Final Report: Center for the Study of Environmental Factors in the Etiology of Autism

EPA Grant Number: R829388
Center: CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism
Center Director: Pessah, Isaac N.
Title: Center for the Study of Environmental Factors in the Etiology of Autism
Investigators: Pessah, Isaac N.
Institution: University of California - Davis
EPA Project Officer: Fields, Nigel
Project Period: November 1, 2001 through October 31, 2006
Project Amount: $7,325,232
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Human Health , Health

Objective:

The principal concern of the UC Davis Center for Children’s Environmental Health (CCEH) is to identify and understand environmental, immunologic, and genetic risk factors contributing to the incidence and severity of childhood autism. Autism is a heterogeneous neurodevelopmental disorder defined by core deficits in social reciprocity, communication, and restrictive/repetitive patterns of interest and behavior (American Psychiatric Association, 2000). Generally accepted estimates of prevalence range from 1:750 for the narrowest diagnostic criteria, to 1:166 for autism spectrum disorder (ASD) (Fombonne 2003). The California Department of Developmental Services records on average approximately 700-750 autism diagnoses each quarter (DDS Report, 2005). Although autism may be one of the most heritable complex disorders (Veenstra-VanderWeele et al. 2004; Wassink and Piven 2000), the defective genes conferring autism risk do not segregate in a simple Mendelian manner (Pickles et al. 1995). The prevalence of autism is approximately four times higher in males than in females. Results from over ten genome-wide autism screens indicate that potential susceptibility genes are spread across the entire genome. Estimates of the number of genes involved in autism range from 3-10 (Pickles et al. 1995; Folstein and Rosen-Sheidley 2001) to 15 (Risch et al. 1999) and up to 100 (Pritchard 2001). However no single locus alone appears to be sufficient to cause the full clinical phenotype (Trikalinos et al. 2005; Maestrini et al. 2000). Evaluation of a broader autistic phenotype that included communication and social disorders increased concordance from 60% to 92% in monozygotic twins and from 0% to 10% in dizygotic pairs (Muhle et al. 2004). These results indicate that interactions among multiple genes are likely to contribute to autism, and that epigenetic factors and exposure to environmental modifiers may contribute significantly to variable expression of autism, and autism-related traits.

The mission of the CCEH is to promote daily interactions among a multidisciplinary team of scientists whose main research interest is to understand the complex web of etiologic factors that contribute to autism. The shared philosophy among Center participants is that a better understanding of the immunological and neurobiological mechanisms associated with this neurodevelopmental disorder can not only lead to a better understanding of the mechanisms that influence it but can also accelerate the discovery of effective intervention strategies. Since it is generally accepted that the earlier an intervention is begun in autistic children, the greater the chances of improvement, an intervention that can be implemented before symptoms have fully manifested should have the strongest impact in reducing severity and potentially even preventing some cases. Thus, early markers of risk are needed to identify children who are at risk. These may include behavioral, environmental, physiologic, biochemical, and genomic markers, and those based on morphological and neuroimaging parameters.

Summary/Accomplishments (Outputs/Outcomes):

Project 1: The CHARGE Study

Specific Aim 1: To determine eligibility and establish protocols for recruitment and data collection for the CHARGE Study.

Project Overview. The CHARGE study enrolled over 500 children from three groups: with autism, with developmental delay but not autism, and from the general population. Inclusion criteria were: aged 24-60 months; born in California; living with at least one biologic parent; having an English- or Spanish-speaking parent; and residing within our catchment area (approximately 1.5 hour drive from Sacramento).

Children with autism (AU) or with developmental delay (DD) were recruited through Regional Centers mandated by the State of California to administer services for persons with disabilities. Children with milder developmental disorders, such as Asperger’s, were not generally eligible for such services, and therefore were not actively recruited into the CHARGE study. Children from the general population (GP) were identified from birth files, frequency-matched for age and gender to the autism case group. Children with developmental delay were not matched.

Each child with autism was assessed by trained staff using both the ADOS (Autism Diagnostic Observation Scale) and the ADI-R (Autism Diagnostic Inventory-Revised). The ADOS is a structured observational assessment of the child, measuring social and communicative behaviors diagnostic of autism. The ADI-R is a structured parent interview that assesses social, communicative and repetitive behavior symptoms of autism. Parents of children from the general population and children with developmental delay were interviewed with the Social Communication Questionnaire to screen for possible symptoms of autism and then followed up with the ADOS and ADI-R if the child’s score was above the accepted cut-off.

For all children, an extensive exposure questionnaire was administered to the mother. This questionnaire collects information on demographics, mother’s pregnancy history, mother’s medical history, fertility and use of assisted reproductive technology, occupational and residential information, dietary exposures of concern, other lifestyle factors and household product use. Additionally, all children were evaluated for cognitive function using the Mullen Scales of Early Learning and for adaptive function using the Vineland Adaptive Behavior Scales. Other forms collected information about sleep patterns, GI problems, family characteristics, loss of social or language skills, use of multiple languages at home, family history of auto-immune disorders, and services and treatments obtained. The child also ws given a medical examination, and the mother was asked to list health care providers and their contact information so we could obtain medical records for her prenatal care, the labor and delivery, and the child’s neonatal and pediatric care. Blood, urine and hair specimens were collected from all children, as well as blood and urine from mothers, fathers, and siblings, if possible. Hair was collected from mothers if long enough to reflect the pregnancy or perinatal period. The parent was asked to provide a few strands of the baby locks (first haircut) if available. Below we report on recruitment, data collection, description of the study population, and results from immunology studies, genomics, metal assays, and co-morbidities.

Specific Aim 2. Recruitment and field work accomplishments

Project Overview. Recruitment began in the fall of 2003. Over 500 children aged 2-5 years were enrolled. Clinical assessments have been conducted on 466 children; blood specimens were collected from 391 index children, 399 mothers, 267 fathers, and 227 siblings; urine specimens on 374 index children, 400 mothers, 316 fathers and 356 siblings; and hair specimens on 312 index children and 283 mothers. Baby locks (first haircut) have been collected on ~100 index children (these were initiated more than a year after recruitment started and not all mothers save them). An exposure interview of 1½ hours in length has been completed on over 443 families. Data entry of all instruments is ongoing. Over 350 psychometric examinations are in the ISAAC (Internet System for Assessing Autistic Children) electronic database, and 200 exposure interviews have been entered into our in-house system. Specimens are also tracked electronically.

Among general population (GP) controls, we have attempted to contact 1,063 families that were selected by stratified random sampling (using a frequency match to cases on age and gender) within the catchment area of the study. Of these, 45% were not reached (they may have moved, we had wrong numbers, or they did not pick up the phone). Of the remaining 585, 22% were not eligible (did not speak either English or Spanish, child not living with a biological parent, child died, family moved too far away), 41% refused, and 36% agreed to participate. Among cases (AU or DD) identified through Regional Centers, we attempted contact with 586, of whom 9% could not be reached. Of the remaining 533, 20% were not eligible, 22% refused, and 58% agreed to participate. Currently, approximately 15-20 families complete the protocol each month and to date, the parent clinical component has been completed for 347 AU cases, 100 GP controls and 54 DD children. With 9 remaining months, and ~20 recruits per month, we expect 650-700 participants by the end of the first funding period. The recruitment of controls began half a year later than cases due to IRB and personnel issues.

Specific Aim 3. To describe the study population

Project Overview.

Table 1 shows the characteristics of the CHARGE children and their parents. The children were, on average about 3 years of age at entry into the study; 88% of the autism group was male (GP’s were selected at 80% probability to be male). Mothers of children with autism (AU) were less likely to be Hispanic or black and more likely to have completed a college degree than those of DD or GP children. GP mothers were more likely to be married or living with their partner. Autoimmune disorders were slightly less prevalent in mothers of GP children. AU children were more likely to be reported as having frequent bloating or sensitivities to foods; both AU and DD children were reported to have frequent other GI problems.

Figure.

Specific Aim 4. To analyze blood specimens from CHARGE children for a variety of immune system functional markers.

Project Overview. Humoral immune response: Using plasma specimens from the CHARGE study children, a significantly lower IgG response to the bacterial vaccine antigen Bordatella pertussis was observed in those with autism compared with general population controls. Similar results were seen for Tetanus and Diptheria. All patients included in this study had received the DTaP vaccine as scheduled.

Detection of autoantibodies: When plasma from CHARGE children was used to detect auto-antibodies to brain antigens by immunoblot, several bands were noted in the autism group but not general population controls. Similarly, immuno-histochemical analysis was used to detect antibodies to cerebellum from a Rhesus monkey in the plasma of autistic children. Intense staining was noted in the Purkinje layer in what appear to be golgi cells.

Figure 1.
Figure 1. Leptin concentrations in children with autism are significantly higher than in general population controls, in children with developmental delay and in siblings.

Assessment of cytokine profile: Plasma leptin levels were measured and found to be significantly higher in children with autism (p<0.016) as compared with controls from the general population, controls with developmental delay, or siblings of children with autism (Figure 1). The increased plasma leptin in children with autism was driven predominantly by children with an early onset phenotype. This finding provides possibly the first evidence of a biologic distinction between those children with early onset disease and those who develop and then lose language and social skills.

Following PHA stimulation, the T cell cytokine response was significantly different in 27 children with autism as compared with 25 from the general population (see Project 2), based on Luminex analysis (*p≤0.05); children with autism showed higher GM-CSF and IL-13 responses and reduced IL-12, IL-10, IL-2 and IL-1b . Following stimulation with tetanus, production of all cytokines was lower in those subjects with autism.

In summary, immune studies illustrate that children with autism have reduced plasma IgG, IgM and IgA, a sub-optimal response to bacterial vaccine antigens, increased plasma leptin (especially in the early onset cases) an altered T cell cytokine response following stimulation with PHA or tetanus, and production of autoantibodies to neuronal self-antigens in some children. These results suggest that the immune dysfunction noted in these subjects may play a role in the pathology of autism.

Specific Aim 5. To assess phenotypic subtypes and to characterize phenotypic variation.

Project Overview. In collaboration with Dr. Jeff Gregg and Dr. Frank Sharp, blood specimens from CHARGE study children were analyzed for gene expression profiles. Children with autism (AU) were compared with those from the general population (GP). Children with autism who had regression of language and/or social skills were also compared to those with early onset autism. Initial analysis using a variety of statistical approaches to clustering yielded significant numbers of differentially regulated genes, with clusters that distinguished AU children with regression from GP children, and another set of genes that distinguished early onset AU children from GP’s. These two contrasts shared 12 genes that were differentially expressed in children with both types of autism as compared with children in the GP group. These genes were highly expressed by natural killer cells and CD8 cells. If validated in a second set of subjects, the findings may point to causative genes that affect signaling in NK and CD8 cells. If these genes also lead to abnormalities in signaling pathways relevant in brain development and function, they may provide a clue about underlying mechanisms of pathogenesis in autism. Changes in gene expression may also represent the effect of some environmental factor(s), a manifestation of an autoimmune disease or a genetic abnormality associated with the propensity for autoimmunity. On the other hand, it is also possible that differential expression may be a result of the disorder with no role in pathogenesis. We are currently testing another set of AU and GP participants to determine if the genes that differentiate the case groups in the first analysis can be replicated. This work will take place in year 5 of the current funding period. Should the results be robust, further mechanistic studies can be undertaken in Projects 2 and 3 (Immunology and Animal Models). Investigation of the stability of gene expression in CHARGE study children will be carried out by Core 4 in the second funding period; also, gene expression during pregnancy in mothers of children who do vs. do not develop autism and in the newborns at birth will be conducted by Core 4.

Specific Aim 6. To examine the association between the risk of autim and the concentration of mercury or other metals in blood.

Project Overview. Preliminary results from metal analyses. Blood concentrations of metals in 325 children were determined using ICP/MS (Inductively Coupled Plasma/Mass Spectrometry). The distribution was highly skewed with a long right tail, and the values were therefore log-transformed. The geometric mean (GM) concentration of Hg from 325 whole blood samples of the 2-5 year old children was 0.22 mg/L, with a geometric standard deviation (GSD) of 3.76 and 90th percentile of 1.16, comparable to NHANES data [138]. Similarly, for Pb, the GM was 1.14 mg/dL, with a GSD of 1.77 and 90th percentile of 2.36. The distributions were similar between AU children (n = 230, GM = 0.21, GSD = 3.83), and GP controls (n=56, GM = 0.25, GSD = 3.63). These results are plotted below (Figure 2). Because current circulating Hg represents a rather recent exposure, measurements taken earlier in life could be potentially more relevant etiologically.

Figure 2.
Figure 2. Distribution of blood mercury levels in CHARGE children, comparing four groups: regressive autism, autism of early onset, general population controls and developmentally delayed children.

Specific Aim 6. To assess prenatal, perinatal, and neonatal risk factors in childhood autism.

Project Overview. Researchers examined several obstetric and neonatal risk factors for autism in a study of children born in Kaiser Permanente Northern California hospitals. Children with autism spectrum disorders (ASD N=420) and randomly selected controls (N=2100), born 1995-1999 were included. Information on autism status and risk factors was ascertained from electronic KPNC clinical databases, a review of prenatal and labor/delivery medical records, and electronic birth files. Maternal psoriasis, asthma, and allergy diagnosed around the time of pregnancy were significantly associated with an increased risk of autism. Major structural congenital anomalies, especially gastrointestinal anomalies, occurred significantly more often in children later diagnosed with autism [139] and children with autism were more likely to experience neonatal gastrointestinal infections in the first two years of life.

Specific Aim 7. To identify early signs of autism.

Project Overview. Infants at Risk of Autism: A Longitudinal Study, R01-MH068398 (Ozonoff, PI) was carried out at the MIND. 180 infant siblings of children with autism and 90 infant siblings of children with typical development were compared on a task battery that includes some of the same tasks proposed for use in the proposed MARBLES study. Testing occured at 6, 12, 18, 30 and 42 months of age. The goal of the study was to intensively track early social, communication, cognitive, and motor development and to identify the earliest signs of autism and the broader autism phenotype. 259 infants have been recruited and tested longitudinally, with the largest cohort reaching the 18 month evaluation. Of the 57 infants in the autism sibling group who are 18 months and older, 8 are over the autism threshold on the Autism Diagnostic Observation Scale (a firm diagnosis of autism is usually made after age 3), with an additional 11 showing some signs of autism, but not the full picture, and 16 demonstrating language delays. Although some children may look less affected over time, others may develop more symptoms. This work demonstrates that the measures used in this battery are sensitive enough to identify a strong likelihood of autism or language delays in over half of the affected infants by 12-months; it also supports the assumption of a minimum of 10% incidence. This work also demonstrates feasibility of recruiting from the target group for the MARBLES study.

Project 2: Immunological Susceptibility in Autism

Specific Aim 1. To perform longitudinal serologic analyses.

Project Overview. Humoral immune response. Findings in our laboratory demonstrated reduced plasma levels of IgG, IgM, and IgA in patients with autism (Table 1). Moreover, patients often demonstratde a sub-optimal or negative response to bacterial vaccine antigens.

Table 1: Immunoglobulin levels in patients with autism.

Immunoglobulin
(mg/ml)

Autism
(n=114)

General Population
(n=100)

Siblings
(n=57)

MR/DD Disease Controls
(n=25)

Total IgA

5.25 ± .0382

9.15* ± 0.61

7.81* ± 1.06

7.90* ± 1.53

Total IgG

7.82 ± 0.34

10.24*# ± 0.57

7.83 ± 0.57

10.35* ± 1.63

Total IgM

0.94 ± 0.07

1.49* ± 0.12

1.24 ± 0.20

1.13 ± 0.19

Total IgE (IU/mL)

52.49 ± 10.1

114.44 ± 27.10

68.14 ± 22.50

47.42 ± 12.60

0.004* compared to patients with autism; # compared with siblings

Using plasma specimens from the CHARGE study children, a significantly lower IgG response to the bacterial vaccine antigen Bordatella pertussis was observed in those with autism compared with general population controls (Table 2).

Table 2: IgG Response to Bacterial Vaccine Antigens in Children With Autism

Antigen

Autism
(n=114)

General Population
(n=100)

Siblings
(n=57)

MR/DD
(n=25)

         

Diptheria

0.28 ± 0.09

0.47 ± 0.06*

0.57 ± 0.03*

0.68 ± 0.18*

Tetanus

0.46 ± 0.12

0.90 ± 0.14*

1.82 ± 0.63*

2.15 ± 0.80*

Bordetella

5.58 ± 0.84

10.50 ± 1.79*

16.46 ± 3.52*

16.18 ± 4.32*

p<0.004* compared to patients with autism Similar results were seen for Tetanus and Diptheria. All patients included in this study had received the DTaP vaccine as scheduled.

Plasma cytokine levels in autism. In initial studies of plasma from CHARGE children, 18 plasma cytokines and chemokines were assessed in autism (n= 40; red) and general population (GP) controls (n= 40; blue) using Luminex multiplex technology (Figure 1).

Fig. 1.

Fig. 2.

Predominantly cytokine/chemokine levels were similar between cases and controls; however, statistically significant differences between autism and general population controls were observed for the potent pro-inflammatory cytokine IL-6, which also affects neurodevelopment, and the chemokine eotaxin (*p<0.05). Similarly, the chemokine RANTES, regulated upon activation normal T cell expressed and secreted, was elevated in plasma samples from children with autism (n=40) compared with GP (n=40), sibling, and developmental disability (DD) control groups (p<0.05, Figure 2).

Fig. 3.
Fig. 3: Patterns of cytokine expression are significantly different between two clinical phenotypes of autism, early onset (blue) and regression (red). Children (2-5 years) were diagnosed by CHARGE clinicians.

In a similar study, samples were analyzed by Luminex multiplex analysis from two distinct clinically behavioral phenotypes as defined above, namely those reported with autism and clinical regression, or the loss of existing language (regression), and those that did not regress (classic/early onset). Patterns of cytokine expression were different between the two behavioral distinct autism phenotypes (Figure 3). In children with regressive autism (n=20), plasma cytokine levels were generally significantly increased compared with the early onset autism group (n=20)(* p<0.05). The cytokine profiles in the two autism groups were substantially different from one another and may indicate the potential use of cytokine measurements in aiding the identification of distinct behavioral autism phenotypes.

TGFb1 levels in autism. The regulatory cytokine transforming growth factor beta -1 (TGFb1) was measured in supernatant plasma samples from autism (n=75), general population (n=36), siblings of autism (n=28), and children with developmental disabilities but not autism (n=32) by specific ELISA. Activated TGFb1 levels were decreased in autism compared with general population (p=0.011) and developmental disability controls (p=0.012) but not sibling controls (Figure 4). When levels were compared between distinct clinically behavioral phenotypes based on regression, no differences were noted. TGFb1 is a key regulator of the immune response. It has widespread actions on the modification and regulatory control of the immune response. Abnormalities of TGFb1 in autism may indicate that there is insufficient and inappropriate control of immune responses that could lead to an imbalanced response and inflammation. The fact that the profile was similar in both behavioral autism groups may suggest a critical role for TGFb1 in the broader phenotype of autism.

Fig. 4.
Fig. 4: Patterns of TGFb1 expression among diagnostic groups enrolled in the CHARGE study.

Leptin. Plasma leptin levels were measured and found to be significantly higher in children with autism (p<0.016) compared with those from the general population, those with developmental delay, or siblings of children with autism (see Figure 5). We further classified children with autism by their developmental pattern as cases with regression (achieved language and social skills but lost them) or early onset autism. The early onset autism group differed significantly from all other groups combined (p<0.026), general population controls only (p<0.0024), or developmentally delayed children (p<0.007). The increased levels of plasma leptin in children with autism was driven predominantly by children with an early onset phenotype. This finding provides evidence of a biologic distinction between those children with early onset disease and those who develop and then lose language and social skills.

Figure.

Specific Aim 2. To analyze the patterns of peripheral blood cell surface marker expression following stimulation/activation.

Project Overview. T cell phenotyping following cellular activation. Preliminary T cell phenotyping studies were performed on 15 patients with autism and 12 typically developing controls using markers for activation expressed on CD3+ T lymphocytes. Cell surface markers of activation including CD25 (IL-2 receptor), CD134 (OX40), and CD137 (4-1BB) were detected by multi-color flow cytometry on the surface of peripheral CD3+ T cells following PHA stimulation. Mononuclear cells were isolated from cases and controls and stimulated for 24 hours in the presence of PHA (10 mg/mL). Following stimulation, T cells were prepared for multi-color flow cytometry analysis. In children with autism, there were decreased numbers of activated CD3+ cell subsets that expressed the cell surface markers CD25 (p=0.004), CD134 (p=0.005), and CD137 (p=0.002) compared with general population controls (Figure 6).

Figure.

These data indicate that patients with autism have reduced numbers of activated CD3+ T cells following mitogen stimulation, which is in concordance with our other T cell findings.

Assessment of cellular cytokine profile. In a non-challenged milieu, the cells from autistic children may behave similarly to those from typically developing normals, but when challenged there may be totally inappropriate and divergent immune responses and elicited cytokine profiles compared with neurotypical controls. In a further study, we measured cytokine production following stimulation in autistic children (n=27) and typically developing age-matched controls (n=25) (Figure 7). Supernatants from cultured peripheral blood mononuclear cells (PBMC) challenged with either mitogen (PHA) or bacterial recall antigen (tetanus toxoid) were assessed using Luminex multiplex analysis. Cytokine responses following PHA stimulation were significantly different between autism cases and controls, with increased levels of GM-CSF and IL-13 and decreased production of IL-12, IL-10, IL-2, and IL-1b in autistic children (Figure 7). Following stimulation with tetanus, there was a surprising decrease in the production of all cytokines in the autism group compared with neurotypical controls. These data illustrate that responses to both antigen-specific and mitogenic stimulation is significantly different between autism cases and neurotypical controls. Also of interest is the differential response noted in autism to two very different exogenous stimuli. Further study of this response and the mechanisms that manifest these differences will be critical to analyze the immune status of children with autism.

Figure.

Specific Aim 3. To identify the differential functional response of peripheral blood cells from autistic children in the presence of low levels of MeHg, PCB95, and BDE47.

Project Overview. In vitro dose-range experiments. In a dose range experiment, we incubated adult peripheral blood mononuclear cells with 0.1 and 1.0 μM concentrations of PCB95 and PBDE47 with and without mitogen stimulation. These studies were performed to establish a working range for our CHARGE-BACK pediatric samples. Figure 8 demonstrates the effects of both PCB95 and PDBE47 on cell proliferation. The data is presented as percent change compared to cells receiving media, PHA, or LPS but no xenobiotic exposure. Interestingly, in naïve cells receiving no stimulation, both PBC 95 and PBDE47 demonstrated a stimulatory effect. However, when the T cell population stimulated by PHA following pre-incubation with 1.0 μM PCB95, there was a negative affect on proliferation. Of great interest was the enhancing effect of both xenobiotics at all concentrations with the cells were subsequently stimulated with LPS, a mitogen that stimulates both B cells and monocyte/macrophages.This finding is paralleled by our result in Table 2 found in Project 3 where splenocytes from mice perinatally exposed to PCB95 demonstrate an exaggerated proliferative response to LPS. This preliminary study provides the template for our future studies regarding Aim 2.3 and the differential analysis of in vitro exposure of PMBCs from patients with autism to MeHg, PCB95, and BDE47.

Figure.

It is now known that some cytokines, such as IL-4, have an effect on cell signaling through an RyR1 dependent mechanism (Ethier et al. 2005; Madison and Ethier 2001). For instance, it was recently shown that IL-4 decreases intracellular calcium stores by mechanisms dependent on RyR, but not on cADPR signaling (Ethier and Madison 2005). Thus, our previous work in RyR signaling in the immune system has particular relevance when taken in the context of the changes noted in some plasma cytokine levels in children with autism compared to controls.

Detection of Ryanodine (RyR) and Inositol 1,4,5 trisphosphate (IP3R) receptor calcium (Ca2+) channels in Murine Dendritic Cells. The RyR and IP3R intracellular Ca2+ channels are known targets of mercury and PCBs/PBDEs (RyR). We stained cultured bone marrow-derived dendritic cells (DCs) with antibodies to the RyR and IP3R and found that immature DCs (IDCs) express IP3Rs in a dense granular distribution, with an overall expression pattern consistent with general targeting to ER membranes (Figure 9). In sharp contrast, intense staining for RyR1 localizes to regions very near the plasma membrane, and discrete foci of protein extend from the base into dendrites. Monocytes from human PBMC express the RyR and IP3R microsomal Ca2+ channels and exhibit staining patterns similar to what we found in murine IDC.

Figure 9.
Figure 9. Expression of RyR (red) and IP3R (green) calcium channels in DCs.

Organic Mercury Dysregulates Ca2+ Signaling. DCs generate a vigorous Ca2+ transient to a 5 s application of extracellular ATP, and the response amplitude is dose dependent between 0.2 and 20 μM (not shown). IDCs were pre-incubated 5 min with either 100 nM MeHgCl or 100 nM thimerosal (THI), and Ca2+ transients elicited by a 5 s puff of ATP (20 μM). Control buffer-treated IDCs respond to ATP with a stereotyped Ca2+ transient (Figure 10, bottom trace). In contrast, DC treated with MeHgCl or THI shortened the duration of the Ca2+ transient and produced a delayed rise in Ca2+ baseline. In vivo ATP steady state levels are nano- and low micro-molar (1-25 μM) concentrations in bulk fluids and at the cell surface respectively. At these agonist concentrations, metabotropic G-protein-coupled P2Y purinergic receptors are engaged. P2Y receptors couple to G(q) protein that initiates signal transduction events leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to IP3 and diacylglycerol. IP3 in turn activates IP3R that mobilizes Ca2+ from ER stores.

Figure 10.
Figure 10. Organic mercury dysregulates calcium signals in DCs.

Organic Mercury disrupts IL-6 secretion by Immature DCs. DCs produce IL-6 in response to IL-1, TNF-α, or LPS, and other myeloid cells secrete IL-6 in response to ATP (Shigemoto-Mogami et al. 2001). We hypothesized that THI-induced uncoupling of ATP-mediated Ca2+ signaling would disrupt IL-6 secretion.We pretreated IDCs with 100 nM THI or the control thiosalicilate (TSA) (20 min) then challenged the cells with graded concentrations of ATP and measured the secreted IL-6 at 20 h. In Figure 11A, IDCs pretreated with THI or TSA alone secreted low levels of IL-6 that did not significantly differ from the medium control. LPS, which induces IL-6 synthesis in myeloid cells by non-Ca2+ dependent pathways, induced a large increase in IL-6. All three ATP concentrations induced secretion of comparable amounts of IL-6 by the TSA-pretreated DCs, and by 20 h, these concentrations were equal to the LPS-treated control. IDCs pretreated with 100 nM THI and challenged with ATP showed attenuated IL-6 secretion compared to TSA-pretreated cells, reaching statistical significance at the lowest (0.2 μM) ATP dose.

We examined the kinetics of IL-6 secretion in the THI-treated DC challenged with 2 μM ATP to determine if attenuation of cytokine production had occurred in earlier time points. DC treated with 2 μM ATP secreted measurable IL-6 by 4 h, consistent with its rapid induction in other myeloid cells. THI pretreatment accelerated the course of IL-6 secretion compared to TSA-pretreated controls, indicating THI sensitized DC to ATP. THI-pretreated DCs secreted maximal IL-6 by 8 h where an additional 12 h was needed by controls to achieve the same concentration. The lowered IL-6 secretion by THI-treated IDCs challenged with 0.2 μM ATP was not due to cell death, as this attenuation was overcome using 2 μM (Figure 11B) and 20 μM (not shown) ATP, and a 20 h exposure to 100 nM THI or ethylmercury (EtHgCl) did not induce significant cell death (Figure 12).

Using bone marrow-derived DCs (BMDCs) as a model, low concentrations of methyl- and ethyl- mercury rapidly disrupt intracellular Ca2+ signaling. A brief THI exposure leads to dysregulated IL-6 secretion when IL-6 secretion is elicted through a Ca2+-dependent mechanism. Organic mercurials may exert their toxic effects by targeting Ca2+ channels that are ubiquitously expressed in PBMC.

Figure 11.
Figure 11A. THI inhibits the accumulation

Figure 11.
Figure 11B. THI accelerates the early

Organic mercury disrupts the generation of surface class II MHC/peptide complexes.

Figure 12.
Figure 12. Dose-response viability curves for DCs treated 20 h with thimerosal (THI), ethylmercuric chloride (EtHgCl) or thiosalicylic acid (TSA).

Presenting antigen to T cells is the primary task of DCs, and we tested whether prolonged treatment of mature DCs (MDCs) with organic mercury (as THI) would affect their antigen-presenting capacity. MDCs were cultured 20 h in medium or with 100 nM THI, then pulsed with biotinylated ovalbumin peptide 323-339 (OVA323-339; 20 μM) in the presence or absence of 10X unlabeled OVA323-339 (10X unlabeled peptide). After peptide pulsing, DC were stained with streptavidin-PE and analyzed by flow cytometry. Figure 13, below, shows that after 20 h exposure to THI, DCs bind more labeled peptide (THI). This increased binding is explained by the appearance on the cell surface of THI-treated DC of empty surface MHC class II or class II MHC with low affinity peptide. This finding indicates that defective antigen processing and/or presentation is induced after exposure to organic mercury.

Figure 13.
Figure 13. MDCs treated 20 h with 100 nM THI (filled area) generate more empty/low affinity peptide bound surface class II MHC complexes.

Chronic low dose organic mercury exposure induces the expression of empty/low affinity peptide/class II MHC complexes on mature DC.

Figure 14.

Specific Aim 5. What is the identity of the antigens recognized by plasma from some children with autism?

Project Overview.
Autoantibodies to brain in children with autism. Autoantibodies to neuronal self-antigens have been reported in some patients with autism. The presence of antibodies reactive to CNS proteins in the sera of autistic children has suggested neuroimmune pathology for this disorder. Comparative analysis of data from small representative groups of patients shows that about 30-70% of autistic patients have anti-brain autoantibodies (van Gent et al. 1997), including autoantibodies to a serotonin receptor (Todd et al. 1988), alpha-2-adrenergic binding sites (Cook et al. 1993), myelin basic protein (Singh et al. 1993), neuron-axon filament protein (Singh et al. 1997), and nerve growth factor (Kozlovskaia et al. 2000). When plasma from CHARGE children was used to detect autoantibodies to human brain antigens by immunoblot, several bands were noted in the autism group but not general population controls. Similarly, immunohistochemical analysis was used to detect antibodies in the plasma of autistic children to cerebellum from a Rhesus monkey. Intense staining was noted in the Purkinje layer in what appear to be golgi cells (Figure 14). Also shown in Figure 14 is a representative Western blot of adult human cerebellum probed with plasma from subjects with autism (A and B) and a typically developing control (C). Interestingly, subjects that produce the band noted by the arrow in Lane A also exhibit cerebellar staining by immunohistochemistry. The incidence for cerebellar staining is noted in Table 3. Currently, approximately 42% of patients possess autoantibodies to the cerebellum. This staining pattern appears to be disease-specific and incidence is equally distributed between both the early and late onset phenotypes.

Table 3: Incidence of autoantibodies to cerebellum in patients with autism compared to general population and MR/DD controls.

 

Cerebellar Staining (golgi cell)

Cerebral Cortex Staining

Occipital Lobe Staining

 
 
 
 

Patients

11/26 (42%)

5/26 (19%)

4/26 (15%)

Controls

2/14 (14%)*

1/14 (7%)

1/14(7%)

Siblings of Patients

1/5 (20%)

0/5 (0%)

0/5 (0%)

MR/DD

0/10 (0%)

0/10 (0%)

0/10(0%)

Figure.

Note that the general population control that exhibited staining in all three regions of the brain was eventually diagnosed with autism.

Specific Aim 6. What is the identity of the fetal brain antigens recognized by some mothers of children with autism. Are these autoantibodies pathogenic? Isolate IgG from sera of mothers that have an autistic child and those who do not for testing in a developmental model of autism.

Project Overview. Maternal autoantibodies to fetal brain. Thus far, we have examined samples from 83 unrelated subjects obtained in the CHARGE study. These include mothers of children with autism (AU), mothers of children with developmental delay (DD), and mothers of children with typical development (Figure 15). To date, the data suggest that there are bands recognized by the plasma from the mothers of autistic children when compared with the mothers of typically developing children and that differ from the DD controls. While the preliminary data show that autoantibodies are not present in 100% of mothers with children who have autism, they may help to define a subphenotype of cases within the broader spectrum of autistic patients. Of greater interest is the preliminary study using plasma from mothers with bands in the MW range between 50 and 70 Kd to induce behavioral changes in Rhesus macaques. This study suggests a pathologic role for in utero exposure to autoantibodies specific for some fetal brain antigens. Clearly, further studies are needed to determine (a) the frequency of reactivity to fetal brain tissue as well as adult brain and (b), the potential role of these autoantibodies in the generation of a behavioral model of autism.

Figure 15.
Figure 15. Western blot analysis of human fetal brain probed with plasma from mothers of children with autism shows bands in the autism group but not the controls (where C1,2 and 3 are control plasma and the remainder are from the autism group).

Project 3: Models of Neurodevelopmental Susceptibility

Specific Aim 1. To assess if mice exposed to PCB 95 perinatally show increased infant ultrasonic vocalization, increased locomotor activity, and fail to show social transfer of food preference.

Project Overview. PregnantC57BL/6J mice were exposed to PCB 95 (6 mg/kg/day) from E5 until weaning and the offspring tested for ultrasonic vocalization on postnatal days 8, 12 and 15. As shown in Figure 2A. PCB exposed mice showed increased vocalization (p<0.05) across days compared to controls, indicating increased distress following separation from their litter. The same animals showed increased locomotor activity over a 2 hr period as shown in Figure 2B. In a test of social interaction (Fig. 2C), PCB exposed mice failed to show social transfer of food preference compared to controls, suggesting impairment in social communication.. These data demonstrate pervasive developmental behavioral impairments from PCB 95 ranging from motor to complex social behaviors, and provide support for Specific Aim 1.1.

Figure 2: Perinatal PCB 95 exposure results in (A) increased infant ultrasonic vocalization, (B) increased locomotor activity, and (C) failure to show social transfer of food preference.

Figure 2.

Postnatal exposure to ethylmercury in thimerosal alters locomotor behavior in SJL/J, but not C57BL/6J mice.
We reported (International Neurotoxicology Conference, RTP, NC 2005) that low-level (i.e., 50μg/kg total over four s.c. injections) postnatal (PDs 7, 9, 11 & 15) exposure to ethylmercury in the form of thimerosal did not impair motor, sensory or social behaviors in C57BL/6J mice. In contrast, our preliminary data in SJL/J mice indicated nearly the identical ethylmercury exposure procedures (39.8 μg/kg over four s.c. injections) reduced exploratory behavior (data not shown). These data strongly suggest that SJL/J mice react differently than C57BL/6J mice, supporting our initial hypothesis that susceptibility to autoimmunity (i.e., SJL/J mice) may be associated with increased mercury toxicity.

Perinatal exposure to non-coplanar PCB congeners alters expression of RyRs: As shown in Fig. 3A (western blot) and Fig. 3B (RyR1&2 expression as % of Control), we recently found that developmental exposure to 1 or 6 mg/kg/day Aroclor 1254 increases basal levels of RyR1 and RyR2 expression in the developing rat cerebella compared to vehicle controls. Shown in Fig 3C, water maze training increased expression of RyR1 and RyR2 in vehicle controls. However Aroclor exposure reversed the water maze activity-induced increase in RyR1 expression, but not RyR2 expression. Maze training also increased dendritic complexity and this was reversed by developmental exposure to Aroclor (Yang et al. 2005). It is well documented that behavioral experience induces quantifiable increases in dendritic arborization and synaptic density in the brain. Because RyR complexes are involved in the dendritic growth and plasticity, the finding that developmental exposure to PCBs alters basal and use dependent expression of RyR1 and RyR2 provides a strong rationale for the experiments proposed in SA 1.2 which examine brain development after PCB 95 exposure.

Fig 3.
Fig 3. Perinatal exposure of rats to Aroclor 1254 significantly alters the expression patterns of RyR1 and RyR2 on P21 and P31 (A), before and after water maze training, compared to controls.

Specific Aim 2. To determine if perinatal PCB 95 exposure lowers splenocyte numbers in mice.
Project Overview. Pregnant C57BL/6J mice were dosed with 6 mg/kg/day PCB 95 or corn oil vehicle from E5 until weaning. No significant differences in dam or pup weights were seen during the treatment period (not shown). Litter offspring were immunized at PD 28 and PD 42 with ovalbumin in Freund’s adjuvant or mock immunized with saline. At PD 56, litter offspring were sacrificed and sera and spleens harvested. Figure 4, below represents pooled data showing significantly lower splenocyte numbers in PCB 95 treated (n=16) vs. corn oil controls (n=15). The PCB 95 effects on splenocyte counts were seen regardless of immunization status or sex (not shown).

Fig 4.
Fig 4. Total splenocyte numbers recovered from mice developmentally exposed to either PCB 95 or corn oil.

Perinatal PCB exposure lowers splenocyte B cell numbers and alters expression of leukocyte markers. Splenocytes from Figure 4 were stained with combinations of antibodies to surface markers CD3, CD4, CD69, CD11b, B220/CD45R, CD16/32, Gr-1, CD16/32, F4-80, CD11b, and CD25. A striking finding is there are ~10 percent fewer B220/CD45R positive B-cells in mice perinatally exposed to PCB 95 (n=5 mice, Fig 5). The PCB 95 effect of lowering splenic B cell counts was dominant, as the same differences were seen regardless of immunization status or sex (not shown).

Fig. 5.
Fig. 5. Perinatal exposure to PCB 95 lowers the total number of splenic B cells compared to corn oil control.

Markers whose expression level differed significantly from control are listed in Table 1 .

Figure.

Splenocytes from mice exposed perinatally to PCB 95 respond more vigorously to LPS challenge than controls. Equal numbers of spleen cells from mice exposed perinatally to PCB 95 or from control mice were tested for their proliferative responses to the mitogens PHA and LPS or to the recall antigen ovalbumin. In Table 2, proliferative responses to PHA and ovalbumin were the same between groups, indicating T cell responses were not impaired by PCB exposure. In contrast, LPS, a B cell and monocyte mitogen, generated 43% greater [3H]thymidine incorporation in splenocytes from mice perinatally exposed to PCB 95 (Table 2).

Figure.

In summary we show that perinatal exposure to PCB 95 results in significant changes to peripheral splenocyte numbers, phenotype and function, with the B cell compartment being especially affected. These findings may be especially relevant to immune dysregulation observed in a subset of children with autism (Project 2).

Specific Aim 3. To analyze whether or not developmental exposure to PCB 95 enhances seizure susceptibility.

Project Overview. We have completed a series of studies that demonstrate that developmental exposure of Wistar rats to PCB 95 (0, 0.6 or 1 mg/kg/day) lowers seizure thresholds to the convulsant fluorothyl (bis-2,2,2-triflurothyl ether) and increases the rate of kindling of pentylenetetrazole (PTZ)-induced seizures. Figure 6, below shows that the offspring of rats exposed to 1 mg/kg/day PCB 95 from E5 through weaning showed significantly shorter onset time for fluorothyl seizures (i.e.,first myoclonic jerk) compared to corn oil control when tested on PN31. These same animals also kindled significantly faster than controls beginning on PD60 (Fig. 7, below). These results provide evidence that developmental exposure to a non-coplanar PCB can significantly alter seizure thresholds and may have significance in seizure-prone children. They also provide support for specific aims 3.1 & 3.2.

In collaboration with the Merzenich lab (UCSF) made possible by CCEH, we have found that the same developmental exposure to PCB 95 causes gross disorganization in the tonotopic organization of the primary auditory cortex (A1). These developmental effects on A1 occurred in the absence of any measurable deficits in ABR curves for clicks or tones, or changes in thresholds (Kenet et al. 2005). Existing collaborations between the UC Davis and University of Illinois Centers have examined the structure-activity of PCB congeners and complex mixtures on ryanodine receptor (RyR) function (Kostyniak et al. 2005; Pessah 2005) Roegge et al., 2005}. In the new project period, these collaborations will be extended through Supplemental Applications we are planning to submit in year 2 to understand how altered RyR receptor function within the CNS and thyroid hormone imbalances caused by developmental exposure to specific PCB congeners and an environmental mixture (the Fox River mixture) are related to hearing loss, altered A1 organization, and increased susceptibility to seizure.

Fig 6.
Fig 6. Developmental exposure to PCB 95 (1mg/kg/day) shortens latency to first flurothyl-triggered (20μL/min) myoclonic jerk.

Fig 7.
Fig. 7: Rats were challenged with PTZ (30mg/kg, i.p. every 48 hrs) beginning on P60 and scored for there seizure responses on a scale of 0-5.

Enhanced excitability is seen in the excitatory postsynaptic potentials recorded from hippocampal slices from mice developmentally exposure to PCB 95. We have tested our hypothesis (Hypothesis 3) that non-coplanar PCBs alter the gain of both excitatory and inhibitory circuits in hippocampus. Hippocampal brain slices were prepared from a subset of offspring (not tested for seizure threshold) exposed through maternal exposure from gestational day E5 through weaning to either corn oil (control) or PCB 95 as described above. Slices were placed on the MED64® electrode array to measure differences in synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSP) were recorded from striatum pyramidale of the CA1 by evoking single pulse stimulation of striatum radiatum. fEPSP slopes were measured before and after acute block of GABA receptor type A (GABRA) neurotransmission with varying concentrations of picrotoxin. Figure 8 (bar graph below), shows that perfusion of 100μM (saturating) picrotoxin caused a significant enhancement in EPSP slope from slices obtained from PCB 95 exposed, but not control, offspring. Furthermore the EPSP waveforms from PCB exposed animals exhibited pronounced after-potentials (Fig 8, black trace) providing direct electrophysiological evidence that developmental exposure to PCB 95 resulted in a persistent change in excitability in the CA1 field that can be unmasked in the presence of a GABR deficiency (modeled by perfusion of picrotoxin). In the acute hippocamapal slice preparation, we have prevented PCB 95-induced increase in EPSP slope with 30μM dantrolene in the ACSF, implicating RyR dysfunction as a contributing mechanism. In view of the evidence that autistic children have deficiencies in GABR neurotransmission and have seizure disorders, our electrophysiological data with perinatal exposure to non-coplanar PCBs and possibly polychlorinated diphenyl ethers (see below) suggest that there may be environmental triggers (i.e., PCBs) to which autistic children are especially susceptible.

Fig. 8.
Fig. 8. Normalized fEPSP slopes from hippocampal slices prepared from rats exposed perinatally to either corn oil (controls) or 6mg/kg/day PCB 95 (E5 through PD21). Slices were prepared on PD35-40. Single pulses were applied every 15s and EPSPs recorded using the MED64® array. Picrotoxin (Ptx) was added to the ACSF where indicated to block GABA transmission. Ptx caused a significant (p<0.01) increase in EPSP slope with slices from PCB exposed animals but not slices prepared from control animals. Note the pronounced after-potentials in the waveform from PCB exposed but not control animals (traces middle panel). The data shown in the left panel are means from n=5 and n=6 slices from PCB exposed and control animals, respectively. Right panel shows the dose-dependent nature of the Ptx effect in slices obtained from PCB-exposed and corn oil controls (n=4 slices each condition).

In the first project period we completed the first extensive SAR analysis of 46 PCBs, hydroxy-PCBs and methylsulfonyl-PCBs toward RyR Ca2+ channels (Pessah et al., 2005; Appendix). The results from this SAR study underscore the importance of meta- and para-substituents in conferring RyR and microsomal Ca2+ releasing activity, and the importance of immunophilin FKBP12-RyR complex in PCB mechanism of action.

The SAR for activating RyR1 is consistent with those previously reported in several in vivo and in vitro studies, suggesting a common mechanism may contribute to the toxicity of non-coplanar PCBs. We have extended our SAR to PBDEs. Figure 9 shows that, like non-coplanar PCBs, BDEs 4, 15, and 47 show a stringent structural requirement for sensitizing the activation of RyR1, and the effect of BDE 47 requires an intact FKBP12-RyR complex since rapamycin is inhibitory (red symbol). A similar SAR was obtained with microsomes enriched in RyR2 (not shown). These results provide the rationale to pursue experiments with environmentally relevant BDE-47 to understand the molecular mechanisms by which they disrupt Ca2+ signaling and affect immunological and neurodevelopment disorders in mice in the next project period.

Figure 9.
Figure 9: BDE-4 and BDE-47 dose-dependently enhances [3H]ryanodine (2nM) binding. RyR1-enriched microsomes were incubated in the absence of presence of the BDE congeners shown. BDE-4 and BDE-47 enhanced RyR1 activity 14- and 10-fold over baseline (EC50s=8 and 1.9μM), respectively. BDE-15 was inactive. The effects of BDE-4 were inhibited by co-incubation with rapamycin (20μM ; Symbol. ) implicating an FKBP12-RyR1 dependent mechanism.

Prenatal exposure to purified IgG isolated from the serum of mothers of autistic children (AA-IgG) will alter brain development, behavior, and susceptibility. Our recent studies have demonstrated that serum samples taken from control mothers (i.e. mothers of healthy children) and mothers of multiple autistic children show different immunoreactivity (Project 2). Project 2 has analyzed serum samples from mothers participating in CHARGE (Project 1) who gave birth to >2 autistic children. In 30-40% of these serum samples Project 2 identified brain directed autoantibodies with a strong immunoreactive doublet at ~60kDa when probed on western blots with human fetal brain homogenates (Fig 10A, below, AA-IgG double arrows). This pattern of autoantibodies has not been found in mother’s who have not given birth to autistic children (Fig 10A, Control). Sera from autistic children participating in CHARGE, but not general population controls, also contained autoantibodies directed against rhesus macaque cerebellum, showing particularly strong focal staining of cells within the cerebellar granular layer (Fig 10B). In order to test for possible developmental neurotoxicity, AA-IgG and control C-IgG were extensively purified for use in the development of an AA-IgG monkey model. Purified IgG was given intravenously to a separate group of 4 pregnant monkeys during gestation. When the average age of each cohort reached 5 months, each mother/infant pair was allowed to interact with other mother/infant pairs in its respective cohort. Infants were observed and behaviors scored. Testing was conducted over 5 consecutive days and each mother and infant were paired with each or another mother and infant twice. Infants exposed prenatally to AA-IgG demonstrated more affiliative behaviors including lipsmacking and cooing and fewer play behaviors than control infants (not shown). One of the most interesting findings to date from our IgG autism monkey model is that of increased activity measured during the mother-preference task by counting the number of midline crossings in a testing arena over a 2 min time period (Fig 10C). The position of the infant's mother and the familiar adult females were balanced across trials. In addition, the results revealed no difference in the preference of the infants towards their own mothers over other mothers (data not shown). We find this very intriguing in light of the increase in activity often exhibited by children with autism (Sturm et al. 2004). In addition to this finding of increased activity during a stressful situation (the infants were just weaned prior to the task and are separated from their mothers by Plexiglas), we have observed what appears to be increased activity in their home cages (they live in social cages with 5 other infants). Similarly, mice prenatally exposed to serum from a mother of multiple autistic children demonstrated behavioral deficits including reduced exploration and subtle motor deficits compared to mice exposed to serum from control mothers (Dalton et al. 2003). The monkey data and those of Dalton and coworkers in mice (Dalton et al. 2003) provide the strong rationale for developing the AA-IgG mouse model as proposed in Hypothesis 4.

Fig. 10
Fig. 10. Identification of autoantibodies in the serum of autistic children and their mothers enrolled in the CHARGE study (panels A&B). One pattern of autoantibodies has a characteristic immunoreactive doublet against fetal brain protein (double arrows in A) . When IgG purified from mothers possessing this pattern of autoantibodies is administered to Rhesus macaques during pregnancy, their offspring develop several behavioral deficits such as increased activity during the mother preference task (panel C). This will be the basis for developing the AA-IgG mouse model.


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Journal Article Ahn KC, Zhao B, Chen J, Cherednichenko G, Sanmarti E, Denison MS, Lasley B, Pessah IN, Kultz D, Chang DPY, Gee SJ, Hammock BD. In vitro biologic activities of the antimicrobials triclocarban, its analogs, and triclosan in bioassay screens:receptor-based bioassay screens. Environmental Health Perspectives 2008;116(9):1203-1210. R829388 (Final)
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  • Journal Article Aleman M, Riehl J, Aldridge BM, Lecouteur RA, Stott JL, Pessah IN. Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia. Muscle & Nerve 2004;30(3):356-365. R829388 (2006)
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  • Journal Article Anderson PJ, Lango J, Carkeet C, Britten A, Krautler B, Hammock BD, Roth JR. One pathway can incorporate either adenine or dimethylbenzimidazole as an α-axial ligand of B12 cofactors in Salmonella enterica. Journal of Bacteriology 2008;190(4):1160-1171. R829388 (Final)
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  • Journal Article Aronov PA, Dettmer K, Hammock BD, Christiansen JA, Cornel AJ. Development of a HPLC/tandem-MS method for the analysis of the larvicides methoprene, hydroprene, and kinoprene at trace levels using Diels-Alder derivatization. Journal of Agricultural and Food Chemistry 2005;53(9):3306-3312. R829388 (2006)
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  • Journal Article Aronov PA, Hall LM , Dettmer K, Stephensen CB, Hammock BD. Metabolic profiling of major vitamin D metabolites using Diels-Alder derivatization and ultra-performance liquid chromatography-tandem mass spectrometry. Analytical and Bioanalytical Chemistry 2008;391(5):1917-1930. R829388 (Final)
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  • Journal Article Ashwood P, Van de Water J. A review of autism and the immune response. Clinical & Developmental Immunology 2004;11(2):165-174. R829388 (Final)
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  • Journal Article Ashwood P, Van de Water J. Is autism an autoimmune disease? Autoimmunity Reviews 2004;3(7-8):557-562. R829388 (2006)
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  • Journal Article Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. Journal of Leukocyte Biology 2006;80(1):1-15. R829388 (2006)
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  • Journal Article Ashwood P, Kwong C, Hansen R, Hertz-Picciotto I, Croen L, Krakowiak P, Walker W, Pessah IN, Van de Water J. Brief report: plasma leptin levels are elevated in autism: association with early onset phenotype? Journal of Autism and Developmental Disorders 2008;38(1):169-175. R829388 (2006)
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  • Journal Article Baron CA, Tepper CG, Liu SY, Davis RR, Wang NJ, Schanen NC, Gregg JP.
 Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Human Molecular Genetics 2006;15(6):853-869. R829388 (2006)
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  • Journal Article Baron CA, Liu SY, Hicks C, Gregg JP. Utilization of lymphoblastoid cell lines as a system for the molecular modeling of autism. Journal of Autism and Developmental Disorders 2006;36(8):973-982. R829388 (2006)
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  • Journal Article Bauman MD, Lavenex P, Mason WA, Capitanio JP, Amaral DG. The development of social behavior following neonatal amygdala lesions in rhesus monkeys. Journal of Cognitive Neuroscience 2004;16(8):1388-1411. R829388 (2006)
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  • Journal Article Berman RF, Pessah IN, Mouton PR, Mav D, Harry J. Low-level neonatal thimerosal exposure: further evaluation of altered neurotoxic potential in SJL mice. Toxicological Sciences 2008;101(2):294-309. R829388 (Final)
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  • Journal Article Berman RF, Pessah IN, Mouton PR, Mav D, Harry GJ. Modeling neonatal thimerosal exposure in mice. Toxicological Sciences 2008;103(2):416. R829388 (Final)
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  • Journal Article Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J. Autism: maternally derived antibodies specific for fetal brain proteins. NeuroToxicology 2008;29(2):226-231. R829388 (Final)
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  • Journal Article Bu B, Ashwood P, Harvey D, King IB, Water JV, Jin LW.
 Fatty acid compositions of red blood cell phospholipids in children with autism.
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  • Journal Article Burke K, Cheng Y, Li B, Petrov A, Joshi P, Berman RF, Reuhl KR, DiCicco-Bloom E. Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E. NeuroToxicology 2006;27(6):970-981. R829388 (2006)
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  • Journal Article Cabanlit M, Wills S, Goines P, Ashwood P, Van de Water J. 
Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. 
Annals of the New York Academy of Sciences 2007;1107:92-103. R829388 (Final)
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  • Journal Article Carkeet C, Dueker SR, Lango J, Buchholz BA, Miller JW, Green R, Hammock BD, Roth JR, Anderson PJ. Human vitamin B12 absorption measurement by accelerator mass spectrometry using specifically labeled 14C-cobalamin. Proceedings of the National Academy of Sciences of the United States of America 2006;103(15):5694-5699. R829388 (2006)
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  • Journal Article Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB Journal 2006;20(2):329-330. R829388 (2006)
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  • Journal Article Chen L, Esteve E, Sabatier J-M, Ronjat M, De Waard M, Allen PD, Pessah IN. Maurocalcine and peptide A stabilize distinct subconductance states of ryanodine receptor type 1, revealing a proportional gating mechanism. Journal of Biological Chemistry 2003;278(18):16095-16106. R829388 (2006)
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  • Journal Article Cherednichenko G, Zima AV, Feng W, Schaefer S, Blatter LA, Pessah IN. NADH oxidase activity of rat cardiac sarcoplasmic reticulum regulates calcium-induced calcium release. Circulation Research 2004;94(4):478-486. R829388 (2006)
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  • Journal Article Cherednichenko G, Hurne AM, Fessenden JD, Lee EH, Allen PD, Beam KG, Pessah IN. Conformational activation of Ca2+ entry by depolarization of skeletal myotubes. Proceedings of the National Academy of Sciences of the United States of America 2004;101(44):15793-15798. R829388 (2006)
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  • Journal Article Croen LA, Grether JK, Yoshida CK, Odouli R, Van de Water J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Archives of Pediatrics and Adolescent Medicine 2005;159(2):151-157. R829388 (2006)
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  • Journal Article Dai JJ, Lieu L, Rocke D.
 Dimension reduction for classification with gene expression microarray data.
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  • Journal Article Davis BB, Thompson DA, Howard LL, Morisseau C, Hammock BD, Weiss RH. Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 2002;99(4):2222-2227. R829388 (2006)
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  • Journal Article Davis BB, Morisseau C, Newman JW, Pedersen TL, Hammock BD, Weiss RH. Attenuation of vascular smooth muscle cell proliferation by 1-cyclohexyl-3-dodecyl urea is independent of soluble epoxide hydrolase inhibition. Journal of Pharmacology and Experimental Therapeutics 2006;316(2):815-821. R829388 (2006)
    R829388 (Final)
    R833292 (Final)
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  • Journal Article Denning L, Anderson JA, Davis R, Gregg JP, Kuzdenyi J, Maselli RA.
 High throughput genetic analysis of congenital myasthenic syndromes using resequencing microarrays. PLoS One 2007;2(9):e918. R829388 (Final)
    R833292 (Final)
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  • Full-text: PLoS ONE-Full Text HTML
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  • Journal Article Dettmer K, Hanna D, Whetstone P, Hansen R, Hammock BD. 
Autism and urinary exogenous neuropeptides: development of an on-line SPE-HPLC-tandem mass spectrometry method to test the opioid excess theory.
 Analytical and Bioanalytical Chemistry 2007;388(8):1643-1651. R829388 (Final)
    R833292 (Final)
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  • Abstract: SpringerLink
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  • Journal Article Dettmer K, Aronov PA, Hammock BD. 
Mass spectrometry-based metabolomics.
 Mass Spectrometry Reviews 2007;26(1):51-78. R829388 (Final)
    R833292 (Final)
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  • Journal Article Dey A, Williams RS, Pollock DM, Stepp DW, Newman JW, Hammock BD, Imig JD. Altered kidney CYP2C and cyclooxygenase-2 levels are associated with obesity-related albuminuria. Obesity Research 2004;12(8):1278-1289. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
  • Abstract from PubMed
  • Full-text: Obesity Research-Full Text
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  • Journal Article Dietrich KN, Eskenazi B, Schantz S, Yolton K, Rauh VA, Johnson CB, Alkon A, Canfield RL, Pessah IN, Berman RF. Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environmental Health Perspectives 2005;113(10):1437-1446. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R827027 (2002)
    R829389 (2005)
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    R829390 (2005)
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    R829390C002 (2005)
    R831710 (2005)
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    R831711 (2005)
    R832141 (2006)
    R832141 (2007)
    R832141 (Final)
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  • Journal Article Dodds ED, German JB, Lebrilla CB. Enabling MALDI-FTICR-MS/MS for high-performance proteomics through combination of infrared and collisional activation. Analytical Chemistry 2007;79(24):9547-9556. R829388 (Final)
    R833292 (Final)
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  • Abstract: Analytical Chemistry-Abstract
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  • Journal Article Du X, Tang Y, Xu H, Lit L, Walker W, Ashwood P, Gregg JP, Sharp FR. Genomic profiles for human peripheral blood T cells, B cells, natural killer cells, monocytes, and polymorphonuclear cells: comparisons to ischemic stroke, migraine, and Tourette syndrome. Genomics 2006;87(6):693-703. R829388 (2006)
    R829388 (Final)
    R833292 (Final)
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  • Full-text: Science Direct-Full Text HTML
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  • Journal Article DuTeaux SB, Newman JW, Morisseau C, Fairbairn EA, Jelks K, Hammock BD, Miller MG. Epoxide hydrolases in the rat epididymis: possible roles in xenobiotic and endogenous fatty acid metabolism. Toxicological Sciences 2004;78(2):187-195. R829388 (2006)
    R829388 (Final)
  • Abstract from PubMed
  • Full-text: Toxicological Sciences-Full Text HTML
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  • Journal Article Enstrom A, Onore C, Hertz-Picciotto I, Hansen R, Croen L, Van de Water J, Ashwood P. Detection of IL-17 and IL-23 in plasma samples of children with autism. American Journal of Biochemistry and Biotechnology 2008;4(2):114-120. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
    R833292 (2008)
    R833292 (2009)
    R833292 (Final)
  • Full-text: Science Publications - Full Text PDF
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  • Journal Article Enstrom A, Onore C, Tarver A, Hertz-Picciotto I, Hansen R, Croen L, Van de Water J, Ashwood P. Peripheral blood leukocyte production of BDNF following mitogen stimulation in early onset and regressive autism. American Journal of Biochemistry and Biotechnology 2008;4(2):121-129. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
    R833292 (2008)
    R833292 (2009)
    R833292 (Final)
  • Full-text: Science Publications - Full Text PDF
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  • Journal Article Esteve E, Smida-Rezgui S, Sarkozi S, Szegedi C, Regaya I, Chen L, Altafaj X, Rochat H, Allen P, Pessah IN, Marty I, Sabatier JM, Jona I, De Waard M, Ronjat M. Critical amino acid residues determine the binding affinity and the Ca2+ release efficacy of maurocalcine in skeletal muscle cells. Journal of Biological Chemistry 2003;278(39):37822-37831. R829388 (2006)
    R829388 (Final)
    R833292 (Final)
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  • Full-text: Journal of Biological Chemistry-Full Text HTML
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  • Other: Journal of Biological Chemistry-Full Text PDF
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  • Journal Article Fang X, Weintraub NL, Oltman CL, Stoll LL, Kaduce TL, Harmon S, Dellsperger KC, Morisseau C, Hammock BD, Spector AA. Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide. American Journal of Physiology-Heart and Circulatory Physiology 2002;283(6):H2306-H2314. R829388 (2006)
    R829388 (Final)
    R829388C001 (2003)
    R829388C001 (2005)
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  • Full-text: AJP-Full Text HTML
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  • Journal Article Fang X, Weintraub NL, McCaw RB, Hu S, Harmon SD, Rice JB, Hammock BD, Spector AA. Effect of soluble epoxide hydrolase inhibition on epoxyeicosatrienoic acid metabolism in human blood vessels. American Journal of Physiology-Heart and Circulatory Physiology 2004;287(6):H2412-H2420. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Journal Article Fang X, Hu S, Watanabe T, Weintraub NL, Snyder GD, Yao J, Liu Y, Shyy JY-J, Hammock BD, Spector AA. Activation of peroxisome proliferator-activated receptor α by substituted urea-derived soluble epoxide hydrolase inhibitors. Journal of Pharmacology and Experimental Therapeutics 2005;314(1):260-270. R829388 (2006)
    R829388 (Final)
    R829389 (Final)
    R833292 (Final)
  • Abstract from PubMed
  • Full-text: JPET-Full Text HTML
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  • Journal Article Feng W, Tu J, Yang T, Vernon PS, Allen PD, Worley PF, Pessah IN. Homer regulates gain of ryanodine receptor type 1 channel complex. Journal of Biological Chemistry 2002;277(47):44722-44730. R829388 (2006)
    R829388 (Final)
    R829388C006 (2003)
    R829388C006 (2005)
  • Abstract from PubMed
  • Full-text: Journal of Biological Chemistry-Full Text
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  • Other: Journal of Biological Chemistry-Full Text PDF
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  • Journal Article Feng W, Tu J, Pouliquin P, Cabrales E, Shen X, Dulhunty A, Worley PF, Allen PD, Pessah IN. Dynamic regulation of ryanodine receptor type 1 (RyR1) channel activity by Homer 1. Cell Calcium 2008;43(3):307-314. R829388 (Final)
    R833292 (2007)
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  • Journal Article Fleming EJ, Mack EE, Green PG, Nelson DC. Mercury methylation from unexpected sources: molybdate-inhibited freshwater sediments and an iron-reducing bacterium. Applied and Environmental Microbiology 2006;72(1):457-464. R829388 (Final)
    R829388C001 (2005)
    R828676C003 (2004)
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  • Journal Article Folkerts MM, Parks EA, Dedman JR, Kaetzel MA, Lyeth BG, Berman RF. Phosphorylation of calcium calmodulin-dependent protein kinase II following lateral fluid percussion brain injury in rats.
 Journal of Neurotrauma 2007;24(4):638-650. R829388 (Final)
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  • Abstract: Journal of Neurotrauma-Abstract
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  • Journal Article Gafni J, Wong PW, Pessah IN. Non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95) amplifies ionotropic glutamate receptor signaling in embryonic cerebellar granule neurons by a mechanism involving ryanodine receptors. Toxicological Sciences 2004;77(1):72-82. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
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  • Full-text: Toxicological Sciences-Full Text HTML
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  • Journal Article Gao J, Voss AA, Pessah IN, Lauer FT, Penning TM, Burchiel SW. Ryanodine receptor-mediated rapid increase in intracellular calcium induced by 7,8-benzo(a)pyrene quinone in human and murine leukocytes. Toxicological Sciences 2005;87(2):419-426. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
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  • Full-text: Toxicological Sciences-Full Text
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  • Journal Article Geller SC, Gregg JP, Hagerman P, Rocke DM. Transformation and normalization of oligonucleotide microarray data. Bioinformatics 2003;19(14):1817-1823. R829388 (2006)
    R829388 (Final)
    R829388C003 (2004)
  • Abstract from PubMed
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  • Journal Article German JB, Hammock BD, Watkins SM. Metabolomics: building on a century of biochemistry to guide human health. Metabolomics 2005;1(1):3-9. R829388 (2006)
    R829388 (Final)
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  • Journal Article German JB, Watkins SM, Fay LB. Metabolomics in practice: emerging knowledge to guide future dietetic advice toward individualized health. Journal of the American Dietetic Association 2005;105(9):1425-1432. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Abstract: Journal of the American Dietetic Association-Abstract
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  • Journal Article German JB, Gillies LA, Smilowitz JT, Zivkovic AM, Watkins SM. Lipidomics and lipid profiling in metabolomics.
 Current Opinion in Lipidology 2007;18(1):66-71. R829388 (Final)
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  • Abstract: Current Opinion in Lipidology-Abstract
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  • Journal Article Gibney MJ, Walsh M, Brennan L, Roche HM, German B, van Ommen B. Metabolomics in human nutrition: opportunities and challenges. American Journal of Clinical Nutrition 2005;82(3):497-503. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Journal Article Goines P, Schauer J, Heuer L, Ashwood P, Van de Water J. Beta-2-microglobulin in autism spectrum disorders. American Journal of Biochemistry and Biotechnology 2007;3(2):87-91. R829388 (Final)
    R833292 (2007)
    R833292 (Final)
  • Full-text: Science Publications-Full Text PDF
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  • Journal Article Goth SR, Chu RA, Pessah IN. Oxygen tension regulates the in vitro maturation of GM-CSF expanded murine bone marrow dendritic cells by modulating class II MHC expression. Journal of Immunological Methods 2006;308(1-2):179-191. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R833292 (2007)
    R833292 (2009)
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  • Journal Article Goth SR, Chu RA, Gregg JP, Cherednichenko G, Pessah IN. Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal. Environmental Health Perspectives 2006;114(7):1083-1091. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R833292 (2007)
    R833292 (Final)
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  • Journal Article Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A, Trapp BD, Iwahashi C, Brunberg J, Grigsby J, Hessl D, Becker EJ, Papazian J, Leehey MA, Hagerman RJ, Hagerman PJ. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 2006;129(1):243-255. R829388 (2006)
    R829388 (Final)
    R829388C005 (2005)
  • Abstract from PubMed
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  • Journal Article Gregg JP, Lit L, Baron CA, Hertz-Picciotto I, Walker W, Davis RA, Croen LA, Ozonoff S, Hansen R, Pessah IN, Sharp FR. Gene expression changes in children with autism. Genomics 2008;91(1):22-29. R829388 (Final)
    R833292 (2008)
    R833292 (2009)
    R833292 (Final)
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  • Journal Article Hansen ME, Pessah IN, Matsumura F. Heptachlor epoxide induces a non-capacitative type of Ca2+ entry and immediate early gene expression in mouse hepatoma cells. Toxicology 2006;220(2-3):218-231. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
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  • Journal Article Hansen RL, Ozonoff S, Krakowiak P, Angkustsiri K, Jones C, Deprey LJ, Le D-N, Croen LA, Hertz-Picciotto I. Regression in autism: prevalence and associated factors in the CHARGE Study. Ambulatory Pediatrics 2008;8(1):25-31. R829388 (2007)
    R829388 (Final)
    R833292 (2008)
    R833292 (2009)
    R833292 (Final)
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  • Journal Article Hertz-Picciotto I, Charles MJ, James RA, Keller JA, Willman E, Teplin S. In utero polychlorinated biphenyl exposures in relation to fetal and early childhood growth. Epidemiology 2005;16(5):648-656. R829388 (2006)
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    R833292 (2007)
    R833292 (Final)
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  • Abstract: Epidemiology-Abstract
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  • Journal Article Hertz-Picciotto I, Croen LA, Hansen R, Jones CR, van de Water J, Pessah IN. The CHARGE Study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environmental Health Perspectives 2006;114(7):1119-1125. R829388 (2006)
    R829388 (Final)
    R829388C004 (2005)
    R833292 (2007)
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  • Journal Article Hertz-Picciotto I, Baker RJ, Yap PS, Dostal M, Joad JP, Lipsett M, Greenfield T, Herr CE, Benes I, Shumway RH, Pinkerton KE, Sram R. Early childhood lower respiratory illness and air pollution. Environmental Health Perspectives 2007;115(10):1510-1518. R829388 (2007)
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  • Journal Article Hertz-Picciotto I, Park H-Y, Dostal M, Kocan A, Trnovec T, Sram R. Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development. Basic & Clinical Pharmacology and Toxicology 2008;102(2):146-154. R829388 (Final)
    R833292 (2008)
    R833292 (2009)
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  • Journal Article Hertz-Picciotto I, Jusko TA, Willman EJ, Baker RJ, Keller JA, Teplin SW, Charles MJ. A cohort study of in utero polychlorinated biphenyl (PCB) exposures in relation to secondary sex ratio. Environmental Health 2008;7:37. R829388 (Final)
    R833292 (2009)
    R833292 (Final)
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  • Full-text: Environmental Health-Full Text HTML
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  • Journal Article Hillyard SL, German JB. Non-essential dietary factors: from test tube to lifespan. Journal of the Science of Food and Agriculture 2007;87(10):1802-1805. R829388 (Final)
    R833292 (Final)
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  • Journal Article Howard AS, Fitzpatrick R, Pessah I, Kostyniak P, Lein PJ. Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicology and Applied Pharmacology 2003;190(1):72-86. R829388 (2006)
    R829388 (Final)
    R829388C006 (2003)
    R829388C006 (2005)
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  • Journal Article Howards PP, Hertz-Picciotto I. Invited commentary: Disinfection by-products and pregnancy loss—lessons. American Journal of Epidemiology 2006;164(11):1052-1055. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
    R833292 (Final)
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  • Full-text: American Journal of Epidemiology-Full Text HTML
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  • Journal Article Huang H, Stok JE, Stoutamire DW, Gee SJ, Hammock BD. Development of optically pure pyrethroid-like fluorescent substrates for carboxylesterases. Chemical Research in Toxicology 2005;18(3):516-527. R829388 (Final)
    R829388C001 (2005)
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  • Full-text: UC Davis-Full Text PDF
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  • Abstract: ACS
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  • Journal Article Huang H, Nishi K, Gee SJ, Hammock BD. Evaluation of chiral α-cyanoesters as general fluorescent substrates for screening enantioselective esterases. Journal of Agricultural and Food Chemistry 2006;54(3):694-699. R829388 (2006)
    R829388 (Final)
    R833292 (Final)
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  • Abstract: Journal of Agricultural and Food Chemistry-Abstract
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  • Journal Article Hurne AM, O'Brien JJ, Wingrove D, Cherednichenko G, Allen PD, Beam KG, Pessah IN. Ryanodine receptor type 1 (RyR1) mutations C4958S and C4961S reveal excitation-coupled calcium entry (ECCE) is independent of sarcoplasmic reticulum store depletion. Journal of Biological Chemistry 2005;280(44):36994-37004. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
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  • Full-text: Journal of Biological Chemistry-Full Text HTML
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  • Journal Article Inceoglu B, Lango J, Jing J, Chen L, Doymaz F, Pessah IN, Hammock BD. One scorpion, two venoms: prevenom of Parabuthus transvaalicus acts as an alternative type of venom with distinct mechanism of action. Proceedings of the National Academy of Sciences of the United States of America 2003;100(3):922-927. R829388 (2006)
    R829388 (Final)
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  • Full-text: PNAS-Full Text HTML
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  • Journal Article Inceoglu B, Lango J, Pessah IN, Hammock BD. Three structurally related, highly potent, peptides from the venom of Parabuthus transvaalicus possess divergent biological activity. Toxicon 2005;45(6):727-733. R829388 (Final)
    R829388C001 (2005)
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  • Journal Article Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD.
 Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). 
Prostaglandins & Other Lipid Mediators 2007;82(1-4):42-49. R829388 (Final)
    R833292 (Final)
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  • Journal Article Jaubert PJ, Golub MS, Lo YY, Germann SL, Dehoff MH, Worley PF, Kang SH, Schwarz MK, Seeburg PH, Berman RF. Complex, multimodal behavioral profile of the Homer1 knockout mouse. Genes, Brain and Behavior 2007;6(2):141-154. R829388 (2006)
    R829388 (Final)
    R829388C005 (2005)
    R833292 (2007)
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  • Full-text: Wiley Online Library-Full Text HTML
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  • Journal Article Jusko TA, Koepsell TD, Baker RJ, Greenfield TA, Willman EJ, Charles MJ, Teplin SW, Checkoway H, Hertz-Picciotto I. Maternal DDT exposures in relation to fetal and 5-year growth. Epidemiology 2006;17(6):692-700. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
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  • Abstract: Epidemiology-Abstract
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  • Journal Article Kenet T, Froemke RC, Schreiner CE, Pessah IN, Merzenich MM. Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex.
 Proceedings of the National Academy of Sciences of the United States of America 2007;104(18):7646-7651. R829388 (2006)
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    R833292 (2008)
    R833292 (Final)
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  • Journal Article Kim H-J, Ahn KC, Ma SJ, Gee SJ, Hammock BD.
 Development of sensitive immunoassays for the detection of the glucuronide conjugate of 3-phenoxybenzyl alcohol, a putative human urinary biomarker for pyrethroid exposure. Journal of Agricultural and Food Chemistry 2007;55(10):3750-3757. R829388 (Final)
    R833292 (Final)
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  • Abstract: Journal of Agricultural and Food Chemistry-Abstract
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  • Journal Article Kim I-H, Morisseau C, Watanabe T, Hammock BD. Design, synthesis, and biological activity of 1,3-disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility. Journal of Medicinal Chemistry 2004;47(8):2110-2122. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Journal Article Kim I-H, Heirtzler FR, Morisseau C, Nishi K, Tsai H-J, Hammock BD. Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility. Journal of Medicinal Chemistry 2005;48(10):3621-3629. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Abstract: ACS-Abstract
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  • Journal Article Kim KH, Inan SY, Berman RF, Pessah IN. Excitatory and inhibitory synaptic transmission is differentially influenced by two ortho-substituted polychlorinated biphenyls in the hippocampal slice preparation. Toxicology and Applied Pharmacology 2009;237(2):168-177. R829388 (Final)
    R829388C006 (2005)
    R833292 (Final)
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  • Journal Article Kim KH, Bose DD, Ghogha A, Riehl J, Zhang R, Barnhart CD, Lein PJ, Pessah IN. Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine receptors and neurotoxicity. Environmental Health Perspectives 2011;119(4):519-526. R829388 (2006)
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    R833292 (2012)
    R833292 (Final)
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  • Journal Article Kostyniak PJ, Hansen LG, Widholm JJ, Fitzpatrick RD, Olson JR, Helferich JL, Kim KH, Sable HJ, Seegal RF, Pessah IN, Schantz SL. Formulation and characterization of an experimental PCB mixture designed to mimic human exposure from contaminated fish. Toxicological Sciences 2005;88(2):400-411. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R829390 (2005)
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  • Full-text: Toxicological Sciences-Full Text HTML
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  • Journal Article Krakowiak P, Goodlin-Jones B, Hertz-Picciotto I, Croen LA, Hansen RL.
Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study. 
Journal of Sleep Research 2008;17(2):197-206. R829388 (Final)
    R833292 (2007)
    R833292 (2008)
    R833292 (2009)
    R833292 (Final)
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  • Full-text: Wiley - Full Text HTML
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  • Journal Article Lange MC, Lemay DG, German JB. A multi-ontology framework to guide agriculture and food towards diet and health. Journal of the Science of Food and Agriculture 2007;87(8):1427-1434. R829388 (Final)
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  • Journal Article Lawler CP, Croen LA, Grether JK, Van de Water J. Identifying environmental contributions to autism: provocative clues and false leads. Mental Retardation & Developmental Disabilities Research Reviews 2004;10(4):292-302. R829388 (2006)
    R829388 (Final)
    R829388C002 (2005)
  • Abstract from PubMed
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  • Journal Article Lemay DG, Neville MC, Rudolph MC, Pollard KS, German JB.
 Gene regulatory networks in lactation: identification of global principles using bioinformatics. BMC Systems Biology 2007;1:56 (24 pp.). R829388 (Final)
    R833292 (Final)
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  • Journal Article Lemay DG, Zivkovic AM, German JB.
 Building the bridges to bioinformatics in nutrition research. American Journal of Clinical Nutrition 2007;86(5):1261-1269. R829388 (Final)
    R833292 (Final)
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  • Abstract: American Journal of Clinical Nutrition-Abstract
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  • Other: American Journal of Clinical Nutrition-Full Text PDF
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  • Journal Article Li L, Li H. Dimension reduction methods for microarrays with application to censored survival data. Bioinformatics 2004;20(18):3406-3412. R829388 (2006)
    R829388 (Final)
    R829388C003 (2005)
  • Abstract from PubMed
  • Full-text: Oxford Journals-Full Text PDF
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  • Abstract: Bioinformatics
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  • Journal Article Li L. Survival prediction of diffuse large-B-cell lymphoma based on both clinical and gene expression information. Bioinformatics 2006;22(4):466-471. R829388 (2006)
    R829388 (Final)
    R833292 (Final)
  • Abstract from PubMed
  • Full-text: Bioinformatics-Full Text HTML
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  • Journal Article Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain, Behavior, and Immunity 2008;22(6):806-816. R829388 (Final)
    R833292 (2008)
    R833292 (Final)
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  • Full-text: ScienceDirect-Full Text HTML
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  • Journal Article Masuno MN, Pessah IN, Olmstead MM, Molinski TF. Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex. Journal of Medicinal Chemistry 2006;49(15):4497-4511. R829388 (2006)
    R829388 (Final)
    R833292 (2007)
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  • Abstract: Journal of Medicinal Chemistry-Abstract
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  • Journal Article Merin N, Young GS, Ozonoff S, Rogers SJ. Visual fixation patterns during reciprocal social interaction distinguish a subgroup of 6-month-old infants at-risk for autism from comparison infants. Journal of Autism and Developmental Disorders 2007;37(1):108-121. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
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  • Full-text: SpringerLink-Full Text HTML
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  • Journal Article Nadig AS, Ozonoff S, Young GS, Rozga A, Sigman M, Rogers SJ. A prospective study of response to name in infants at risk for autism. Archives of Pediatrics & Adolescent Medicine 2007;161(4):378-383. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
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  • Full-text: Archives of Pediatrics & Adolescent Medicine-Full Text
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  • Abstract: Archives of Pediatrics & Adolescent Medicine
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  • Journal Article Newman JW, Watanabe T, Hammock BD. The simultaneous quantification of cytochrome P450 dependent linoleate and arachidonate metabolites in urine by HPLC-MS/MS. Journal of Lipid Research 2002;43(9):1563-1578. R829388 (2006)
    R829388 (Final)
    R829388C001 (2003)
    R829388C001 (2005)
  • Abstract from PubMed
  • Full-text: Journal of Lipid Research-Full Text HTML
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  • Journal Article Newman JW, Morisseau C, Harris TR, Hammock BD. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proceedings of the National Academy of Sciences of the United States of America 2003;100(4):1558-1563. R829388 (2006)
    R829388 (Final)
    R829388C001 (2003)
    R829388C001 (2005)
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  • Journal Article Newman JW, Morisseau C, Hammock BD. Epoxide hydrolases: their roles and interactions with lipid metabolism. Progress in Lipid Research 2005;44(1):1-51. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Full-text: University of California-Davis
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  • Journal Article Newman JW, Kaysen GA, Hammock BD, Shearer GC. Proteinuria increases oxylipid concentrations in VLDL and HDL, but not LDL particles in the rat. Journal of Lipid Research 2007;48(8):1792-1800. R829388 (Final)
    R833292 (Final)
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  • Journal Article Nguyen DV, Senturk D. Distortion diagnostics for covariate-adjusted regression: graphical techniques based on local linear modeling.
 Journal of Data Science 2007;5(4):471-490. R829388 (Final)
    R833292 (Final)
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  • Abstract: Journal of Data Science-Abstract
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  • Journal Article Nguyen DV, Senturk D. 
Multicovariate-adjusted regression models.
 Journal of Statistical Computation and Simulation 2008;78(9):813-827. R829388 (Final)
  • Full-text: University of California-Davis
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  • Abstract: IngentaConnect-Abstract
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  • Journal Article Ninonuevo MR, Park Y, Yin H, Zhang J, Ward RE, Clowers BH, German JB, Freeman SL, Killeen K, Grimm R, Lebrilla CB. A strategy for annotating the human milk glycome.
 Journal of Agricultural and Food Chemistry 2006;54(20):7471-7480. R829388 (Final)
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  • Abstract: Journal of Agricultural and Food Chemistry-Abstract
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  • Journal Article Ninonuevo MR, Ward RE, LoCascio RG, German JB, Freeman SL, Barboza M, Mills DA, Lebrilla CB. 
Methods for the quantitation of human milk oligosaccharides in bacterial fermentation by mass spectometry.
 Analytical Biochemistry 2007;361(1):15-23. R829388 (Final)
    R833292 (Final)
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  • Full-text: Science Direct-Full Text HTML
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  • Journal Article Ninonuevo MR, Perkins PD, Francis J, Lamotte LM, LoCascio RG, Freeman SL, Mills DA, German JB, Grimm R, Lebrilla CB. Daily variations in oligosaccharides of human milk determined by microfluidic chips and mass spectrometry. 
Journal of Agricultural and Food Chemistry 2008;56(2):618-626. R829388 (Final)
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  • Abstract: Journal of Agricultural and Food Chemistry-Abstract
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  • Journal Article Ostrovskaya O, Goyal R, Osman N, McAllister CE, Pessah IN, Hume JR, Wilson SM. 
Inhibition of ryanodine receptors by 4-(2-aminopropyl)-3,5-dichloro-N,N-dimethylaniline (FLA 365) in canine pulmonary arterial smooth muscle cells.
 Journal of Pharmacology and Experimental Therapeutics 2007;323(1):381-390. R829388 (Final)
    R833292 (2007)
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  • Abstract: Journal of Pharmacology and Experimental Therapeutics-Abstract
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  • Journal Article Ozonoff S, Young GS, Goldring S, Greiss-Hess L, Herrera AM, Steele J, Macari S, Hepburn S, Rogers SJ. Gross motor development, movement abnormalities, and early identification of autism. Journal of Autism and Developmental Disorders 2008;38(4):644-656. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
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  • Full-text: SpringerLink-Full Text HTML
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  • Journal Article Palkovicova L, Ursinyova M, Masanova V, Yu Z, Hertz-Picciotto I. Maternal amalgam dental fillings as the source of mercury exposure in developing fetus and newborn. Journal of Exposure Science & Environmental Epidemiology 2008;18(3):326-331. R829388 (2007)
    R829388 (Final)
    R833292 (2007)
    R833292 (2008)
    R833292 (2009)
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  • Journal Article Paolini C, Fessenden JD, Pessah IN, Franzini-Armstrong C. Evidence for conformational coupling between two calcium channels. Proceedings of the National Academy of Sciences of the United States of America 2004;101(34):12748-12752. R829388 (Final)
    R829388C006 (2005)
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  • Journal Article Park H-Y, Hertz-Picciotto I, Petrik J, Palkovicova L, Kocan A, Trnovec T.
 Prenatal PCB exposure and thymus size at birth in neonates in Eastern Slovakia.
 Environmental Health Perspectives 2008;116(1):104-109. R829388 (Final)
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  • Journal Article Pessah IN, Hansen LG, Albertson TE, Garner CE, Ta TA, Do Z, Kim KH, Wong PW. Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1). Chemical Research in Toxicology 2006;19(1):92-101. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R833292 (2007)
    R833292 (2009)
    R833292 (Final)
  • Abstract from PubMed
  • Full-text: University of California, Davis-PDF
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  • Abstract: ACS Publications-Abstract
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  • Journal Article Pessah IN, Seegal RF, Lein PJ, LaSalle J, Yee BK, Van de Water J, Berman RF. Immunologic and neurodevelopmental susceptibilities of autism. NeuroToxicology 2008;29(3):532-545. R829388 (Final)
    R833292 (2008)
    R833292 (Final)
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  • Journal Article Phimister AJ, Lango J, Lee EH, Ernst-Russell MA, Takeshima H, Ma J, Allen PD, Pessah IN.
 Conformation-dependent stability of junctophilin 1 (JP1) and ryanodine receptor type 1 (RyR1) channel complex is mediated by their hyper-reactive thiols.
 Journal of Biological Chemistry 2007;282(12):8667-8677. R829388 (Final)
    R833292 (2007)
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  • Full-text: Journal of Biological Chemistry-Full Text HTML
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  • Journal Article Ran R, Pan R, Lu A, Xu H, Davis RR, Sharp FR. 
A novel 165-kDa Golgin protein induced by brain ischemia and phosphorylated by Akt protects against apoptosis. 
Molecular and Cellular Neuroscience 2007;36(3):392-407. R829388 (Final)
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  • Abstract: Science Direct-Abstract
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  • Journal Article Roegge CS, Morris JR, Villareal S, Wang VC, Powers BE, Klintsova AY, Greenough WT, Pessah IN, Schantz SL. Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg. Neurotoxicology and Teratology 2006;28(1):74-85. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R829390 (2005)
    R829390C001 (2005)
  • Abstract from PubMed
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  • Journal Article Sakimura JN, Dang MT, Ballard KB, Hansen RL. Cognitive and temperament clusters in 3- to 5-year-old children with aggressive behavior. Journal of School Health 2008;78(1):38-45. R829388 (Final)
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  • Abstract: Journal of School Health-Abstract
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  • Journal Article Schmelzer KR, Kubala L, Newman JW, Kim I-H, Eiserich JP, Hammock BD.
 Soluble epoxide hydrolase is a therapeutic target for acute inflammation.
 Proceedings of the National Academy of Sciences of the United States of America 2005;102(28):9772-9777. R829388 (Final)
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  • Journal Article Schmelzer KR, Inceoglu B, Kubala L, Kim IH, Jinks SL, Eiserich JP, Hammock BD. Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors. Proceedings of the National Academy of Sciences of the United States of America 2006;103(37):13646-13651. R829388 (Final)
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  • Journal Article Schmelzer KR, Wheelock AM, Dettmer K, Morin D, Hammock BD. The role of inflammatory mediators in the synergistic toxicity of ozone and 1-nitronaphthalene in rat airways.
 Environmental Health Perspectives 2006;114(9):1354-1360. R829388 (Final)
    R833292 (Final)
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  • Journal Article Shearer GC, Newman JW, Hammock BD, Kaysen GA. Graded effects of proteinuria on HDL structure in nephrotic rats. Journal of the American Society of Nephrology 2005;16(5):1309-1319. R829388 (2006)
    R829388 (Final)
    R833292 (Final)
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  • Full-text: Journal of the American Society of Nephrology-Full Text HTML
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  • Abstract: Journal of the American Society of Nephrology-Abstract
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  • Journal Article Smilowitz JT, Dillard CJ, German JB. Milk beyond essential nutrients: the metabolic food.
 Australian Journal of Dairy Technology 2005;60(2):77-83. R829388 (Final)
    R833292 (Final)
  • Abstract: Dairy Industry Association of Australia-Abstract
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  • Other: ProQuest-Abstract
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  • Journal Article Smith KR, Pinkerton KE, Watanabe T, Pedersen TL, Ma SJ, Hammock BD. Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor. Proceedings of the National Academy of Sciences of the United States of America 2005;102(6):2186-2191. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Journal Article Sonneborn D, Park H-Y, Petrik J, Kocan A, Palkovicova L, Trnovec T, Nguyen D, Hertz-Picciotto I. Prenatal polychlorinated biphenyl exposures in eastern Slovakia modify effects of social factors on birthweight. Paediatric and Perinatal Epidemiology 2008;22(3):202-213. R829388 (Final)
    R833292 (Final)
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  • Abstract: Wiley Online-Abstract
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  • Journal Article Ta TA, Feng W, Molinski TF, Pessah IN. Hydroxylated xestospongins block inositol-1,4,5-trisphosphate-induced Ca2+ release and sensitize Ca2+-induced Ca2+ release mediated by ryanodine receptors. Molecular Pharmacology 2006;69(2):532-538. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
    R833292 (Final)
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  • Full-text: Molecular Pharmacology-Full Text HTML
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  • Journal Article Ta TA, Pessah IN. Ryanodine receptor type 1 (RyR1) possessing malignant hyperthermia mutation R615C exhibits heightened sensitivity to dysregulation by non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95). NeuroToxicology 2007;28(4):770-779. R829388 (2006)
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    R833292 (2007)
    R833292 (2008)
    R833292 (2009)
    R833292 (Final)
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  • Full-text: ScienceDirect - Full Text HTML
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  • Journal Article Viswanathan S, Hammock BD, Newman JW, Meerarani P, Toborek M, Hennig B. Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells. Journal of the American College of Nutrition 2003;22(6):502-510. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
  • Abstract from PubMed
  • Full-text: Journal of the American College of Nutrition-Full Text HTML
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  • Abstract: Journal of the American College of Nutrition
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  • Other: Journal of the American College of Nutrition-Full Text PDF
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  • Journal Article Voss AA, Lango J, Ernst-Russell M, Morin D, Pessah IN. Identification of hyperreactive cysteines within ryanodine receptor type 1 by mass spectrometry. Journal of Biological Chemistry 2004;279(33):34514-34520. R829388 (2006)
    R829388 (Final)
    R829388C006 (2005)
  • Abstract from PubMed
  • Full-text: Journal of Biological Chemistry
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  • Abstract: Journal of Biological Chemistry
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  • Other: Journal of Biological Chemistry PDF
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  • Journal Article Ward CW, Feng W, Tu J, Pessah IN, Worley PK, Schneider MF. Homer protein increases activation of Ca2+ sparks in permeabilized skeletal muscle. Journal of Biological Chemistry 2004;279(7):5781-5787. R829388 (Final)
    R829388C006 (2005)
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  • Full-text: Journal of Biological Chemistry
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  • Abstract: Journal of Biological Chemistry
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  • Journal Article Ward RE, Ninonuevo M, Mills DA, Lebrilla CB, German JB. In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri. Applied and Environmental Microbiology 2006;72(6):4497-4499. R829388 (Final)
    R833292 (Final)
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  • Full-text: AEM-Full Text HTML
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  • Journal Article Ward RE, Ninonuevo M, Mills DA, Lebrilla CB, German JB. In vitro fermentability of human milk oligosaccharides by several strains of bifidobacteria. Molecular Nutrition & Food Research 2007;51(11):1398-1405. R829388 (Final)
    R833292 (Final)
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  • Abstract: Wiley Online-Abstract
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  • Journal Article Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J. Autoantibodies in autism spectrum disorders (ASD).
 Annals of the New York Academy of Sciences 2007;1107:79-91. R829388 (Final)
    R833292 (2007)
    R833292 (Final)
  • Abstract from PubMed
  • Full-text: University of Texas-Dallas-Full Text PDF
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  • Abstract: Wiley Online-Abstract
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  • Journal Article Yang T, Riehl J, Esteve E, Matthaei KI, Goth S, Allen PD, Pessah IN, Lopez JR. Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. Anesthesiology 2006;105(6):1164-1175. R829388 (Final)
    R833292 (2007)
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  • Abstract: Anesthesiology
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  • Journal Article Yang T, Allen PD, Pessah IN, Lopez JR. Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. 
Journal of Biological Chemistry 2007;282(52):37471-37478. R829388 (Final)
    R833292 (2007)
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  • Journal Article Yang W, Yaoi T, Huang S, Yang Q, Hatcher S, Seet H, Gregg JP. Detecting the C282Y and H63D mutations of the HFE gene by Holliday Junction-based allele-specific genotyping methods. Clinical Chemistry 2005;51(1):210-213. R829388 (2006)
    R829388 (Final)
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  • Full-text: Clinical Chemistry-Full Text HTML
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  • Abstract: Clinical Chemistry
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  • Journal Article Zhao X, Yamamoto T, Newman JW, Kim I-H, Watanabe T, Hammock BD, Stewart J, Pollock JS, Pollock DM, Imig JD. Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. Journal of the American Society of Nephrology 2004;15(5):1244-1253. R829388 (2006)
    R829388 (Final)
    R829388C001 (2005)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, Toxics, Toxicology, Health Risk Assessment, Chemistry, Epidemiology, climate change, pesticides, Air Pollution Effects, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Disease & Cumulative Effects, Physical Processes, Children's Health, genetic susceptability, Biology, Atmosphere, environmental monitoring, pesticide exposure, neurotoxic, chemical exposure, biomarkers, xenobiotics, exposure, gene-environment interaction, neurodevelopment, halogenated aromatics, children, neurobehavioral, neurodevelopmental, neurotoxicity, etiology, human exposure, susceptibility, autism, neurobehavioral effects, biological markers, mechanisms, exposure assessment, human health risk, synergistic interactions, halogenated aromatic hydrocarbons, biomarker, neurological development

    Progress and Final Reports:

    Original Abstract
    2006 Progress Report
    2007 Progress Report

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