Grantee Research Project Results
2015 Progress Report: The UC Davis Center for Children's Environmental Health and Disease Prevention
EPA Grant Number: R835432Center: 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
Current Investigators: Van de Water, Judith , Bennett, Deborah H. , Lein, Pamela J , LaSalle, Janine M , Pessah, Isaac N. , Puschner, Birgit , Walker, Cheryl , Sharp, Frank , Hertz-Picciotto, Irva , Ritchie, Marylyn , Hagerman, Paul , Ashwood, Paul , Schmidt, Rebecca , Hansen, Robin , Lin, Yanping
Institution: University of California - Davis
EPA Project Officer: Hahn, Intaek
Project Period: June 1, 2013 through May 31, 2018 (Extended to May 31, 2019)
Project Period Covered by this Report: June 1, 2015 through May 31,2016
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 , Human Health
Objective:
The overarching aims of the University of California-Davis Center for Children’s Environmental Health are:
- 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 CHARGE (CHildhood Autism Risks from Genetics and the Environment) study, as well as the epidemiological and clinical studies involving prospective parents, pregnant women, and children from the ongoing MARBLES (Markers of Autism Risk in Babies - Learning Early Signs) study—both of which grew out of previous years of Center funding;
- 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;
- 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;
- Train new investigators, including pre- and post-doctoral fellows and junior faculty, to address emerging issues in children’s environmental health with cross-cutting technologies and integrated multidisciplinary approach; and
- 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)
The manuscript on ozone and genetic copy number variant (CNV) burden based on our collaboration with Drs. Selleck and Ritchie, which demonstrated an elevated risk for ASD in those with the highest levels of ozone who also had a high CNV burden, now is in final revisions and publication is expected soon in Autism Research. Because of limitations in the sample size, and the older platform used for the CNV calls, this team now is working to make the CNV calls using the single nucleotide polymorphism (SNP) array that was conducted on a much larger sample of CHARGE Study children. Once that work is completed, we will extend results on gene-by-environment interactions.
A manuscript reporting PBDE levels in pregnant women from MARBLES has received generally positive peer review, but further quality control was requested. Working with Core C, we have embarked on further analyses to be conducted on samples from the low-risk pregnant women in CHARGE (no older sibling with ASD) to serve as a control to the MARBLES pregnant women (in Core C).
In the MARBLES cohort study, we extended analyses of the second and third trimester urine specimens to more than 500 samples and the resulting data are suggesting that metabolites of pyrethroid insecticides are associated with poorer scores in cognitive domains, particularly in the first year of life. We continue to await the full set of results from the laboratory at Emory University. The manuscript on self-reported pesticide use is being drafted.
More extensive analyses now have been conducted on CHARGE children for whom RNAseq analyses were completed. In particular, further quality control was conducted using DESeq2, which provides very accurate identification of outliers. The RNAseq data were aligned and analyzed for the 296 children (78 Typically Developing (TD); 71 Developmentally Delayed (DD); 147 ASD) who also had data on indoor pesticide exposure. DESeq2 was used to identify differentially expressed genes comparing those exposed vs. not exposed to indoor pesticide applications in 6 or more months of pregnancy. As this package allows for multivariate control of covariates, we adjusted for sex and age in all of the analyses.
When combining the three diagnostic groups, we identified 16 genes showing altered expression in relation to prenatal pesticide exposure with the majority of these genes being noncoding RNA. Additionally, when we stratified by diagnostic group, we discovered that children with ASD have twice as many genes that are differentially expressed (54 genes) when compared to DD and TD (19 genes and 21 genes, respectively). Additionally, the genes differentially expressed within the ASD group are significantly enriched in gene ontology terms related to the immune response. No significant gene ontology terms were identified in the TD and DD groups. Additional sites differentially expressed in the ASD group were significantly enriched with genes previously associated with organophosphate and pyrethroid exposure in literature from the Comparative Toxicogenomics Database (p=0.002).
Project 2 (Perinatal Epigenetic Signatures of Environmental Exposures)
Dr. LaSalle’s lab has isolated DNA and prepared MethylC-seq libraries from 54 MARBLES cord blood samples, including 26 typical and 26 ASD. Sequencing was performed on the first batch of 22 samples and the remaining samples are in the sequencing queue. DNA methylation analysis of FOXP3 and a putative enhancer of FOXP3 was performed in sorted cord blood samples from the Ashwood lab and DNA isolated from cell pellets of CHARGE sample ex vivo PBDE treatments from the Van de Water lab.
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 determine the most effective current sequencing strategy for genomic DNA from MARBLES samples to identify structural variants once all MARBLES samples are obtained.
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 (Figure 1).
- 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 (Figure 2).
- 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 PCB and PBDE levels measured by the Analytic Core. No significant associations were observed with PBDE congeners, but several significant associations were observed between placental DNA methylation and PCBs (Table 1). PCB 175 was associated with a significantly higher proportion of the placental methylome in partially methylated domains (PMDs) after false discovery rate (FDR) correction (p=0.01). After adjustment for PMD methylation, PCB 136 was significantly associated with higher highly methylated domain (HMD, p=0.002).
Table 1. PCB Predictors of Placenta Methylation
Methylation | PCB |
Estimate (95% Confidence Interval) |
Pr > |t| |
FDR Corrected P-Value |
N | AIC |
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PMD | PCB 118 | 0.07 (0.05, 0.1) | <.0001 | 0.002 | 40 | 73.81 |
PCB 196 | -0.24 (-0.34, -0.14) | <.0001 | 0.002 | |||
PCB 153 | -0.05 (-0.09, -0.02) | 0.002 | 0.04 | |||
PCB 175 | 0.14 (0.04, 0.24) | 0.007 | 0.11 | |||
PMD Adjusted for HMD |
PCB 196 | -0.15 (-0.21, -0.08) | <.0001 | 0.002 | 40 | 52.01 |
PCB 118 | 0.04 (0.02, 0.06) | 0.0002 | 0.003 | |||
PCB 153 | -0.03 (-0.04, -0.01) | 0.007 | 0.10 | |||
HMD Methylation | 0.76 (0.56, 0.97) | <.0001 | 0.002 | |||
HMD | PCB 118 | 0.06 (0.03, 0.1) | 0.001 | 0.01 | 40 | 69.56 |
PCB 175 | 0.13 (0.05, 0.21) | 0.002 | 0.04 | |||
PCB 11 | -0.005 (-0.01, 0) | 0.005 | 0.08 | |||
PCB 91 | -0.21 (-0.37, -0.05) | 0.013 | 0.20 | |||
PCB 153 | -0.03 (-0.06, 0) | 0.074 | 0.73 | |||
HMD adjusted for PMD |
PCB 136 | 0.1 (0.06, 0.14) | <.0001 | 0.002 | 40 | 36.09 |
PCB 91 | -0.2 (-0.34, -0.06) | 0.007 | 0.11 | |||
PCB 52 | 0.01 (0, 0.03) | 0.080 | 0.76 | |||
PMD Methylation | 0.57 (0.4, 0.74) | <.0001 | 0.002 | |||
% 20 Kb Regions with Methylation <60% |
PCB 175 | 0.21 (0.1, 0.31) | 0.0003 | 0.01 | 40 | 70.81 |
PCB 91 | -0.17 (-0.34, -0.01) | 0.040 | 0.50 | |||
PCB 196 | -0.12 (-0.24, 0) | 0.052 | 0.59 | |||
PCB 153 | -0.03 (-0.06, 0) | 0.079 | 0.75 | |||
PCB 118 | 0.04 (-0.01, 0.09) | 0.087 | 0.79 | |||
PCB 101 | 0.02 (-0.02, 0.07) | 0.295 | 1.00 |
Project 3 (Immune Environment Interactions and Neurodevelopment)
Sample analysis by Core C was completed for samples from children in the CHARGE study and the data collated with our cytokine/chemokine profiles. Maternal sample profiles from Core C now are completed and Project 1 has these data. We now are assaying the collected samples for their cytokine/chemokine profiles, with and without ex vivo BDE-49 exposure. We have 75% of the samples completed.
Aim 1.3: We are actively working on the mTOR analysis via PCR. We have analyzed cytokine/chemokine levels in the plasma and activated immune cells from children in CHARGE. One paper was recently published in the Journal of Neuroimmunology on the elevated IL-17 found in ASD children compared to TD controls. We also found a correlation with asthma and allergy and elevated IL-17 in the ASD children but not controls. Working with Project 4, we have begun work on the LUHMES cells using the cytokine/chemokine profile found to be elevated mid-gestation in women who go on to have a child with ASD + intellectual disability. We are finalizing the preparation of the manuscript on total body burden of PBDEs and immune function in ASD. Working with Project 2, early pilot data suggest that FOXP3 TSDR Methylation and IL-10 expression in PBMCs exposed to BDE-49 differs between ASD and TD subjects whereby there is no demethylation and thus low activation of the Treg cells in PBMC from the children with ASD.
Significant Results
We sought to examine the relationships between blood levels of PBDE and immune cell function in children with and without ASD. Differential sensitivity of cultured immune cells harvested from the two diagnostic groups were compared for their ex vivo responses to an exemplary congener, 2,2',4,5'-tetrabromodiphenylether (BDE-49), which accumulates in fetal tissue. We took advantage of banked plasma from children with ASD (n=38), and age- and geographically- matched typically developing control (TD)(n=53) children enrolled in the CHARGE study, and working with Core C, analyzed for blood levels of 11 major PBDE congeners using mass GC-tandem spectrometry. Cytokine/chemokine production in activated peripheral blood mononuclear cell (PBMC) supernatants were measured with and without ex vivo BDE-49 exposure. Total body burden (ΣPBDE12) and individual congener levels then were correlated with T cell cytokine/chemokine production.
Although ΣPBDE12 did not differ between the two diagnostic groups (Figure 3), body burden of PBDE correlated with a suppressed immune response, particularly in children with ASD. There was a differential effect of ΣBDE12 on baseline (no activation) immune function between ASD and TD children whereby T cell function was more negatively affected in children with ASD than the TD controls as measured by lower levels of IL-2, IL-13, and IFN-γ. Therefore, we demonstrated that despite a nearly identical body burden of the flame-retardant PBDE in ASD and TD children, there is a differential impact of PBDE exposure on immune system function in children with ASD compared to little or no impact on the TD control children. This suggests an underlying susceptibility to environmental toxicant exposure in children with ASD that could relate to immune anomalies reported in these children.
Figure 3: Body burden of PBDE in typically developing children and children with ASD
Finally, working with Project 2, early pilot data suggests that FOXP3 TSDR Methylation and IL-10 expression in PBMCs exposed to BDE-49 differs between ASD and TD subjects whereby there is no demethylation and thus low activation of the Treg cells in PBMC from the children with ASD. This suggests a differential effect of BDE-49 on immune cell function in children with ASD.
Project 4 (Calcium Signaling Defects in Autism)
The major goals in Project 4 this past funding period remained unchanged and have centered on establishing human neuronal cell models with which to study how environmental chemicals can influence early biomarkers that are relevant to childhood neurodevelopmental disorders. Both the Pessah and Lein labs are investigating novel molecular and cellular mechanisms for classes of chemicals of concern to children’s environmental health that are relevant to ASD using neuronal cells models expressing FMR1 CGG expansion repeats in the premutation and full range from mouse and human. In addition to progress made last year establishing human NPCs in the mid and high premutation range, the Pessah lab has verified early neuronal markers for NPCs derived from two unrelated full mutation males, one with 230 FXS-CGG expansion, the other with 280 FXS-CGG expansion. These new models are being used along side our established wild type (WT) and premutation mouse models to test responses to three classes of environmental chemicals of significance to human environmental health issues: PCBs, with one manuscript accepted and one in revision; chlorpyrifos and its active oxon metabolite, with a manuscript submitted for review; and eight pyrethroids (research underway). In addition to PCBs and related persistant organic pollutants that have RyR channel activity (PBDES, DDE), the organophosphate (OP) chlorpyrifos and its oxon, and pyrethroids are being investigated.
The Lein lab has validated a high content imaging approach for assessing the differentiation of the human LUHMES neuronal cell line. Studies have been initiated to screen cytokine profiles associated with autistic versus neurotypical children as identified in Project 3 and the MARBLES PCB mix, based on PCB congener profiles identified in MARBLES mothers by Core C. In addition, the Lein lab has been refining culture conditions for the differentiation of human neural crest stem cells into sympathetic neurons. The Lein lab also has extended studies characterizing the effects of ortho-substituted PCBs on the mTOR signaling pathway in neurons, and completed studies of PBDE effects on neuronal morphogenesis in vitro. Both are significant findings and were presented at the March 2016 Society of Toxicology annual meeting in New Orleans, LA. A manuscript describing the PBDE findings is in review at Toxicological Sciences and a manuscript describing PCB study is being prepared for submission to Environmental Health Perspectives.
Significant Results:
- Produced and verified isogenic isoautosomal iPSC-derived neuronal precursor cells (NPCs) possessing a normal FMR1 gene and NPCs possessing an active FMR1 CGG repeat expansion in the mid-premutation, high-premutation, and full-mutation (FXS) range. We are comparing morphological, biochemical neuronal markers, and neurochemical pathways among iPSC-derived NPCs, premutation mouse model and human premutation brains. In the mouse premutation models, we have completed a study that links chronic Ca2+ dysregulation, abnormal mGluR1 signaling, and the μCalpain-Cdk5-ATM pathway is being translated to the iPSC-derived NPCs we have established. Our results are being finalized for publication and have been presented at several meetings. Specifically, we have made and verified two additional iPSC-derived NPC lines from male human patients with CGG expansions in the full mutation range. Specifically, we now have two full mutations from unrelated males that have produced stable NPC lines, one with 230 FXS-CGG expansion, the other with 280 FXS-CGG expansion. These will be compared to unrelated neurotypical iPSC-derived lines. Unlike isolation of isogenic iPSC NPC lines from mosaic females, this isogenic approach has not been possible for thus we will rely on a non-isogenic approach with the male full mutation NPC lines we have banked. Nevertheless, the female isogenic premutation lines will provide internal control for FMR1 related mechanism in the absence of background gene influences. We have verified that NPC lines with FMR1 expansions are genetically stable over at least 15 passages in culture and once the neuronal differentiation is promoted. However, our goal to produce mature neural networks from these NPC to investigate long-range network activity has proved most challenging. Although the cultures increase their morphological complexity over a 5-6 week period in neuronal differentiation medium, they have failed to demonstrate the typical synchronous network activity in membrane electrical spiking or Ca2+ oscillatory behavior. Although a modest fraction (1-2%) of neighboring neurons show localized synchronized activity using microscopic imaging approaches and whole cell current clamp recordings, the use of multielectrode array technology or voltage-sensitive fluorescent indicator FluoVolt indicate that broader long-distance network fail to form, even 5-weeks after initiating differentiation, at which time evidence of non-neuronal cell overgrowth and neurotoxicity becomes evident. By contrast, analysis of the high CGG premutation (170-200 repeats) KI mouse brains and neuronal cultures derived from them, we have made significant advances in testing our overarching hypothesis in year 4. We are preparing a manuscript that links early abnormal growth and Ca2+ dynamics in the brains of FMR1 premutation preCGG knock-in mice and neuronal cultures derived from them long before there are indications of neurodegeneration and biomarkers of FXTAS. It is important to determine whether intranuclear inclusions containing DNA damage response (DDR) proteins, pathologic hallmark of FXTAS, could provide a causally link between early Ca2+ dysregulation and abnormal neuronal growth and survival. We therefore hypothesize a role for CdK5 and ATM in early pathogenesis, long before the neurodegenerative phase of FXTAS can be detected. These two key signaling kinases are known to be involved in both DDR and synaptic signaling, but their contribution to FMR1-related disorders have not been previously implicated. FMRP expression in postnatal day 0 (P0), 6-week- and 6-month-old preCGG mouse brain is reduced by 60-, 50- and 30% compared to WT, respectively. In primary preCGG hippocampal neurons, FMRP reduction is more pronounced in soma (20% reduction, p<0.0001) compared to neurites (5% reduction, p=0.0177). Importantly resting cytoplasmic Ca2+ concentration ([Ca2+]i) in preCGG hippocampal neurons is chronically elevated 3-fold compared to WT as early as 7 DIV, and persists at 14 and 21DIV, and can be reversed by exposure to 10μM dantrolene. Elevated [Ca2+]i-dependent calpain activity (20-40% increase) and p25/p35 (20-45% increase) at 6-weeks and 6-months in preCGG cortex indicate abnormal CdK5 up-regulation, consistent with chronically elevated [Ca2+]i. CdK5 substrate ATM is upregulated by 1.5-2-fold and P-Ser1981-ATM is increased by 1.5-fold (p<0.01-0.007) compared to wt at P0 and 6 months in preCGG brain. Finally, the ratio Bax:Bcl-2 is higher by 30% in 6-months-old cortical and hippocampal tissue in preCGG mice compared to WT, that suggests a greater vulnerability of CGG expansion cells to apoptotic activation. We are therefor proposing that early chronic Ca2+ dysregulation, possibly through leaky RyR channels, amplifies Cdk5/ATM signaling pathway activity possibly linking early defects in Ca2+ dynamics and impaired glutamatergic signaling with impaired mitochondrial stress and DDR response. The balance of these mechanisms appears to be influences by the size of the FMR1 CGG expansion and could provide a mechanism linking early neurodevelopmental abnormalities know to occur in young premutation carriers with risk for late onset FXTAS. A manuscript is being prepared and these results have been presented at several national meetings.
- Non-dioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca2+ channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals and have been implicated the etiology of ASDs. RyR-active congeners follow a distinct structure activity relationship and a quantitative structure activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assay but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [3H]Ryanodine ([3H]Ry) binding to assess the RyR-activity of 14 previously untested PCB congeners evaluating the predictability of the QSAR. Congeners determined to display widely varying potency were then assayed with single channel voltage clamp analysis to assess direct influences on channel gating kinetics. The RyR-activity of individual PCBs assessed in in vitro assays followed the general pattern predicted by the QSAR but binding and lipid bilayer experiments demonstrated higher potency than predicted. Of the 49 congeners tested to date, tetra-ortho PCB 202 was found to be the most potent RyR-active congener increasing channel open probability at 200 pM. Shifting meta-substitutions to the para-position resulted in a >100-fold reduction in potency as seen with PCB 197. Non-ortho PCB 11 was found to lack activity at the receptor supporting a minimum mono-ortho substitution for PCB RyR activity. These findings expand and support previous SAR assessments; where out of the 49 congeners tested to date 42 activate the receptor, demonstrating that the RyR is a sensitive and common target of PCBs.
- Rare variants enriched for gene functions in chromatin regulation and neuronal synapses have been identified in autism. How the epigenetic layers of chromatin and DNA methylation interact with environmental exposures at synaptic genes in the etiology of autism and the possible role of PCB exposure in such mechanisms are currently unknown. Utilizing whole genome bisulfite sequencing, we show that both chromosome 15q11.2-q13.3 maternal duplication brain and a neuronal cell culture model exhibit significant global DNA hypomethylation, enriched over autism candidate genes, impacting their transcriptional stability. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95, whose elevated brain levels we previously showed were highly associated with 15q11.2-q13.3 maternal duplication, are now found to be associated with altered methylation of >1,000 genes. Mechanistically, hypomethylated genes are enriched for gene-body H2A.Z, increased maternal UBE3A in Dup15q correspond to reduced levels of RING1B, and bivalently modified H2A.Z is impacted by cumulative hits. These are the first results to demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge in the dysregulation of chromatin and synaptic gene pathways.
- Chlorpyrifos (CPF), O,O-diethyl O-3,5,6-trichloropyridin-2-yl phosphorothioate, is one of the most widely used organophosphate insecticides in agriculture. Acute and long-term exposures to CPF lead to persistent neurological, developmental and autoimmune disorders. Interference of signaling from the neurotransmitter acetylcholine is well known as a primarily underlined mechanism for the toxicity of CPF and its metabolite chlorpyrifos oxon (CPFO) that induces irreversible inhibition of acetylcholinesterase (AChE). However, increasing numbers of studies of CPF and CPFO have exhibited significant toxicity associated with mechanisms unrelated to cholinergic pathway. Here, we demonstrate that intracellular Ca2+ release channel, ryanodine receptors (RyRs), is a specific target of CPF and CPFO. In cultured mouse neocortical neurons, both CPF and CPFO, but not DFP up to 10µM, were found to consistently cause significant alternations in amplitude and frequency of simultaneous Ca2+ oscillations (SCOs). Challenging the cells with ryanodine, we demonstrate that SCOs are RyRs-dependent events. Using human kidney embryonic cells (HEK) expressed with RyR1, we confirmed that the RyR1-mediated Ca2+ release was directly affected by both CPF and CPFO. Using mouse cortical homogenate to assess the specific binding of [3H]ryanodine, we clearly demonstrated that both CPF and CPFO significantly increased RyRs binding activity. Single RyR1 channel incorporated bilayer upon exposing to CPF or CPFO, manifested significantly modified gating kinetics. All these findings taken together unambiguously indicate that intracellular Ca2+ release channel RyR is a key target of CPF and CPFO. The results reveal a novel and critically important mechanism that underlines the link of neurotoxicity of CPF and CPFO with disruption of Ca2+ homeostasis.
Future Activities:
Individual component plans are described in the sections above and there are no plans that deviate from the activities in the original proposal. 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 Center workgroups and will continue to do so in the subsequent reporting period.
Journal Articles: 134 Displayed | Download in RIS Format
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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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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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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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Bal-Price A, Lein PJ, Keil KP, Sethi S, Shafer T, Barenys M, Fritsche E, Sachana M, Meek MEB. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. NeuroToxicology 2017;59:240-255. |
R835432 (2015) |
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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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Barkoski J, Philippat C, Tancredi D, Schmidt R, Ozonoff S, Barr D, Elms W, Bennett D, Hertz-Picciotto I. In utero pyrethroid pesticide exposure in relation to autism spectrum disorder ASD and other neurodevelopmental outcomes at 3 years in the MARBLES longitudinal cohort. ENVIRONMENTAL RESEARCH 2021;194(110495). |
R835432 (Final) |
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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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Bennett D, Calafat A, Hertz-Piccioltto I, Shin H, Tancredi D. Modeled prenatal exposure to per-and polyfluoroalkyl substances in association with child autism spectrum disorder:A case-control study. Enviornmenal Research 2020;186(109514). |
R835432 (Final) R833292 (Final) |
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Bennett D, Bgang S, Kannan K, Parsons P, Takazawa M, Palmer C, Schmidt R, Doucette J, Schweitzer J, Gennings C, Hertz-Picciotto I. Environmental exposures to pesticides, phthalates, phenols and trace elements are associated with neurodevelopment in the CHARGE study. ENVIRONMENT INTERNATIONAL 2022;161(10705). |
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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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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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Breen M, Garg P, Tang L, Mendonca D, Levy T, Barbosa M, Arnett A, Kurtz-Nelson E, Agolini E, Battaglia A. Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype. American Journal of Human Genetics 2020;107(3):555-563. |
R835432 (Final) R829388 (Final) |
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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) R835432 (2017) R835442 (2017) |
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Bruce M, Streifel K, Boosalis C, Heuer L, Gonzalez E, Li S, Harvey D, Lein P, Va de Water J. Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain. JOURNAL OF NEUROINFLAMMATION 2019;16(1):200. |
R835432 (Final) |
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Bruce M, Hones K, Vernon A, Silverman J, Crawley J, Ellegood J, Lerch J, Va de Water J, Hertz-Picciotto I. Sexually dimorphic neuroanatomical differences relate to ASD-relevant behavioral outcomes in a maternal autoantibody moe model. MOLECULAR PSYCHIATRY 2021;26(12):7530-7537. |
R835432 (Final) |
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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) R835432 (2014) |
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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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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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Cao Z, Zou X, Cui Y, Hulsizer S, Lein PJ, Wulff H, Pessah IN. Rapid throughput analysis demonstrates that chemicals with distinct seizurogenic mechanisms differentially alter Ca2+ dynamics in networks formed by hippocampal neurons in culture. Molecular Pharmacology 2015;87(4):595-605. |
R835432 (2014) |
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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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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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Careaga M, Rogers S, Hansen RL, Amaral DG, Van de Water J, Ashwood P. Immune Endophenotypes in Children With Autism Spectrum Disorder. Biological Psychiatry 2017;81(5):434-441. |
R835432 (2015) R835432 (2016) |
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Chen X, Lin Y; Dang K, Puschner B. Quantification of Polychlorinated Biphenyls and Polybrominated Diphenyl Ethers in Commercial Cows’ Milk from California by Gas Chromatography--Triple Quadruple Mass Spectrometry. <PLosOne 2017;12(1):e0170129. |
R835432 (2016) R835432 (Final) R829388 (Final) R833292 (Final) |
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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) |
Exit |
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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) R833292 (2012) |
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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) |
Exit Exit |
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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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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) |
Exit Exit |
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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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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) |
Exit |
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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) R835550 (Final) |
Exit Exit |
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Hart L, Thigpen A, Willits N, Lyons L, Hertz-Picciotto I, Hart B. Affectionate Interactions of Cats with Children Having Autism Spectrum Disorder. FRONTIERS IN VETERINARY SCIENCE 2018;5(39). |
R835432 (Final) R829388 (Final) R833292 (Final) |
Exit |
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Hennebelle M, Morgan R, Sethi S, Zhang Z, Chen H, Grodzki A, Lein P, Taha A. Linoleic acid-derived metabolites constitute the majority of oxylipins in the rat pup brain and stimulate axonal growth in primary rat cortical neuron-glia co-cultures in a sex-dependent manner. JOURNAL OF NEUROCHEMISTRY 2020;152(2):195-207. |
R835432 (Final) |
Exit Exit |
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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) |
Exit Exit |
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Keil KP, Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? |
R835432 (2015) |
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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) |
Exit Exit |
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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) |
Exit |
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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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Kim D, Shin H, Bgang S, Barr D, Panuwet P, Schmidt R, Hertz-Picciotto I, Bennett D. Temporal Trends of Phenol, Paraben, and Triclocarban Exposure in California Pregnant Women during 2007-2014. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2021;55(16):11155-11165. |
R835432 (Final) |
Exit Exit |
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Kim D, Krakowiak P, Meltzer A, Hertz-Picciotto I, Van de Water J. Neonatal chemokine markers predict subsequent diagnosis of autism spectrum disorder and delayed development. BRAIN BEHAVIOR AND IMMUNITY 2022;100:121-133. |
R835432 (Final) |
Exit Exit |
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Kim K, Bennett D, Calafat A, Hertz-Piccioltto I, Shin H. Temporal trends and determinants of serum concentrations of per-and polyfluoroalkyl substances among Northern California mothers with a young child, 2009-2016. Enviornmenal Research 2020;186(109491). |
R835432 (Final) |
Exit Exit |
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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) R833292 (2012) |
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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 2017;81(5): 442-451. doi:10.1016/j.biopsych.2015.08.007. |
R835432 (2015) |
Exit |
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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) R835432 (2015) |
Exit Exit |
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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 2017;10(1): 89-98. doi: 10.1002/aur.1657 |
R835432 (2015) |
Exit |
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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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LaSalle JM. Autism genes keep turning up chromatin. OA Autism 2013;1(2):14. |
R835432 (2013) |
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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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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) |
Exit |
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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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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) R833292 (2012) |
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Lopez S, Dunaway K, Islam M, Mordaunt C, Ciernia A, Meguro-Horike M, Hornike S, Segal D, LaSalle J. UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons. EPIGENETICS 2017;12(11):982-990. |
R835432 (Final) |
Exit Exit |
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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) |
Exit Exit Exit |
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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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Lyall K, Ashwood P, Van de Water J, Hertz-Picciotto I. Maternal immune-mediated conditions, autism spectrum disorders, and developmental delay. Journal of Autism and Developmental Disorders 2014;44(7):1546-1555. |
R835432 (2013) R835432 (2014) |
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Lyall K, Van de Water J, Ashwood P, Hertz-Picciotto I. Asthma and allergies in children with autism spectrum disorders: results from the CHARGE Study. Autism Research 2015;8(5):567-574. |
R835432 (2014) R835432 (2015) |
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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) R835432 (2015) |
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Matelski L, Van de Water J. Risk factors in autism: thinking outside the brain. Journal of Autoimmunity 2016;67:1-7. |
R835432 (2015) |
Exit Exit |
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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) R835432 (2015) |
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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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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) R833292 (2012) R833292 (Final) |
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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. doi:10.1007/s10803-016-2913-3. |
R835432 (2015) |
Exit Exit |
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Oh J, Bennett D, Calafat A, Tancredi D, Roa D, Schmidt R, Hertz-Picciotto I, Shin H. Prenatal exposure to per-and polyfluoroalkyl substances in association with autism spectrum disorder in the MARBLES study. Enviornmenal International 2020;(106328). |
R835432 (Final) R829388 (Final) R829389 (Final) R833292 (Final) |
Exit Exit |
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Oh J, Shin H, Kannan K, Busgang S, Schmidt R, Schweitzer J, Hertz-Picciotto I, Bennett D. Childhood exposure to per- and polyfluoroalkyl substances and neurodevelopment in the CHARGE case-control study. ENVIRONMENTAL RESEARCH 2022;215(2):114322 |
R835432 (Final) |
Exit |
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Oh J, Bennett D, Tancredi D, Calafat A, Schmidt R, Hertz-Picciotto I, Shin H. Longitudinal Changes in Maternal Serum Concentrations of Per-and Polyfluoroalkyl Substances from Pregnancy to Two Years Postpartum. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022;56(16):11449-11459. |
R835432 (Final) R829388 (Final) |
Exit Exit |
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Oh J, Shin H, Kannan K, Calafat A, Schmidt R, Hertz-Picciotto I, Bennett D. Per- and Polyfluoroalkyl Substances (PFAS) in Serum of 2 to 5 year-Old Children: Temporal Trends, Determinants, and Correlations with Maternal PFAS Concentrations. ENVIRONEMTAL SCIENCE & TECHNOLOGY 2024;58(9):3151-3162 |
R835432 (Final) |
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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) R831540 (Final) |
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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) R829388 (Final) R833292 (Final) |
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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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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) |
Exit Exit Exit |
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Powell WT, LaSalle JM. Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment. Human Molecular Genetics 2015;24(R1):R1-R9. |
R835432 (2015) |
Exit Exit Exit |
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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) |
Exit Exit |
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Ramirez-Celis A, Edmiston E, Schauer J, Vu T, Van de Water J. Peptides of neuron specific enolase as potential ASD biomarkers:From discovery to epitope mapping. BRAIN BEHAVIOR AND IMMUNITY 2020;84:200-208. |
R835432 (Final) |
Exit Exit |
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Ramirez-Celis A, Becker M, Nuno M, Schauer J, Aghaeepour N, Van de Water J. Risk assessment analysis for maternal autoantibody-related autism MAR-ASD:a subtype of autism. MOLECULAR PSYCHIATRY 2021;26(5):1551-1560. |
R835432 (Final) |
Exit Exit |
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Ramirez-Celis A, Croen L, yoshida C, Alexeeff S, Schauer J, Yolken R, Ashwood P, Van de Water J. Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability. MOLECULAR PSYCHIATRY 2022;13(6):1098. |
R835432 (Final) |
Exit Exit |
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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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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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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) |
Exit |
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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) R829388 (Final) R833292 (Final) |
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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) R829388 (Final) R833292 (Final) |
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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) R829388 (Final) R833292 (Final) |
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Schroeder DI, LaSalle JM. How has the study of the human placenta aided our understanding of partially methylated genes? Epigenomics 2013;5(6):645-654. |
R835432 (2013) |
Exit Exit |
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Sethi S, Keil KP, Chen H, Hayakawa K, Li X, Lin Y, Lehmler HJ, Puschner B, Lein PJ. Detection of 3,3'-dichlorobiphenyl in human maternal plasma and its effects on axonal and dendritic growth in primary rat neurons. Toxicological Sciences 2017;158(2):401-411. |
R835432 (2017) |
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Sethi S, Keil K, Lein P. Species and sex differences in the morphogenic response of primary rodent neurons to 3, 3′-dichlorobiphenyl (PCB 11). Toxics 2018;6(1): 4. doi: 10.3390/toxics6010004 |
R835432 (2017) |
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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) R833292 (Final) |
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Shin H, Oh J, Kim K, Bgang S, Barr D, Panuwet P, Schmidt R, Hertz-Picciotto I, Bennett D. Variability of Urinary Concentrations of Phenols, Parabens, and Triclocarban during Pregnancy in First Morning Voids and Pooled Samples. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2021;55(23):16001-16010. |
R835432 (Final) |
Exit Exit |
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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. |
R835432 (2015) |
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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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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) |
Exit Exit |
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Van de Water J, Jones K, Silverman J, Yang M, Crawley J. Autism-Specific Maternal Autoantibodies Produce ASD Relevant Behaviors in a Moe Model. BIOLOGICAL PSYCHIATRY 2018;83(9):S147-S148. |
R835432 (Final) |
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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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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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Walter K, Lin Y, Kass P, Puschner B. Association of Polybrominated Diphenyl Ethers PBDEs and Polychlorinated Biphenyls PCBs with Hyperthyroidism in Domestic Felines, Sentinels for Thyroid Hormone Disruption. BMC VETERINARY RESEARCH 2017;13(120). |
R835432 (Final) |
Exit Exit |
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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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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) R833292 (Final) |
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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) |
Exit Exit |
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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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Zhu Y, Mordaunt CE, Yasui DH, Marathe R, Coulson R, Dunaway K, Walker C, Ozonoff S, Hertz-Picciotto I, Schmidt RJ, LaSalle JM. Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study. Human Molecular Genetics 2019;28(16):2659-2674 |
R835432 (Final) |
Exit Exit |
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Zhu Y, Gomez J, Laufer B, Mordaunt C, Mouat J, Soto D, Dennis M, Benke K, Bakulski K, Dou J, Marathe R, Jianu J, Williams L, Fugon O, Walker C, Ozonoff S, Daniels J, Grosvenor L, Volk H, Feinberg J, Fallin M, Hertz-Picciotto I, Schmidt R, Yasui D, LaSalle J. Placental methylome reveals a 22q13.33 brain regulatory gene loc associated with autism. GENOME BIOLOGY 2022;23(1):46-56 |
R835432 (Final) |
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Fritsch EB, Stegeman JJ, Goldstone JV, Nacci DE, Champlin D, Jayaraman S, Connon RE, Pessah IN. Expression and function of ryanodine receptor related pathways in PCB tolerant Atlantic killifish (Fundulus heteroclitus) from New Bedford Harbor, MA, USA. Aquatic Toxicology 2015;159:156-166. doi:10.1016/j.aquatox.2014.12.017. |
R835432 (Final) |
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Vogel Ciernia A, LaSalle JM. The landscape of DNA methylation amidst a perfect storm of autism etiologies. Nature Reviews Neuroscience 2016;17:411-23. doi:10.1038/nrn.2016.41. |
R835432 (2015) |
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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 (2015) R835432 (2016) |
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Meltzer A, Van de Water J. The role of the immune system in autism spectrum disorder. Neuropsychopharmacology 2017;42(1):284-298. doi:10.1038/npp.2016.158. |
R835432 (Final) |
Exit Exit |
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Onore C, Yang H, Van de Water J, Ashwood P. Dynamic Akt/mTOR signaling in children with autism spectrum disorder. Frontiers in Pediatrics 2017;5:43. |
R835432 (2016) |
Exit Exit |
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Sethi S, Morgan RK, Feng W, Lin Y, Li X, Luna C, Koch M, Bansal R, Duffel MW, Puschner B, Zoeller RT. Comparative analyses of the 12 most abundant PCB congeners detected in human maternal serum for activity at the thyroid hormone receptor and ryanodine receptor. Environmental science & technology 2019;53(7):3948-3958 |
R835432 (Final) |
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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. |
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Aschner M, Ceccatelli S, Daneshian M, Fritsche E, Hasiwa N, Hartung T, Hogberg HT, Leist M, Li A, Mundy WR, Padilla S. Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. Altex 2017;34(1):49. |
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Wong S, Giulivi C. Autism, mitochondria and polybrominated diphenyl ether exposure. CNS & Neurological Disorders-Drug Targets. 2016 May 1;15(5): 614-623. |
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Edmiston, Elizabeth; Ashwood, Paul; Van de Water, Judy . Biological psychiatry. 2017 Mar 01; Autoimmunity, Autoantibodies, and Autism Spectrum Disorder. |
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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. |
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Tylee DS, Hess JL, Quinn TP, Barve R, Huang H, Zhang‐James Y, Chang J, Stamova BS, Sharp FR, Hertz‐Picciotto I, Faraone SV. Blood transcriptomic comparison of individuals with and without autism spectrum disorder: a combined‐samples mega‐analysis. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2017;174(3): 181-201. |
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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. |
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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. |
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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. |
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Zhang R, Pessah IN. Divergent mechanisms leading to signaling dysfunction in embryonic muscle by bisphenol A and tetrabromobisphenol A. Molecular Pharmacology 2017;91(4): 428-436. |
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Vogel Ciernia A, Pride MC, Durbin-Johnson B, Noronha A, Chang A, Yasui DH, Crawley JN, LaSalle JM. Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering. Human Molecular Genetics 2017;26(10): 1839-1854. |
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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. |
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Keil KP, Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders?. Environmental Epigenetics 2016;2(1). |
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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. |
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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. |
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Matelski, Lauren; Van de Water, Judy. Journal of autoimmunity. 2016 Feb; Risk factors in autism:Thinking outside the brain. |
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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. |
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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. |
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Vogel Ciernia, Annie; LaSalle, Janine. Nature reviews. Neuroscience. 2016 07; The landscape of DNA methylation amid a perfect storm of autism aetiologies. |
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Bal-Price A, Lein PJ, Keil KP, Sethi S, Shafer T, Barenys M, Fritsche E, Sachana M, Meek MB. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. Neurotoxicology 2017;59: 240-55. |
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Sethi S, Chen X, Kass PH, Puschner B. Polychlorinated biphenyl and polybrominated diphenyl ether profiles in serum from cattle, sheep, and goats across California. Chemosphere 2017;181: 63-73. |
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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. |
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Wong S, Napoli E, Krakowiak P, Tassone F, Hertz-Picciotto I, Giulivi C. Role of p53, mitochondrial DNA deletions, and paternal age in autism: a case-control study. Pediatrics 2016;137(4): e20151888. |
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Dach K, Bendt F, Huebenthal U, Giersiefer S, Lein PJ, Heuer H, Fritsche E. BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action. Scientific Reports 2017;7: 44861. |
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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. |
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Chen H, Streifel KM, Singh V, Yang D, Mangini L, Wulff H, Lein PJ. From the cover: BDE-47 and BDE-49 inhibit axonal growth in primary rat hippocampal neuron-glia co-cultures via ryanodine receptor-dependent mechanisms. Toxicological Sciences 2017;156(2): 375-386. |
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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. |
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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. |
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Wilson MD, Sethi S, Lein PJ, Keil KP. Valid statistical approaches for analyzing sholl data: Mixed effects versus simple linear models. Journal of Neuroscience Methods 2017;279: 33-43. |
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Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2017 Progress Report
- 2016 Progress Report
- 2014 Progress Report
- 2013 Progress Report
- Original Abstract
134 journal articles for this center