerging pollutants of concern to human health. Experiments were also performed on ex vivo tissues from the knock-in mouse model of FMR1 premutation.

Significant Results

The Pessah Laboratory has worked closely with NeuCyte to develop new approaches to differentiate induced pluripotent stem cells (iPSC) directly into neuronal cells, bypassing the neural precursor stage. This was deemed warranted and important to bypass the major roadblocks to developmental maturation of functional neuronal networks that display synchronized electrical spike activity and synchronized calcium oscillations (SCOs), hallmarks of network maturation typically observed with rodent models.

Direct transformation of iPSC to neurons with glutamatergic or GABAergic neurochemistry occurs efficiently in the presence of glial cells derived from the same iPSC clone. Within 2 weeks these cultures exhibit voltage-activated inward Na+ and outward K+ currents with anticipated I/V relationships, and high-frequency action potentials. Importantly, co-cultured glutamatergic and GABAergic neurons form extensive mature neuronal networks that develop spontaneous electrical spike activity transmitted long distances across and microelectrode arrays and are regulated by both iPSC and EPSC typically observed with primary hippocampal cultures from the mouse premutation KI model (Cao et al., 2012; Robin et al., 2017), and is a promising approach to circumvent road blocks encountered to with iPSC derived neuronal precursor cells that have limited the utility of human cultures for developmental maturation and neurotoxicology studies (Liu et al., 2012; Robin et al., 2017).

Toxicological studies use "specialty chemicals" and, thus, should assess and report both identity and degree of purity (homogeneity) of the chemicals (or toxicants) under investigation to ensure that other scientists can replicate experimental results. Although detailed reporting criteria for the synthesis and characterization of organic compounds have been established by organic chemistry journals, such criteria are inconsistently applied to the chemicals used in toxicological studies. Biologically active trace impurities may lead to incorrect conclusions about the chemical entity responsible for a biological response, which in turn may confound risk assessment. Based on our experience with the synthesis of PCBs and their metabolites, Pessah Laboratory recently completed a study in collaboration with the Lehmler laboratory (University of Iowa) to propose guidelines for the "authentication" of synthetic PCBs and, by extension, other organic toxicants and provide a checklist for documenting the authentication of toxicants reported in the peer-reviewed literature (Li et al., 2018). As an extension of this concept, we successfully separated PCB 95 enantiomers to purity using three chiral-column HPLC and circular dichroism spectroscopy to assigned aR- and aS-PCB 95. aR-PCB 95 was shown greater potency and higher efficacy than aS-PCB 95 as an allosteric modifier of ryanodine receptors. As predicted from this activity, chronic exposure of hippocampal neuronal networks to nanomolar PCB 95 during a critical developmental period shows divergent influences on synchronous Ca2+ oscillation: rac-PCB 95 increasing and aR-PCB 95 decreasing SCO frequency at 50 nM, although the latter's effects are nonmonotonic at higher concentration. aS-PCB95 shows the greatest influence on inhibiting responses to 20 Hz electrical pulse trains. Considering persistence of PCB 95 in the environment, stereoselectivity toward RyRs and developing neuronal networks may clarify health risks associated with enantioisomeric enrichment of PCBs (Feng et al., 2017).

Contemporary sources of organohalogens produced as disinfection byproducts (DBPs) are receiving considerable attention as emerging pollutants because of their abundance, persistence and potential to structurally mimic natural organohalogens produced by bacteria that serve signaling or toxicological functions in marine environments. The Pessah Laboratory tested 34 organohalogens from anthropogenic and marine sources to identify compounds active toward ryanodine receptor (RyR1), known toxicological targets of non-dioxin-like PCBs and PBDEs. [3H]Ryanodine ([3H]Ry) binding screening (≤ 2 μM) identified 10 highly active organohalogens. Further analysis indicated that 2,3-dibromoindole (14), tetrabromopyrrole (31), and 2,3,5-tribromopyrrole (34) at 10 μM were the most efficacious at enhancing [3H]Ry binding. Interestingly, these congeners also inhibited microsomal sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA1a).

Dual SERCA1a inhibition and RyR1 activation triggered Ca2+ efflux from microsomal vesicles with initial rates rank ordered 31 > 34 > 14. Hexabromobipyrroles (25) enhanced [3H]Ry binding moderately with strong SERCA1a inhibition, whereas pyrrole (24), 2,3,4-tribromopyrrole (26), and ethyl-4-bromopyrrole-2-carboxylate (27) were inactive. Of three PBDE derivatives of marine origin active in the [3H]Ry assay, 4'- hydroxy-2,3',4,5',6-pentabromodiphenyl ether (18) was also a highly potent SERCA1a inhibitor. Molecular targets of marine organohalogens that are also DBPs of emerging environmental concern are likely to contribute to their toxicity (Zheng et al., 2018).

The Lein Laboratory has completed studies screening the cytokine profiles associated with autistic versus neurotypical children identified in Project 3 for effects on cell viability, neuronal apoptosis, neurite outgrowth, neurite retraction and synaptogenesis in the human LUHMES neuronal cell line. We found that the cytokine profile associated with autistic children significantly modulated these endpoints in LUHMES cells. These data, which have significant implications for understanding the role of neuroimmune interactions in ASD, are currently in preparation for submission to a peer review journal.

In addition, the Lein Laboratory completed studies examining the role of mTOR in PCB developmental neurotoxicity (see publication list) and has completed a comprehensive study of interactions between fmr1 premutation, gain of function mutations in RyR1 and developmental exposure to a mixture of PCBs identified in MARBLES mothers by Core C. Several manuscripts from this work are currently under review, and others are being prepared for submission by October 2019 to peer review journals. The Lein Laboratory is also working with the Pessah Laboratory to identify the effects of developmental exposure to chlorpyrifos on ryanodine receptor activation in a mouse model.

Core A (Administrative Core)

The Administrative Core continues to work with project and core leaders and their unit grants management staff to update and align budgets and distribute federal funds as well as institutional matching funds in support of the center program. The Core helped to organize the 2-day meeting Environmental Contributors to Autism (see Core B) and has also collaborated with the Community Engagement Core of the University of California, Davis (UC Davis) Environmental Health Sciences Center, notably, for the Environmental Justice Tour and Workshop held in Fresno, California on July 19, 2018 (see Core B). The Core continues to provide oversight and support for the Center's biological resources.

Core B (Community Outreach and Translation)

Significant Results

Communicating Results

Judy Van de Water served as the local host for the Environmental Contributors to Autism Comprehensive Grantee Meeting, which was held at the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute March 7-8. Several CCEH investigators presented their work and/or organized sessions at the meeting: Judy Van de Water, Irva Hertz-Picciotto, Rebecca Schmidt, Cheryl Walker and Janine LaSalle.

Regulatory and Other Policy Work

Project TENDR: Targeting Environmental Neuro-Developmental Risks, co-led by Irva Hertz-Picciotto and Learning Disabilities Association Director Maureen Swanson, continues to raise awareness among policymakers and the public about the influence of environmental exposures on children's neurodevelopmental health. In July 2017, a TENDR paper was published in JAMA Pediatrics, "Establishing and achieving national goals for preventing lead toxicity and exposure in children" (Bellinger et al.) A TENDR paper on organophosphate pesticides and neurodevelopmental outcomes has been accepted at PLOS Medicine and will include recommendations for reducing children's exposure to organophosphate pesticides. The American Public Health Association has recently signed on to the Project TENDR Consensus Statement.

Community Outreach and Partnerships

Center Director Judy Van de Water and Project 1 Leader Irva Hertz-Picciotto participated in a workshop in Fresno, California on July 19th. The workshop was supported by funding from the National Institute of Environmental Health Sciences and hosted by several environmental justice groups in the Central Valley of California. The workshop covered issues related to the Valley's complex environmental and social problems, which include water quality and water access, pesticide exposure and some of the worst air pollution in the nation. An article about the meeting was published in the August issue of Environmental Factor. Workshop participants visited neighborhood and school sites located in proximity to significant sources of air pollution and pesticides—exposures that CCEH research findings link to autism and other neurodevelopmental disorders.

Core C (Analytical Core)

During the review period, we completed analysis of plasma of 104 mothers for PBDEs and PCBs. Participants were mother-child pairs from the MARBLES cohort, a high-risk pregnancy cohort that enrolls families that have one child diagnosed with ASD and are planning to have another child. PCB concentrations were measured in maternal blood at each trimester of pregnancy using gas chromatography coupled with triple quadruple mass spectrometry. PBDE congeners included BDE-17, -28, -47, -49, -52, -66, -85 -95, -99, -100, -153, -154 and -183. PCB congeners included 11, 28, 52, 66, 77, 84, 91, 95, 101, 118, 131, 132, 135, 136, 138, 149, 153, 174, 175, 176, 180 and 196.

PBDE concentrations were normalized to plasma volume (ng/ml) and plasma total lipids (ng/g). Compared to U.S. National Health and Nutritional Examination Survey, BDE-28 and BDE-99 were 126 percent and 39 percent higher in MARBLES samples. The sum of five commonly assessed PBDEs (BDE-28, -47, -99, -100 and -153) was more than twice in MARBLES compared to California women participating in the Center for the Health Assessment of Mothers and Children of Salinas study. MARBLES data were also compared to data from two San Francisco Bay Area studies, and despite geographical proximity, BDE-28, -47 and -100 were consistently higher in MARBLES. Although elevated gestational PBDEs during pregnancy observed in MARBLES does not permit causality with ASD outcome, it does highlight the need for additional studies that address the source and mechanisms accounting for the significant differences in PBDE levels reported among pregnant women, especially those women with a family history of heritable neurodevelopmental disorders.

There were no significant associations for total PCB; however, there were borderline significant associations between DL-PCBs and decreased risk for non-TD diagnosis (adjusted OR: 0.41 [95% CI 0.15 to 1.14]) and between RyR-activating PCBs and increased risk for ASD diagnosis (adjusted OR: 2.63 [95% CI 0.87 to 7.97]). This study does not provide strong supporting evidence that PCBs are risk factors for ASD or non-TD. However, these analyses suggest the need to explore more deeply into subsets of PCBs as risk factors based on their function and structure in larger cohort studies where non-monotonic dose-response patterns can be better evaluated.

We developed a unique, simple, cost-efficient, single-step cleanup method for small tissue samples that allows for the sensitive and selective quantitation of both low and highly chlorinated PCB congeners. A novel extraction method was developed using an automated homogenization method (Geno/Grinder) and the Phenomenex PHREE 96-well plate. Analysis of extracts was based on execution of standard curves in matrix using the GC/MS-MS system. The method was validated through the use of quality control and certified standard reference material samples to calculate intra-day and inter-day recovery, accuracy and precision for liver and brain. The intra-day accuracy for liver ranged from 85.4-123 percent while that of brain ranged from 84.3-116.6 percent. Additionally, the liver validation possessed an intra-day precision of 1.5-34.4 percent; intra-day precision calculated for brain ranged from 1.5-18.9 percent. Percent recoveries were calculated using both an external calibration curve and standard curve in matrix. Recoveries in matrix ranged from 63-130.9 percent for brain and from 46.8-167.3 percent in liver, varying significantly from those presented in solvent. Levels of detection (LODs) for brain ranged from 0.05-0.79 ng/g and from 0.04-0.75 ng/g in liver. Limits of quantification (LOQs) ranged from 0.17-2.63 ng/g in brain and from 0.14-2.5 ng/g in liver. The method was applied in the analysis of POPs in tissues of animals dosed with the MARBLES mixture.

Future Activities:

As a whole, the Center plans to hold a meeting of the Scientific Advisory Committee in winter 2017. Furthermore, several members from our Center are participating in CEHC workgroups and will continue to do so in the subsequent reporting period.

Project 1 (Epidemiology and Environment)

PBDEs and Early Child Development

Development of models that will allow combining data across laboratories with different sets of data and, most importantly, different LODs will be performed. This will allow for a more statistically powerful analysis with greater validity than our earlier analyses. This will lead to revising the manuscript and resubmission.

Pyrethroid Pesticides and Early Child Development

The final analyses will be conducted with newly received data pertaining to prenatal exposures on additional children and for additional samples from the earlier batch of children whose mothers' late gestational specimens were previously analyzed for pesticides. We will submit the final results to a peer-reviewed journal in epidemiology, autism or pediatrics.

Gene Expression in Children at Ages 2-5

Prenatal Pesticide Exposures

Additional work is being done to synthesize the multiple analyses in order to confidently interpret the results.

Maternal Metabolic Conditions

This manuscript needs final revisions to submit for publication.

CHARGE Study Exposome Analyses

Additional analyses will be conducted with a focus on environmental, medical and phenotypic domains that differentiate ASD from TD children.

References:

Bellinger, DC, Chen A, Lanphear BP. Establishing and achieving national goals for preventing lead toxicity and exposure in children. JAMA Pediatr 2017;171(7):616-618. doi:10.1001/jamapediatrics.2017.0775

Cao Z, Hulsizer S, Tassone F, Tang H, Hagerman RJ, Rogawski MA, Hagerman PJ, Pessah IN. Clustered burst firing in FMR1 premutation hippocampal neurons: Amelioration with allopregnanolone.  Human Molec Genetics 2012;21:2923-2935. doi: 10.1093/hmg/dds118.

Feng W, Zheng J, Robin G, Dong Y, Ichikawa M, Inoue Y, Mori T, Nakano T, Pessah IN.  Enantioselectivity of 2,2',3,5',6-pentachlorobiphenyl (PCB 95) atropisomers toward ryanodine receptors (RyRs) and their influences on hippocampal neuronal networks. Environ Sci Technol 2017;51(24):14406-14416. doi: 10.1021/acs.est.7b04446

Li X, Holland EB, Feng W, Zheng J, Dong Y, Pessah IN, Duffel MW, Robertson LW, Lehmler HJ. Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: polychlorinated biphenyls as an example. Environ Sci Pollut Res Int 2018;25(17):16508-16521. doi: 10.1007/s11356-017-1162-0

Liu J, Kościelska KA, Cao Z, Hulsizer S, Grace N, Mitchell, G, Nacey C, Githinji J, McGee J, Garcia-Arocena D, Hagerman RJ, Nolta J, Pessah IN, Hagerman PJ.  Signaling defects in iPSC-derived fragile X premutation neurons. Human Molec Genetics 2012;21:3795-3805.  doi: 10.1093/hmg/dds207.

Robin G, Lopez JR, Espinal GM, Hulsizer S, Hagerman PJ, Pessah IN. Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome. Hum Mol Genet 2017;26(14):2649-2666. doi: 10.1093/hmg/ddx148.

Zheng J, McKinnie SMK, El Gamal A, Feng W, Dong Y, Argawal V, Fenical W, Kumar A, Cao Z, Moore BS, Pessah IN. Organohalogens naturally biosynthesized in marine environments and produced as disinfection byproducts alter sarco/endoplasmic reticulum Ca(2+) dynamics. Environ Sci Technol 2018;52(9):5469-5478. doi: 10.1021/acs.est.8b00512


Journal Articles: 109 Displayed | Download in RIS Format

Other center views: All 109 publications 109 publications in selected types All 109 journal articles
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Journal Article Akins RS, Krakowiak P, Angkustsiri K, Hertz-Picciotto I, Hansen RL. Utilization patterns of conventional and complementary/alternative treatments in children with autism spectrum disorders and developmental disabilities in a population-based study. Journal of Developmental and Behavioral Pediatrics 2014;35(1):1-10. R835432 (2013)
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  • Journal Article Akintunde ME, Rose M, Krakowiak P, Heuer L, Ashwood P, Hansen R, Hertz-Picciotto I, Van de Water J. Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma. Journal of Neuroimmunology 2015;286:33-41. R835432 (2014)
    R835432 (2015)
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  • Journal Article Ariza J, Hurtado J, Rogers H, Ikeda R, Dill M, Steward C, Creary D, Van de Water J, Martinez-Cerdeno V. Maternal autoimmune antibodies alter the dendritic arbor and spine numbers in the infragranular layers of the cortex. PLoS One 2017;12(8):e0183443 (13 pp.). R835432 (2017)
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  • Journal Article Bal-Price A, Lein PJ, Keil KP, Sethi S, Shafer T, Barenys M, Fritsche E, Sachana M, Meek ME. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity.NeuroToxicology 2016 May 17, doi:10.1016/j.neuro.2016.05.010 [Epub ahead of print]. R835432 (2015)
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  • Journal Article Barkoski J, Bennett D, Tancredi D, Barr DB, Elms W, Hertz-Picciotto I. Variability of urinary pesticide metabolite concentrations during pregnancy in the MARBLES Study. Environmental Research 2018;165:400-409. R835432 (2017)
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  • Journal Article Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Translational Psychiatry 2013;3(7):e278 (12 pp.). R835432 (2013)
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  • Journal Article Berthelot CC, Kamita SG, Sacchi R, Yang J, Nording ML, Georgi K, Hegedus Karbowski C, German JB, Weiss RH, Hogg RJ, Hammock BD, Zivkovic AM. Changes in PTGS1 and ALOX12 gene expression in peripheral blood mononuclear cells are associated with changes in arachidonic acid, oxylipins, and oxylipin/fatty acid ratios in response to omega-3 fatty acid supplementation. PLoS One. 2015;10(12):e0144996 (13 pp.). R835432 (2015)
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  • Journal Article Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, Hertz-Picciotto I, Pessah IN, Van de Water J. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Translational Psychiatry 2013;3(7):e277. R835432 (2013)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. R835432 (2016)
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  • Journal Article Camacho J, Jones K, Miller E, Ariza J, Noctor S, Van de Water J, Martinez-Cerdeno V. Embryonic intraventricular exposure to autism-specific maternal autoantibodies produces alterations in autistic-like stereotypical behaviors in offspring mice. Behavioural Brain Research 2014;266:46-51. R835432 (2013)
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  • Journal Article Cao Z, Hulsizer S, Cui Y, Pretto DL, Kim KH, Hagerman PJ, Tassone F, Pessah IN. Enhanced asynchronous Ca2+ oscillations associated with impaired glutamate transport in cortical astrocytes expressing Fmr1 gene premutation expansion. The Journal of Biological Chemistry 2013;288(19):13831-13841. R835432 (2013)
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  • Journal Article Cao Z, Cui Y, Nguyen HM, Jenkins DP, Wulff H, Pessah IN. Nanomolar bifenthrin alters synchronous Ca2+ oscillations and cortical neuron development independent of sodium channel activity. Molecular Pharmacology 2014;85(4):630-639. R835432 (2013)
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  • Journal Article Careaga M, Hansen RL, Hertz-Piccotto I, Van de Water J, Ashwood P. Increased anti-phospholipid antibodies in autism spectrum disorders. Mediators of Inflammation 2013;2013:935608, doi:10.1155/2013/935608. R835432 (2013)
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  • Journal Article Careaga M, Noyon T, Basuta K, Van de Water J, Tassone F, Hagerman RJ, Ashwood P. Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome. Journal of Neuroinflammation 2014;11:110, doi:10.1186/1742-2094-11-110. R835432 (2014)
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  • Journal Article Careaga M, Rogers S, Hansen RL, Amaral DG, Van de Water J, Ashwood P. Immune endophenotypes in children with autism spectrum disorder. Biological Psychiatry 2015 Sep 11, doi:pii:S0006-3223(15)00738-6. 10.1016/j.biopsych.2015.08.036 [Epub ahead of print]. R835432 (2015)
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  • Journal Article Chen X, Walter KM, Miller GW, Lein PJ, Puschner B. Simultaneous quantification of T4, T3, rT3, 3,5-T2 and 3,3'-T2 in larval zebrafish (Danio rerio) as a model to study exposure to polychlorinated biphenyls. Biomedical Chromatography 2018;32(6):e4185. R835432 (2017)
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  • Journal Article Cherednichenko G, Zhang R, Bannister RA, Timofeyev V, Li N, Fritsch EB, Feng W, Barrientos GC, Schebb NH, Hammock BD, Beam KG, Chiamvimonvat N, Pessah IN. Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle. Proceedings of the National Academy of Sciences of the United States of America 2012;109(35):14158-14163. R835432 (2013)
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  • Journal Article Ciernia AV, LaSalle J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nature Reviews Neuroscience 2016;17(7):411-423. R835432 (2015)
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  • Journal Article Crawley JN, Heyer W-D, LaSalle JM. Autism and cancer share risk genes, pathways, and drug targets. Trends in Genetics 2016;32(3):139-146. R835432 (2015)
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  • Journal Article Edmiston E, Jones KL, Vu T, Ashwood P, Van de Water J. Identification of the antigenic epitopes of maternal autoantibodies in autism spectrum disorders. Brain, Behavior, and Immunity 2018;69:399-407. R835432 (2017)
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  • Journal Article Fox-Edmiston E, Van de Water J. Maternal anti-fetal brain IgG autoantibodies and autism spectrum disorder: current knowledge and its implications for potential therapeutics. CNS Drugs 2015;29(9):715-724. R835432 (2015)
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  • Journal Article Girirajan S, Johnson RL, Tassone F, Balciuniene J, Katiyar N, Fox K, Baker C, Srikanth A, Yeoh KH, Khoo SJ, Nauth TB, Hansen R, Ritchie M, Hertz-Picciotto I, Eichler EE, Pessah IN, Selleck SB. Global increases in both common and rare copy number load associated with autism. Human Molecular Genetics 2013;22(14):2870-2880. R835432 (2013)
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  • Journal Article Goodrich AJ, Volk HE, Tancredi DJ, McConnell R, Lurmann FW, Hansen RL, Schmidt RJ. Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. Austism Research 2018;11(1):69-80. R835432 (2017)
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  • Journal Article Harrill JA, Chen H, Streifel KM, Yang D, Mundy WR, Lein PJ. Ontogeny of biochemical, morphological and functional parameters of synaptogenesis in primary cultures of rat hippocampal and cortical neurons. Molecular Brain 2015;8:10 (15 pp.). R835432 (2014)
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  • Journal Article Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, DeLorenze GN, Kharrazi M, Yolken R, Ashwood P, Van de Water J. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Molecular Psychiatry 2016 May 24, doi:10.1038/mp.2016.77 [Epub ahead of print]. R835432 (2015)
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  • Journal Article Keil KP, Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? 2016;2(1):dvv012 (15 pp.). R835432 (2015)
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  • Journal Article Keil KP, Sethi S, Wilson MD, Chen H, Lein PJ. In vivo and in vitro sex differences in the dendritic morphology of developing murine hippocampal and cortical neurons. Scientific Reports 2017;7(1):8486 (15 pp.). R835432 (2017)
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  • Journal Article Kerin T, Volk H, Li W, Lurmann F, Eckel S, McConnell R, Hertz-Picciotto I. Association between air pollution exposure, cognitive and adaptive function, and ASD severity among children with autism spectrum disorder. Journal of Autism and Developmental Disorders 2018;48(1):137-150. R835432 (2017)
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  • Journal Article Kim D, Volk H, Girirajan S, Pendergrass S, Hall MA, Verma SS, Schmidt RJ, Hansen RL, Ghosh D, Ludena-Rodriguez Y, Kim K, Ritchie MD, Hertz-Picciotto I, Selleck SB. The joint effect of air pollution exposure and copy number variation on risk for autism. Autism Research 2017;10(9):1470-1480. R835432 (2017)
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  • Journal Article Koenig CM, Lango J, Pessah IN, Berman RF. Maternal transfer of BDE-47 to offspring and neurobehavioral development in C57BL/6J mice. Neurotoxicology and Teratology 2012;34(6):571-580. R835432 (2013)
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  • Journal Article Krakowiak P, Goines PE, Tancredi DJ, Ashwood P, Hansen RL, Hertz-Picciotto I, Van de Water J. Neonatal cytokine profiles associated with autism spectrum disorder. Biological Psychiatry 2015 Aug 14, doi:pii:S0006-3223(15)00655-1 [Epub ahead of print]. R835432 (2015)
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  • Journal Article Krakowiak P, Walker CK, Tancredi DJ, Hertz-Picciotto I. Maternal recall versus medical records of metabolic conditions from the prenatal period: a validation study. Maternal and Child Health Journal 2015;19(9):1925-1935. R835432 (2014)
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  • Journal Article Krakowiak P, Walker CK, Tancredi D, Hertz-Picciotto I, Van de Water J. Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Research 2016 Jun 17, doi:10.1002/aur.1657 [Epub ahead of print]. R835432 (2015)
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  • Journal Article LaSalle JM. Epigenomic strategies at the interface of genetic and environmental risk factors for autism. Journal of Human Genetics 2013;58(7):396-401. R835432 (2013)
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  • Journal Article LaSalle JM. Autism genes keep turning up chromatin. OA Autism 2013;1(2):14. R835432 (2013)
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  • Journal Article Lesiak A, Zhu M, Chen H, Appleyard SM, Impey S, Lein PJ, Wayman GA. The environmental neurotoxicant PCB 95 promotes synaptogenesis via ryanodine receptor-dependent miR132 upregulation. The Journal of Neuroscience 2014;34(3):717-725. R835432 (2013)
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  • Journal Article Li X, Holland EB, Feng W, Zheng J, Dong Y, Pessah IN, Duffel MW, Robertson LW, Lehmler HJ. Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: polychlorinated biphenyls as an example. Environmental Science and Pollution Research International 2018;25(17):16508-16521. R835432 (2017)
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  • Journal Article Lin YP, Pessah IN, Puschner B. Simultaneous determination of polybrominated diphenyl ethers and polychlorinated biphenyls by gas chromatography-tandem mass spectrometry in human serum and plasma. Talanta 2013;113:41-48. R835432 (2013)
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  • Journal Article Liu J, Koscielska KA, Cao Z, Hulsizer S, Grace N, Mitchell G, Nacey C, Githinji J, McGee J, Garcia-Arocena D, Hagerman RJ, Nolta J, Pessah IN, Hagerman PJ. Signaling defects in iPSC-derived fragile X premutation neurons. Human Molecular Genetics 2012;21(17):3795-3805. R835432 (2013)
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  • Journal Article Lyall K, Baker A, Hertz-Picciotto I, Walker CK. Infertility and its treatments in association with autism spectrum disorders: a review and results from the CHARGE study. International Journal of Environmental Research and Public Health 2013;10(8):3715-3734. R835432 (2013)
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  • Journal Article Lyall K, Schmidt RJ, Hertz-Picciotto I. Maternal lifestyle and environmental risk factors for autism spectrum disorders. International Journal of Epidemiology 2014;43(2):443-464. R835432 (2013)
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  • Journal Article Martinez-Cerdeno V, Camacho J, Fox E, Miller E, Ariza J, Kienzle D, Plank K, Noctor SC, Van de Water J. Prenatal exposure to autism-specific maternal autoantibodies alters proliferation of cortical neural precursor cells, enlarges brain, and increases neuronal size in adult animals. Cerebral Cortex 2016;26(1):374-383. R835432 (2014)
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  • Journal Article Matelski L, Van de Water J. Risk factors in autism: thinking outside the brain. Journal of Autoimmunity 2016;67:1-7. R835432 (2015)
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  • Journal Article McKean SJ, Bartell SM, Hansen RL, Barfod GH, Green PG, Hertz-Picciotto I. Prenatal mercury exposure, autism, and developmental delay, using pharmacokinetic combination of newborn blood concentrations and questionnaire data: a case control study. Environmental Health 2015;14:62. R835432 (2014)
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  • Journal Article Miller GW, Chandrasekaran V, Yaghoobi B, Lein PJ. Opportunities and challenges for using the zebrafish to study neuronal connectivity as an endpoint of developmental neurotoxicity. NeuroToxicology; 2018;67:102-111. R835432 (2017)
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  • Journal Article Mitchell MM, Woods R, Chi L-H, Schmidt RJ, Pessah IN, Kostyniak PJ, LaSalle JM. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental and Molecular Mutagenesis 2012;53(8):589-598. R835432 (2013)
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  • Journal Article Nguyen CT, Krakowiak P, Hansen R, Hertz-PicciottoI I, Angkustsiri K. Sociodemographic disparities in intervention service utilization in families of children with autism spectrum disorder. Journal of Autism and Developmental Disorders 2016 Sep 17, doi:10.1007/s10803-016-2913-3 [Epub ahead of print]. R835432 (2015)
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  • Journal Article Philippat C, Bennett D, Calafat AM, Picciotto IH. Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children. Environmental Research 2015;140:369-376. R835432 (2015)
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  • Journal Article Philippat C, Bennett DH, Krakowiak P, Rose M, Hwang HM, Hertz-Picciotto I. Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study. Environmental Health 2015;14:56 (10 pp.). R835432 (2014)
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  • Journal Article Philippat C, Barkoski J, Tancredi DJ, Elms B, Barr DB, Ozonoff S, Bennett DH, Hertz-Picciotto I. Prenatal exposure to organophosphate pesticides and risk of autism spectrum disorders and other non-typical development at 3 years in a high-risk cohort. International Journal of Hygiene and Environmental Health 2018;221(3):548-555. R835432 (2017)
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  • Journal Article Piras IS, Haapanen L, Napolioni V, Sacco R, Van de Water J, Persico AM. Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder. Brain, Behavior, and Immunity 2014;38:91-99. R835432 (2013)
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  • Journal Article Powell WT, LaSalle JM. Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment. Human Molecular Genetics 2015;24(R1):R1-R9. R835432 (2015)
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  • Journal Article Pretto DI, Kumar M, Cao Z, Cunningham CL, Durbin-Johnson B, Qi L, Berman R, Noctor SC, Hagerman RJ, Pessah IN, Tassone F. 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. Neurobiology of Aging 2014;35(5):1189-1197. R835432 (2013)
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  • Journal Article Robin G, Lopez JR, Espinal GM, Hulsizer S, Hagerman PJ, Pessah IN. Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome. Human Molecular Genetics 2017;26(14):2649-2666. R835432 (2017)
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  • Journal Article Rose DR, Yang H, Serena G, Sturgeon C, Ma B, Careaga M, Hughes HK, Angkustsiri K, Rose M, Hertz-Picciotto I, Van de Water J, Hansen RL, Ravel J, Fasano A, Ashwood P. Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain, Behavior, and Immunity 2018;70:354-368. R835432 (2017)
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  • Journal Article Rossi CC, Fuentes J, Van de Water J, Amaral DG. Brief report: antibodies reacting to brain tissue in Basque Spanish children with Autism Spectrum Disorder and their mothers. Journal of Autism and Developmental Disorders 2014;44(2):459-465. R835432 (2013)
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  • Journal Article Saldarriaga W, Lein P, Gonzalez Teshima LY, Isaza C, Rosa L, Polyak A, Hagerman R, Girirajan S, Silva M, Tassone F. Phenobarbital use and neurological problems in FMR1 premutation carriers. NeuroToxicology 2016;53:141-147. R835432 (2015)
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  • Journal Article Schmidt RJ, Tancredi DJ, Krakowiak P, Hansen RL, Ozonoff S. Maternal intake of supplemental iron and risk of autism spectrum disorder. American Journal of Epidemiology 2014;180(9):890-900. R835432 (2014)
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  • Journal Article Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Sconberg JL, Schmidt LC, Volk HE, Tassone F. Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early Human Development 2015;91(8):483-489. R835432 (2014)
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  • Journal Article Schmidt RJ, Kogan V, Shelton JF, Delwiche L, Hansen RL, Ozonoff S, Ma CC, McCanlies EC, Bennett DH, Hertz-Picciotto I, Tancredi DJ, Volk HE. Combined prenatal pesticide exposure and folic acid intake in relation to autism spectrum disorder. Environmental Health Perspectives 2017;125(9):097007 (12 pp.). R835432 (2017)
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  • Journal Article Sethi S, Keil KP, Lein PJ. Species and sex differences in the morphogenic response of primary rodent neurons to 3,3'-dichlorobiphenyl (PCB 11). Toxics 2017;6(4):4 (15 pp.). R835432 (2017)
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  • Journal Article Shelton JF, Hertz-Picciotto I, Pessah IN. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environmental Health Perspectives 2012;120(7):944-951. R835432 (2013)
    R833292 (2012)
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  • Journal Article Sirish P, Li N, Timofeyev V, Zhang XD, Wang L, Yang J, Lee KS, Bettaieb A, Ma SM, Lee JH, Su D, Lau VC, Myers RE, Lieu DK, Lopez JE, Young JN, Yamoah EN, Haj F, Ripplinger CM, Hammock BD, Chiamvimonvat N. Molecular mechanisms and new treatment paradigm for atrial fibrillation. Circulation:Arrhythmia and Electrophysiology 2016;9(5)e003721 (13 pp.). R835432 (2015)
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  • Journal Article Stamou M, Uwimana E, Flannery BM, Kania-Korwel I, Lehmler HJ, Lein PJ. Subacute nicotine co-exposure has no effect on 2,2',3,5',6-pentachlorobiphenyl disposition but alters hepatic cytochrome P450 expression in the male rat. Toxicology 2015;338:59-68. R835432 (2015)
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  • Journal Article Stamou M, Grodzki AC, van Oostrum M, Wollscheid B, Lein PJ. Fc gamma receptors are expressed in the developing rat brain and activate downstream signaling molecules upon cross-linking with immune complex. Journal of Neuroinflammation 2018;15(1):7 (23 pp.). R835432 (2017)
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  • Journal Article Vogel CFA, Wu D, Goth SR, Baek J, Lollies A, Domhardt R, Grindel A, Pessah IN. Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunology and Cell Biology 2013;91(9):568-575. R835432 (2013)
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  • Journal Article Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, Hertz-Picciotto I. Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. Journal of the American Medical Association Pediatrics 2015;169(2):154-162. R835432 (2014)
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  • Journal Article Wayman GA, Bose DD, Yang D, Lesiak A, Bruun D, Impey S, Ledoux V, Pessah IN, Lein PJ. PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environmental Health Perspectives 2012;120(7):1003-1009. R835432 (2013)
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  • Journal Article Wayman GA, Yang D, Bose DD, Lesiak A, Ledoux V, Bruun D, Pessah IN, Lein PJ. PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. Environmental Health Perspectives 2012;120(7):997-1002. R835432 (2013)
    R833292 (2012)
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  • Journal Article Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, Croen LA. Maternal infection during pregnancy and autism spectrum disorders. Journal of Autism and Developmental Disorders 2015;45(12):4015-4025. R835432 (2015)
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  • Journal Article Zheng J, McKinnie SMK, El Gamal A, Feng W, Dong Y, Agarwal V, Fenical W, Kumar A, Cao Z, Moore BS, Pessah IN. Organohalogens naturally biosynthesized in marine environments and produced as disinfection byproducts alter sarco/endoplasmic reticulum Ca2+ dynamics. Environmental Science & Technology 2018;52(9):5469-5478. R835432 (2017)
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  • Journal Article Krakowiak, Paula; Walker, Cheryl K; Tancredi, Daniel; Hertz-Picciotto, Irva; Van de Water, Judy Autism research:official journal of the International Society for Autism Research.2017 Jan;Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. R835432 (2016)
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    Journal Article Onore, Charity; Yang, Houa; Van de Water, Judy; Ashwood, Paul Frontiers in pediatrics. 2017; Dynamic Akt/mTOR Signaling in Children with Autism Spectrum Disorder. R835432 (2016)
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    Journal Article Aschner, Michael; Ceccatelli, Sandra; Daneshian, Mardas; Fritsche, Ellen; Hasiwa, Nina; Hartung, Thomas; Hogberg, Helena T; Leist, Marcel; Li, Abby; Mundi, William R; Padilla, Stephanie; Piersma, Aldert H; Bal-Price, Anna; Seiler, Andrea; Westerink, Remco H; Zimmer, Bastian; Lein, Pamela J. ALTEX. 2017; Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals:example lists and criteria for their selection and use. R835432 (2016)
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    Journal Article Tylee, Daniel S; Hess, Jonathan L; Quinn, Thomas P; Barve, Rahul; Huang, Hailiang; Zhang-James, Yanli; Chang, Jeffrey; Stamova, Boryana S; Sharp, Frank R; Hertz-Picciotto, Irva; Faraone, Stephen V; Kong, Sek Won; Glatt, Stephen J. American journal of medical genetics. Part B, Neuropsychiatric genetics:the official publication of the International Society of Psychiatric Genetics.2017 Apr;Blood transcriptomic comparison of individuals with and without autism spectrum disorder:A combined-samples mega-analysis. R835432 (2016)
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    Journal Article Edmiston, Elizabeth; Ashwood, Paul; Van de Water, Judy . Biological psychiatry. 2017 Mar 01; Autoimmunity, Autoantibodies, and Autism Spectrum Disorder. R835432 (2016)
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    Journal Article Krakowiak, Paula; Goines, Paula E; Tancredi, Daniel J; Ashwood, Paul; Hansen, Robin L; Hertz-Picciotto, Irva; Van de Water, Judy. Biological psychiatry.2017 Mar 01;Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder. R835432 (2016)
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    Journal Article Careaga, Milo; Rogers, Sally; Hansen, Robin L; Amaral, David G; Van de Water, Judy; Ashwood, Paul. Biological psychiatry.2017 Mar 01;Immune Endophenotypes in Children With Autism Spectrum Disorder. R835432 (2016)
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    Journal Article Wong, Sarah; Giulivi, Cecilia. CNS & neurological disorders drug targets. 2016; Autism, Mitochondria and Polybrominated Diphenyl Ether Exposure. R835432 (2016)
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    Journal Article Dunaway, Keith W; Islam, M Saharul; Coulson, Rochelle L; Lopez, S Jesse; Vogel Ciernia, Annie; Chu, Roy G; Yasui, Dag H; Pessah, Isaac N; Lott, Paul; Mordaunt, Charles; Meguro-Horike, Makiko; Horike, Shin-Ichi; Korf, Ian; LaSalle, Janine M. Cell reports. 2016 Dec 13; Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes. R835432 (2016)
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    Journal Article Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth; Miller, Elaine; Ariza, Jeanelle; Kienzle, Devon; Plank, Kaela; Noctor, Stephen C; Van de Water, Judy. Cerebral cortex. 2016 Jan; Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals. R835432 (2016)
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    Journal Article Sethi, S; Chen, X; Kass, P H; Puschner, B. Chemosphere. 2017 Aug;Polychlorinated biphenyl and polybrominated diphenyl ether profiles in serum from cattle, sheep, and goats across California. R835432 (2016)
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    Journal Article Sirish, Padmini; Li, Ning; Timofeyev, Valeriy; Zhang, Xiao-Dong; Wang, Lianguo; Yang, Jun; Lee, Kin Sing Stephen; Bettaieb, Ahmed; Ma, Sin Mei; Lee, Jeong Han; Su, Demetria; Lau, Victor C; Myers, Richard E; Lieu, Deborah K; López, Javier E; Young, J Nilas; Yamoah, Ebenezer N; Haj, Fawaz; Ripplinger, Crystal M; Hammock, Bruce D; Chiamvimonvat, Nipavan. Circulation. Arrhythmia and electrophysiology. 2016 May; Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. R835432 (2016)
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    Journal Article Schmidt, Rebecca J; Schroeder, Diane I; Crary-Dooley, Florence K; Barkoski, Jacqueline M; Tancredi, Daniel J; Walker, Cheryl K; Ozonoff, Sally; Hertz-Picciotto, Irva; LaSalle, Janine M. Environmental epigenetics. 2016 Dec; Self-reported pregnancy exposures and placental DNA methylation in the MARBLES prospective autism sibling study. R835432 (2016)
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    Journal Article Keil, Kimberly P; Lein, Pamela J. Environmental epigenetics.2016 Mar;DNA methylation:a mechanism linking environmental chemical exposures to risk of autism spectrum disorders?. R835432 (2016)
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    Journal Article Crary-Dooley, Florence K; Tam, Mitchell E; Dunaway, Keith W; Hertz-Picciotto, Irva; Schmidt, Rebecca J; LaSalle, Janine M. Epigenetics. 2017 Mar 04; A comparison of existing global DNA methylation assays to low-coverage whole-genome bisulfite sequencing for epidemiological studies. R835432 (2016)
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    Journal Article Vogel Ciernia, Annie; Pride, Michael C; Durbin-Johnson, Blythe; Noronha, Adriana; Chang, Alene; Yasui, Dag H; Crawley, Jacqueline N; LaSalle, Janine M. Human molecular genetics. 2017 May 15; Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering. R835432 (2016)
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    Journal Article Nguyen, Cathina T; Krakowiak, Paula; Hansen, Robin; Hertz-Picciotto, Irva; Angkustsiri, Kathleen. Journal of autism and developmental disorders. 2016 Dec; Sociodemographic Disparities in Intervention Service Utilization in Families of Children with Autism Spectrum Disorder. R835432 (2016)
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    Journal Article Matelski, Lauren; Van de Water, Judy. Journal of autoimmunity. 2016 Feb; Risk factors in autism:Thinking outside the brain. R835432 (2016)
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    Journal Article Wilson, Machelle D; Sethi, Sunjay; Lein, Pamela J; Keil, Kimberly P. Journal of neuroscience methods.2017 Mar 01; Valid statistical approaches for analyzing sholl data:Mixed effects versus simple linear models. R835432 (2016)
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    Journal Article Schroeder, Diane I; Schmidt, Rebecca J; Crary-Dooley, Florence K; Walker, Cheryl K; Ozonoff, Sally; Tancredi, Daniel J; Hertz-Picciotto, Irva; LaSalle, Janine M. Molecular autism. 2016; Placental methylome analysis from a prospective autism study. R835432 (2016)
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    Journal Article Zhang, Rui; Pessah, Isaac N. Molecular pharmacology. 2017 Apr; Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A. R835432 (2016)
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    Journal Article Jones, K L; Croen, L A; Yoshida, C K; Heuer, L; Hansen, R; Zerbo, O; DeLorenze, G N; Kharrazi, M; Yolken, R; Ashwood, P; Van de Water, J. Molecular psychiatry. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. R835432 (2016)
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    Journal Article Vogel Ciernia, Annie; LaSalle, Janine. Nature reviews. Neuroscience. 2016 07; The landscape of DNA methylation amid a perfect storm of autism aetiologies. R835432 (2016)
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    Journal Article Saldarriaga, Wilmar; Lein, Pamela; González Teshima, Laura Yuriko; Isaza, Carolina; Rosa, Lina; Polyak, Andrew; Hagerman, Randi; Girirajan, Santhosh; Silva, Marisol; Tassone, Flora. Neurotoxicology. 2016 Mar;Phenobarbital use and neurological problems in FMR1 premutation carriers. R835432 (2016)
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    Journal Article Bal-Price, Anna; Lein, Pamela J; Keil, Kimberly P; Sethi, Sunjay; Shafer, Timothy; Barenys, Marta; Fritsche, Ellen; Sachana, Magdalini; Meek, M E Bette. Neurotoxicology. 2017 March. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. R835432 (2016)
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    Journal Article Chen, Xiaopeng; Lin, Yanping; Dang, Katherine; Puschner, Birgit. PLoS One. 2017 Jan; Quantification of Polychlorinated Biphenyls and Polybrominated Diphenyl Ethers in Commercial Cows’ Milk from California by Gas Chromatography–Triple Quadruple Mass Spectrometry. R835432 (2016)
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    Journal Article Wong, Sarah; Napoli, Eleonora; Krakowiak, Paula; Tassone, Flora; Hertz-Picciotto, Irva; Giulivi, Cecilia. Pediatrics. 2016 Apr; Mitochondrial DNA Deletions, and Paternal Age in Autism:A Case-Control Study. R835432 (2016)
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    Journal Article Ronjat, Michel; Feng, Wei; Dardevet, Lucie; Dong, Yao; Al Khoury, Sawsan; Chatelain, Franck C; Vialla, Virginie; Chahboun, Samir; Lesage, Florian; Darbon, Hervé; Pessah, Isaac N; De Waard, Michel. Proceedings of the National Academy of Sciences of the United States of America. 2016 Apr 26; In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide. R835432 (2016)
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    Journal Article Dach, Katharina; Bendt, Farina; Huebenthal, Ulrike; Giersiefer, Susanne; Lein, Pamela J; Heuer, Heike; Fritsche, Ellen. Scientific reports. 2017 Mar 20; BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action. R835432 (2016)
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    Journal Article Dunaway, Keith; Goorha, Sarita; Matelski, Lauren; Urraca, Nora; Lein, Pamela J; Korf, Ian; Reiter, Lawrence T; LaSalle, Janine M. Stem cells (Dayton, Ohio).2017 Apr;Dental Pulp Stem Cells Model Early Life and Imprinted DNA Methylation Patterns. R835432 (2016)
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    Journal Article Chen, Hao; Streifel, Karin M; Singh, Vikrant; Yang, Dongren; Mangini, Linley; Wulff, Heike; Lein, Pamela . Toxicological sciences:an official journal of the Society of Toxicology. 2016 Dec 20; BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms. R835432 (2016)
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    Journal Article Holland, Erika B; Feng, Wei; Zheng, Jing; Dong, Yao; Li, Xueshu; Lehmler, Hans-Joachim; Pessah, Isaac N. Toxicological sciences:an official journal of the Society of Toxicology. An Extended Structure-Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors. R835432 (2016)
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    Journal Article Crawley, Jacqueline N; Heyer, Wolf-Dietrich; LaSalle, Janine M. Trends in genetics:TIG. 2016 Mar; Autism and Cancer Share Risk Genes, Pathways, and Drug Targets. R835432 (2016)
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    Progress and Final Reports:

    Original Abstract
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • 2016 Progress Report