Grantee Research Project Results
Final Report: Center for Childhood Neurotoxicology and Assessment
EPA Grant Number: R829391Center: Health Effects Institute (2005 — 2010)
Center Director: Greenbaum, Daniel S.
Title: Center for Childhood Neurotoxicology and Assessment
Investigators: Lambert, George H. , Wagner, George , Wilson, Daniel , Polunas, Marianne , Halladay, Alycia , DiCicco-Bloom, Emanuel , Burke, Kelly , Davidovics, Zev , Rossman, Ian , Ruehl, Kenneth R
Institution: University of Medicine and Dentistry of New Jersey
EPA Project Officer: Hahn, Intaek
Project Period: November 1, 2001 through October 31, 2006 (Extended to October 31, 2008)
Project Amount: $6,751,466
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
This research drove the scientists into studying the relationship and mechanism of oxidative stress as it relates to environmental chemical and a wide variety of clinical disease processes. The Center continues to work with the cohort and families of children with autism, but the Center has expanded the clinical disease states to include a wider variety of environmental health issues. These include asthma, reproductive endocrine disruption of the male, and health disparities of an African American poor community with devastating environmental conditions.
Summary/Accomplishments (Outputs/Outcomes):
A) Major Clinical findings
The most important clinical findings are in regards to autism. The most important clinical and research findings are in 3 areas: oxidative stress, genes, and exposure monitoring.
In the genetic areas the work of Johnson, Ming, Mars, Novotny, Stenroos and Buyske resulted in several major findings (Buyske 2006, Williams 2007). The glutathione transferase (GST) null polymorphism were more at risk of having autism then children with the wild type gene. The children with autism had the null gene almost 70% of the time while the normal population had the null GSTM1 gene at about 42% of the population. This gene association carried for the father also. We also identified that if the mother had a gene polymorphism of the GSTP1 the child was at greater risk for developing autism.
These GST polymorphisms which would decrease the children’s ability to detoxify active endogenous and exogenous reactive molecules, would indicate that the GST enzymes and the capacity to detoxify reactive chemicals may be deficient in the children and the parents of children who get autism. Indicating that they may have genetic increased susceptibility to develop autism. What we found of most interest was that these were the same polymorphism that have been linked o increased susceptibility to other diseases states including asthma and cancer. In fact as we were identifying that the children did not seem to have markedly increased body burdens of environmental chemicals (See below), that the key to their susceptibility would for some children with autism lie in the genes and possibly one or two major pathways of toxicity such as the oxidative stress/inflammatory pathway. We had developed a model system of gene-environment-autism paradigm and even held a major scientific symposium on the topic with 20 outside speakers at the inception of the Center.
Our next major breakthrough occurred with the coloration of the neurogenetists (Johnson), the autism expert and pharmacologist (Ming) and the biochemist (Stein). Stein had been working many years on oxidative stress and they ran isoprostane assays on the urine of children with autism. The Center members were not totally surprised with the finding, but they were surprised at the degree of elevation. The urinary isoprostane levels of the children with autism were several fold higher than the children without autism (Ming 2005). We next examined the levels to see if there was a genetic link. Not to our surprise we found that the children with autism and with the null GSTM1 gene had the highest levels of urinary isoprostane levels as compare to the children with autism and the wild type GSTM1. This did not hold true for maternal or paternal genotype (unpublished).
Since our work and the work of others such as James identified the GSH related pathways were involved, the same group took the Center children and other children and looked at glutathione peroxidase and found the possessing the ALA6 allele may be protective of acquiring autism, (Ming 2009).
Finally our work and a growing number of others indicated that not only oxidative stress but inflammation and in particular autoimmune function may be in autism. Johnson with the labs in Harvard identified a autiimmune associated haplotype that is identified with children with autism (in press, see autism project).
These discoveries of the Center could not have been possible without two additional factors. Dr Johnson has been championing the gene transmission disequilibrium testing for essentially maternal / congenital disease states. This is where the genes of multiple generation are testing to determine which genes increase the risk of the disease state. Also Steve Buyske from Rutgers was developing new methods of neurogene statistics (2006). It took the Center to bring all of the forces together and work collectively. But this did not end the story as identified in the current Center application and with other studies that have been going on with the Center’s no cost extension.
Since one of the factors was oxidative stress and inflammation and possible the exaggerated response, the next question turned to how to better regulate these pathways. As science goes, the lab next door to Dr Stein, who is the oxidative stress biomarker core leader is Dr Spur had been working on the lipid mediators of oxidative stress and inflammation for years. He had done of the sentinel work of these factors in asthma and also he was part of the only group who has ever given them to the human. His interests were in these so-called proresolutin lipids for over 20 years. So a few years ago he joined the group. With his input the group expanded its interest to lipid modulators of inflammation and oxidative stress. The group developed clinical protocols looking at the biochemical effect of the 3 omega PUFA, docosahexaenoic acid (DHA), since it appears to downregulate these toxic pathways, and some reports from Austria (Amminger, 2007-see autism sectioni) had early evidence that they may improve the behavior of children with autism. There two studies were developed using the Omega threes in autism and both were funded (NIH, & DOD) 1-2 years ago. See autism section for more discussion.
The next Center development was the start of the study and work with lipoxins and resolvins. The critical nature of these chemicals had been worked out by Serhan and his group at Harvard and several others. The DHA and arachnaedonic acid are metabolized to these compounds and they appear to be the true regulators of the proresolving function of DHA. The group then synthesized the molecules (Spur) and began testing these as biomarkers of the lipid regulators. It appears that they will be important as biomarkers but also potential innovative drugs to treat a wide variety of disease. That brings these finding and researchers to the end of the EPA extension and to the work proposed in this application and extension of this work.
The autism clinical studies had a few more important findings not related to OS or inflammation. One was the study of Carmody and Lambert (Carmody 2007) looking at the functional MRI of children with autism and they showed that the brain of children with autism response to names at a different intensity and location than children without autism. Dr Lambert who was present for all these studies, stopped them when he felt that the children’s conscious sedation which was for slightly over an hour a put the children at risk for airway blockage and potential respiratory arrest. There were 11 children studied and two had mucous plugs removed just before aspiration, Therefore these studies were stopped by Dr. Lambert. These were important findings but the risk/ benefit ratio was a concern.
The last of the clinical studies were that of Dr. Lioy on exposure measuring. The homes and the children did not have any increase of the environmental chemicals that were tested. The only increase found in the homes was where the mother reported more frequent use of home care products. The relevance was not determined. But the children’s blood, hair and urine did not have any increase of chemicals nor the did dust, dirt, or air in the homes. We looked at regression and did not find increased levels in the home or children with autistic regression and were not able to quantitate a markedly increased hand to mouth relationship with regression.
Beside the federal grants obtained by the Center, a potentially more potent accomplishments is in that over the last 7 years the Center members using some of the data and other data they developed had 8 patents filed and accepted by the patent office. The patents include synthesis of lipid mediators, and isoprostane, use of gene and biomarkers to identify children with disorders and develop personalized approaches to treat or ameliorate these diseases, use of biomarkers in diagnosis and treatment, the therapeutic use of some of the resolvins and Lipoxins.
B) Animal Studies
There were 3 animal studies, all three made great progress. One of the animal studies, That of Dr Wagner is asked for funding in this current proposal. See animal studies.
The other studies are going on but funding is not requested due to the focus of their research is not into oxidative stress – inflammation and these research did not want to go in that direction at the time. Also due to severe funding limitation of the Center funding, there are major projects that the Center is caring out under outside third party grants or without grant support that appear to be finding clinically important findings on other pediatric environmental health diseases. Therefore funding is only requested for George Wagner animal project.
Dr Wagner has been interested in the role of oxidative stress and regulation of oxidative stress in controlling chemical induced altered neurodevelopment. He developed a- regression – like mouse model induced by exposure to environmental chemicals and was able to show he could protect the developing mouse to the point of having normal development with antioxidants. He has been working with the group for the pat 7 years and his animal project is listed in the animal project section of the this current grant submission.
Finally Dr Wagner was instrumental in deciding to pay for the development of a GSTM! Knockout mouse from U Conn which was paid for by the original Center. From his preliminary studies he was able to show this mouse has heightened sensitivity to chemical induced toxicity and the male is more sensitive than the female. Please see his Project for his vision of future research. He has been working with two cores and his work is relevant to all the clinical studies.
The RFA requested a detailed report of the two animal studies not being funded, but we will provide all the reports of the animal studies that were sent in when to NIH and EPA when funding stopped in 2006.
Animal Project #1 Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury—Reuhl, Zhou and Lowndes
Overview: The goal of this project was to test the hypothesis that neurotoxic metals perturb brain development/morphogenesis by disrupting the co-regulated expression and function of critical morphoregulatory adhesion and repulsion molecules. The project had four specific questions:
- Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules during critical stages of brain development and thereby compromise morphogenesis?
- Do selective transcriptional, translational or posttranslational processes mediate metal-induced changes in adhesion and repulsion molecules?
- What are the behavioral consequences of toxicant-disturbed adhesion and repulsion molecules?
- Can the deleterious effects of toxic metals on morphoregulatory molecules be modified or ameliorated by intervention strategies?
Results: Significant progress was made on each of the research questions. They will be discussed individually.
- Our data convincingly demonstrate that adhesion and repulsion molecules represent a significant target for neurotoxic heavy metals during neural development. Several representative molecules for both the adhesion (NCAM and L1) and repulsion family (Eph-ephrin) families of molecules were studies. Expression of each of these molecules is developmentally regulated, and the molecules appear to serve a number of morphoregulatory roles as the brain forms. Moreover, the expression of each is influenced by the expression of the other, reflecting the complex interplay of morphogenetic cues during cytoarchitectural formation. Using MeHg and trimethyltin as model toxicants, we examined the roles of these molecules using cell culture and in vivo models. In the P19 embryonal carcinoma cell model of neurogenesis, MeHg induced increases in specific classes of Ephs and their ephrin ligands. Both A and B class Ephs were involved, with the most pronounced effects in the -A2, -A3 and –B3 forms, and significant induction of the ephrin –A5, -A6, -B1 and B-2 ligands. These studies were supported by in vivo experiments, in which low-level MeHg exposure caused changes in hippocampal ephrin A5, A6 and ephrin A2. Studies performed in parallel demonstrated that MeHg inhibited the expression of sialylated NCAM 180 isoform without major change of the NCAM 120 isoform. The effects on NCAM were most pronounced later in brain development and during weaning, whilst those on the Eph/ephrin system appeared during early neurogenesis. In aggregate, these experiments indicate that the effects are molecule- and developmental stage specific, and involve processes central to brain development.
- Our studies have identified defects at the transcriptional, translational and posttranslational levels; however, these defects are not global (ie. are not non-specific reflections of overall cell damage, but rather specific effects on these molecular targets). In a comprehensive study of Eph/ephrin RNAs during neuronal development using an RNAse protection assay, we demonstrated alterations in RNAs for specific families of the ligand and its receptors. These data were supported by Western blot analysis, indicating that the protein changes were associated with RNA alterations. In contrast, at the highest MeHg concentration proteins decreased, suggesting that MeHg is affecting the protein synthesis, perhaps at the level of translation (a logical conclusion since high level MeHg exposure disassembles ribosomes and would inhibit synthesis). In contrast, the effects of MeHg and trimethyltin on NCAM appear at several levels. Translational efficiency for the molecule is reduced, and at low concentration, both appear to affect golgi sialyltransferase activity. This enzyme is critical for the addition of sialic acids to the extracellular domain of NCAM, a critical step in its function in morphogenesis and synaptic plasticity. The effects on the sialyltransferase were persistent likely contribute to the behavioral effects displayed by organisms intoxicated with these metals. This hypothesis was tested in question #3.
- The mechanisms underlying cognitive disturbances following heavy metal exposure during development are largely unknown. Numerous studies have shown the critical roles of adhesion/repulsion molecules during development and in behavioral performance. We examined the behavioral consequences of toxicant disturbance on adhesion molecule expression. Using the trimethyltin model to selectively target the limbic system, specific changes in PSA-NCAM expression were shown to underlie altered performance. Decrements in performance on a spatial memory task (water maze) were associated with loss of PSA-NCAM, and conversely, learning performance improved with enhanced expression of PSA-NCAM. Trimethyltin blocked enhanced expression of the molecule normally associated with learning and synaptic plasticity. Studies to extend this hypothesis to the developing brain are still ongoing and are by design significantly more complicated. However, preliminary data confirm the strong association of PSA-NCAM with cognitive performance. We are currently investigating whether PSA-NCAM expression (or that of other adhesion/repulsion molecules) may serve as a biomarker for CNS integrity. Cerebral spinal fluid is being banked for molecular analysis and will be the subject of a future grant application.
- We have demonstrated that the levels of both NCAM 180 and several Eph/ephrins can be influenced by behavioral learning paradigms, as their recognized role in learning and memory would suggest. These data suggest that behavioral enrichment strategies may be therapeutically valuable during the early stages of developmental insult. We have also studied whether antioxidants such as vitamin E and Trolox might mediate their protective effects against metals vial protection of adhesion/repulsion molecules. Trolox is protective against MeHg but not trimethyltin, suggesting that MeHg is mediating its effects, in part, thorough an ROS pathway, while trimethyltin is not. Trolox also appears to afford some protection against opening of the mitochondrial transition pore in neurons, an event often associated with release of activated caspase 3 and activation of the apoptotic pathway. Trolox appears to protect against some of the long term and delayed effects of MeHg, which may have implication for the longitudinal management of affected children.
Animal Project #2 Disruption of Ontogenic Development of Cognitive and Sensory/Motor Skills by Exposure to Metals
First an animal model of autism was developed. This required individuals with expertise in behavior, genetics, toxicology, and community medicine joining forces as the Center grant provided. The animal behavior component provided the functional evaluation of mice following early toxicant exposure, especially in the context of genetic manipulation. Mice were evaluated for toxicant-induced deficits following pre- or post-natal exposure. The functional deficits were in the broad behavioral classes of social, cognitive, emotional and/or motoric. For each of these classes, the toxicant-induced deficits were classified as developmental retardation, developmental regression, or intrusive behaviors. But these behavioral deficits had to be linked to human developmental disorders. This link was provided by the community medicine and toxicology components identifying toxicants and the genetics component identifying genes associated with autism and providing the gene-altered mice to test in our behavioral battery.
Second, the Center provided translational research opportunities. Specifically, Dr. Xue Ming, M.D., Ph.D., a pediatric neurologist from UMDNJ and GCW teamed up to examine oxidative stress in humans and toxicant-exposed mice. These ongoing studies lead to testing antioxidants in the mouse model, a feature that was also examined in the human with autism and found to be altered (Ming et al 2004).
Direct impacts of research from the Center on clinical medicine, public health, public policy, as related to children's health.
The most important observation is that application of the mouse model lead us to identify oxidative stress as a final common path of a wide variety of toxicants. With this, it was soon observed that humans with autism have increased levels of biomarkers of oxidative stress in their urine. We next demonstrated that antioxidants at the time of toxicant exposure completely protect mice against the functional consequences. This observation is of importance because there are events that may place a fetus or neonate "at risk" and this may be the prudent time to administer the antioxidants.
Animal Project #3 Neuronal Growth and Environmental Chemicals
Our work on autism models directly benefited from our continuing interactions with other animal modelers working with neurotoxicants on the one hand and clinicans and families with environmental concerns. Direct impacts of research from the Center on clinical medicine, public health, public policy as related to chldren's health. The discovery of effects of methylmercury on hippocampal neurogenesis and learning may impact policies regarding dietary restrictions on Hg containing fish pre- and postnatally in those possibly at risk, especially as we discover the lowest doses at which there are negative consequences for brain structure and function. The discovery of En2 as an autism susceptibility gene is allowing definition of developmental pathways that contribute to producing the brain phenotype. This may allow early assessment of what is altered to produce dysfunction and allow new treatments to emerge. Trainees (students and post docs) mentored within the Center since inception, what they did, and their career paths since the time they were with the center.
Conclusions:
From the perspective of the basic sciences projects, three major achievements stand out. All of these achievements required the interactions of multiple participants from the Center, and without the Center it is unlikely that these collaborative bridges would have been developed.
Work in Dr. Wagner’s laboratory has developed and validated several valuable models of autism in mice using toxicants, and has performed extensive behavioral characterization and morphological assessment of these animals. He has also examined the ability of antioxidants to prevent or ameliorate these behavioral effects
Work in Dr. Dicicco-Bloom’s laboratory has identified a sensitive period of neurogenesis during which the toxicant methylmercury (MeHg) exerts a strong inhibitory effect on hippocampal granule cell formation. Further mechanistic studies identified cyclin E, a regulator of cell cycle entry, was inhibited by the toxicant at low doses. These studies have led to the development of a program in Dr. Dicicco-Bloom’s lab examining the effects of toxicants on early hippocampal development and its functional consequences.
Work in Dr. Reuhl’s laboratory has identified adhesion-repulsion molecules as major targets of several classes of environmental neurotoxicants, most notably metals. Using an RNAse protection model, we identified persistent, altered expression of NCAM, L1 adhesion molecules and multiple Eph-ephrin repulsion molecules during brain development. Significantly, these molecules are key participants in topographic modeling of brain pathways and in synaptogenesis.
The effect of MeHg on the adhesion molecules was shown to involve inhibition of a golgi sialyltransferase. These effects were shown to have behavioral consequences, and could be at least partially ameliorated by the synthetic vitamin E, Trolox.
The findings reiterate the importance of limiting exposure to MeHg (and other toxicants) during pregnancy. The data also suggest that high-risk females might consider taking supplemental vitamin E, although this conclusion is not sufficiently strong to suggest policy.
Journal Articles: 85 Displayed | Download in RIS Format
| Other center views: | All 122 publications | 86 publications in selected types | All 85 journal articles |
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Akland GG, Pellizzari ED, Hu Y, Roberds M, Rohrer CA, Leckie JO, Berry MR. Factors influencing total dietary exposures of young children. Journal of Exposure Analysis and Environmental Epidemiology 2000;10(6 Pt 2):710-722. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2005) |
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Ayotte P, Dewailly E, Lambert GH, Perkins SL, Poon R, Feeley M, Larochelle C, Pereg D. Biomarker measurements in a coastal fish-eating population environmentally exposed to organochlorines. Environmental Health Perspectives 2005;113(10):1318-1324. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C005 (2006) |
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Benayed R, Gharani N, Rossman I, Mancuso V, Lazar G, Kamdar S, Bruse SE, Tischfield S, Smith BJ, Zimmerman RA, DiCicco-Bloom E, Brzustowicz LM, Millonig JH. Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. American Journal of Human Genetics 2005;77(5):851-868. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C001 (2006) |
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Black K, Shalat SL, Freeman NCG, Jimenez M, Donnelly KC, Calvin JA. Children's mouthing and food-handling behavior in an agricultural community on the US/Mexico border. Journal of Exposure Analysis and Environmental Epidemiology 2005;15(3):244-251. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2004) R829391C004 (2005) |
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Brenz Verca MS, Bahi A, Boyer F, Wagner GC, Dreyer J-L. Distribution of α- and γ-synucleins in the adult rat brain and their modification by high-dose cocaine treatment. European Journal of Neuroscience 2003;18(7):1923-1938. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2005) |
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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. |
R829391 (2006) R829391 (Final) R829388 (2006) R829388 (Final) R829388C005 (2005) R833292 (2009) R833292 (Final) |
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Buyske S, Williams TA, Mars AE, Stenroos ES, Ming SX, Wang R, Sreenath M, Factura MF, Reddy C, Lambert GH, Johnson WG. Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism. BMC Genetics 2006;7(1):8 (9 pp.). |
R829391 (2006) R829391 (Final) |
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Calafat AM, Needham LL, Silva MJ, Lambert G. Exposure to di-(2-ethylhexyl) phthalate among premature neonates in a neonatal intensive care unit. Pediatrics 2004;113(5):e429-e434. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C005 (2006) |
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Carlson KM, Wagner GC. Effects of phencyclidine on schedule-controlled responding following neurotoxic lesions of the striatum. Life Sciences 2005;77(4):372-385. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C003 (2006) |
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Carmody DP, Dunn SM, Boddie-Willis AS, DeMarco JK, Lewis M. A quantitative measure of myelination development in infants, using MR images. Neuroradiology 2004;46(9):781-786. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C005 (2006) |
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Carmody DP, Moreno R, Mars AE, Seshadri K, Lambert GH, Lewis M. Brief report: brain activation to social words in a sedated child with autism. Journal of Autism and Developmental Disorders 2007;37(7):1381-1385. |
R829391 (2006) R829391 (Final) |
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Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, Kamdar S, Wagner GC. En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Research 2006;1116(1):166-176. |
R829391 (2006) |
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Chen T-F, Zhang Y-L, Xu W-L, Li Z-Q, Hou B, Wang C-L, Fan M, Qian L-J, Zhou R-P, Zhang C-G. Prokaryotic expression, polyclonal antibody preparation, and sub-cellular localization analysis of Na+, K+-ATPase β2 subunit. Protein Expression and Purification 2004;37(1):47-52. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C002 (2006) |
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Chen Z-Y, Sun C, Reuhl K, Bergemann A, Henkemeyer M, Zhou R. Abnormal hippocampal axon bundling in EphB receptor mutant mice. Journal of Neuroscience 2004;24(10):2366-2374. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C002 (2005) |
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Davidovics Z, DiCicco-Bloom E. Moderate lead exposure elicits neurotrophic effects in cerebral cortical precursor cells in culture. Journal of Neuroscience Research 2005;80(6):817-825. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C001 (2006) |
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Falluel-Morel A, Sokolowski K, Sisti HM, Zhou X, Shors TJ, Dicicco-Bloom E. Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty. Journal of Neurochemistry 2007;103(5):1968-1981. |
R829391 (2006) R829391 (Final) |
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Fitzgerald EF, Hwang SA, Lambert G, Gomez M, Tarbell A. PCB exposure and in vivo CYP1A2 activity among Native Americans. Environmental Health Perspectives 2005;113(3):272-277. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C005 (2006) |
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Freeman NCG, Jimenez M, Reed KJ, Gurunathan S, Edwards RD, Roy A, Adgate JL, Pellizzari ED, Quackenboss J, Sexton K, Lioy PJ. Quantitative analysis of children's microactivity patterns: the Minnesota Children's Pesticide Exposure Study. Journal of Exposure Analysis and Environmental Epidemiology 2001;11(6):501-509. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2005) |
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Freeman NCG, Sheldon L, Jimenez M, Melnyk L, Pellizzari E, Berry M. Contribution of children's activities to lead contamination of food. Journal of Exposure Analysis and Environmental Epidemiology 2001;11(5):407-413. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2005) |
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Freeman NCG, Shalat SL, Black K, Jimenez M, Donnelly KC, Calvin A, Ramirez J. Seasonal pesticide use in a rural community on the U.S./Mexico border. Journal of Exposure Analysis and Environmental Epidemiology 2004;14(6):473-478. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2004) |
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Georgopoulos PG, Wang S-W, Vyas VM, Sun Q, Burke J, Vedantham R, McCurdy T, Ozkaynak H. A source-to-dose assessment of population exposures to fine PM and ozone in Philadelphia, PA, during a summer 1999 episode.Journal of Exposure Analysis and Environmental Epidemiology 2005;15(5):439-457. |
R829391 (Final) R826768 (Final) |
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Georgopoulos PG, Lioy PJ. From a theoretical framework of human exposure and dose assessment to computational system implementation: the Modeling ENvironment for TOtal Risk Studies (MENTOR). Journal of Toxicology and Environmental Health, Part B-Critical Reviews 2006;9(6):457-483. |
R829391 (2006) R829391 (Final) R826768 (Final) |
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Halladay AK, Kusnecov A, Michna L, Kita T, Hara C, Wagner GC. Relationship between methamphetamine-induced dopamine release, hyperthermia, self-injurious behaviour and long term dopamine depletion in BALB/c and C57BL/6 mice. Pharmacology & Toxicology 2003;93(1):33-41. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2004) |
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Halladay AK, Tessarollo L, Zhou R, Wagner GC. Neurochemical and behavioral deficits consequent to expression of a dominant negative EphA5 receptor. Molecular Brain Research 2004;123(1-2):104-111. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2005) |
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Halladay AK, Wagner GC, Sekowski A, Rothman RB, Baumann MH, Fisher H. Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan. Synapse 2006;59(5):277-289. |
R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2006) |
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Halladay AK, Wilson DT, Wagner GC, Reuhl KR. Trimethyltin-induced alterations in behavior are linked to changes in PSA-NCAM expression. NeuroToxicology 2006;27(2):137-146. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C002 (2005) |
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Hsu PC, Lai TJ, Guo NW, Lambert GH, Leon Guo Y. Serum hormones in boys prenatally exposed to polychlorinated biphenyls and dibenzofurans. Journal of Toxicology and Environmental Health-Part A 2005;68(17-18):1447-1456. |
R829391 (2006) R829391 (Final) |
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Hsu P-C, Huang W, Yao W-J, Wu M-H, Guo YL, Lambert GH. Sperm changes in men exposed to polychlorinated biphenyls and dibenzofurans. Journal of the American Medical Association 2003;289(22):2943-2944. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C005 (2004) |
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Hu Z, Yue X, Shi G, Yue Y, Crockett DP, Blair-Flynn J, Reuhl K, Tessarollo L, Zhou R. Corpus callosum deficiency in transgenic mice expressing a truncated ephrin-A receptor. Journal of Neuroscience 2003;23(34):10963-10970. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C002 (2005) |
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Hu Z, Cooper M, Crockett DP, Zhou R. Differentiation of the midbrain dopaminergic pathways during mouse development. Journal of Comparative Neurology 2004;476(3):301-311. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C002 (2006) |
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Israel BA, Parker EA, Rowe Z, Salvatore A, Minkler M, Lopez J, Butz A, Mosley A, Coates L, Lambert G, Potito PA, Brenner B, Rivera M, Romero H, Thompson B, Coronado G, Halstead S. Community-based participatory research:lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environmental Health Perspectives 2005;113(10):1463-1471. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C005 (2006) R826710 (Final) R831709 (2005) R831709 (2007) R831709 (Final) R831709C003 (2005) R831709C003 (2006) R831710 (2004) R831710 (2005) R831710 (Final) R831710C001 (2006) R831710C002 (2006) R831710C004 (2006) R831711 (2005) R831711 (2006) R831711 (2007) R831711 (Final) R831711C001 (2006) R831711C002 (2006) R831711C003 (2006) R832139 (2006) |
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Johnson SK, Carlson KM, Lee J, Burr LE, Wagner GC. Effects of nicotine on target biting and resident-intruder attack. Life Sciences 2003;73(3):311-317. |
R829391 (2006) R829391 (Final) |
Exit Exit |
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Johnson WG, Scholl TO, Spychala JR, Buyske S, Stenroos ES, Chen X. Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery. American Journal of Clinical Nutrition 2005;81(3):664-668. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C005 (2006) |
Exit Exit |
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Kita T, Wagner GC, Nakashima T. Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. Journal of Pharmacological Sciences 2003;92(3):178-195. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2005) |
Exit Exit |
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Lioy PJ, Freeman NC, Millette JR. Dust: a metric for use in residential and building exposure assessment and source characterization. Environmental Health Perspectives 2002;110(10):969-983. |
R829391 (2006) R829391 (Final) |
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Lioy PJ. Employing dynamical and chemical processes for contaminant mixtures outdoors to the indoor environment: the implications for total human exposure analysis and prevention. Journal of Exposure Science & Environmental Epidemiology 2006;16(3):207-224. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2006) |
Exit Exit |
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Martin JV, Nolan B, Wagner GC, Fisher H. Effects of dietary caffeine and alcohol on liver carbohydrate and fat metabolism in rats. Medical Science Monitor 2004;10(12):BR455-BR461. |
R829391 (2006) R829391 (Final) |
Exit Exit |
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Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins, Leukotrienes and Essential Fatty Acids 2005;73(5):379-384. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2006) |
Exit Exit |
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Prozialeck WC, Grunwald GB, Dey PM, Reuhl KR, Parrish AR. Cadherins and NCAM as potential targets in metal toxicity. Toxicology and Applied Pharmacology 2002;182(3):255-265. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C002 (2004) |
Exit Exit |
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Shalat SL, Donnelly KC, Freeman NCG, Calvin JA, Ramesh S, Jimenez M, Black K, Coutinho C, Needham LL, Barr DB, Ramirez J. Nondietary ingestion of pesticides by children in an agricultural community on the U.S./Mexico border: preliminary results. Journal of Exposure Analysis and Environmental Epidemiology 2003;13(1):42-50. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C004 (2004) R829391C004 (2005) |
Exit Exit |
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Turan VK, Sanchez RI, Li JJ, Li SA, Reuhl KR, Thomas PE, Conney AH, Gallo MA, Kauffman FC, Mesia-Vela S. The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone. Journal of Endocrinology 2004;183(1):91-99. |
R829391 (2006) R829391 (Final) |
Exit Exit |
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Wagner GC, Avena N, Kita T, Nakashima T, Fisher H, Halladay AK. Risperidone reduction of amphetamine-induced self-injurious behavior in mice. Neuropharmacology 2004;46(5):700-708. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C003 (2004) |
Exit |
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Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. Journal of Autism and Developmental Disorders 2006;36(6):779-793. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C002 (2006) R829391C003 (2004) |
Exit |
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Wagner GC, Reuhl KR, Ming X, Halladay AK. Behavioral and neurochemical sensitization to amphetamine following early postnatal administration of methylmercury (MeHg). NeuroToxicology 2007;28(1):59-66. |
R829391 (2006) R829391 (Final) |
Exit Exit |
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Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-Santiago MF, Lambert GH, Johnson WG. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Archives of Pediatric Adolescent Medicine 2007;161(4):356-361. |
R829391 (2006) R829391 (Final) |
Exit |
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Wilson DT, Polunas MA, Zhou R, Halladay AK, Lowndes HE, Reuhl KR. Methylmercury alters Eph and ephrin expression during neuronal differentiation of P19 embryonal carcinoma cells. NeuroToxicology 2005;26(4):661-674. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391 (Final) R829391C002 (2005) |
Exit Exit |
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Yang C-Y, Yu M-L, Guo H-R, Lai T-J, Hsu C-C, Lambert G, Guo YL. The endocrine and reproductive function of the female Yucheng adolescents prenatally exposed to PCBs/PCDFs. Chemosphere 2005;61(3):355-360. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C005 (2006) |
Exit Exit |
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Ye X, Fitzgerald EF, Gomez MI, Lambert GH, Longnecker MP. The ratio of specific polychlorinated biphenyls as a surrogate biomarker of cytochrome P4501A2 activity--a pharmaco-metabonomic study in humans. Cancer Epidemiology Biomarkers & Prevention 2008;17(4):1013-1025. |
R829391 (2006) R829391 (Final) |
Exit Exit |
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Yu CH, Yiin LM, Lioy PJ. The bioaccessibility of lead (Pb) from vacuumed house dust on carpets in urban residences. Risk Analysis 2006;26(1):125-134. |
R829391 (2006) R829391 (Final) |
Exit |
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Zhang C, Meng F, Wang C, Guo H, Fan M, Liu S, Zhou R, He F. Identification of a novel alternative splicing form of human netrin-4 and analyzing the expression patterns in adult rat brain. Molecular Brain Research 2004;130(1-2):68-80. |
R829391 (2004) R829391 (2005) R829391 (2006) R829391C002 (2006) |
Exit Exit |
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Hassett AL, Radvanski DC, Vaschillo EG, Vaschillo B, Sigal LH, Karavidas MK, Buyske S, Lehrer PM. A pilot study of the efficacy of heart rate variability (HRV) biofeedback in patients with fibromyalgia. Applied Psychophysiology and Biofeedback 2007;32:1-10. |
R829391 (Final) |
Exit |
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Matise TC, Chen F, Chen W, De La Vega FM, Hansen M, He C, Hyland FC, Kennedy GC, Kong X, Murray SS, Ziegle JS. A second-generation combined linkage–physical map of the human genome. Genome Research 2007;17(12):1783-1786. |
R829391 (Final) |
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Gernez Y, Tirouvanziam R, Nguyen KD, Herzenberg LA, Krensky AM, Nadeau KC. Altered phosphorylated signal transducer and activator of transcription profile of CD4+ CD161+ T cells in asthma:modulation by allergic status and oral corticosteroids. Journal of Allergy and Clinical Immunology 2007;120(6):1441-1448. |
R829391 (Final) |
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Goodin S, Shen F, Shih WJ, Dave N, Kane MP, Medina P, Lambert GH, Aisner J, Gallo M, DiPaola RS. Clinical and biological activity of soy protein powder supplementation in healthy male volunteers. Cancer Epidemiology Biomarkers & Prevention 2007;16(4):829-833. |
R829391 (Final) |
Exit |
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Mitchell CS, Zhang J, Sigsgaard T, Jantunen M, Lioy PJ, Samson R, Karol MH. Current state of the science:health effects and indoor environmental quality. Environmental Health Perspectives 2007;115(6):958-964. |
R829391 (Final) |
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Golbe LI, Iorio GD, Markopoulou K, Athanassiadou A, Papapetropoulos S, Watts RL, Vance JM, Bonifati V, Williams TA, Spychala JR, Stenroos ES. Glutathione S‐transferase polymorphisms and onset age in α‐synuclein A53T mutant Parkinson's disease. American Journal of Medical Genetics Part B:Neuropsychiatric Genetics 2007;144(2):254-258. |
R829391 (Final) |
Exit |
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Yin K, Gribbin E, Emanuel S, Orndorff R, Walker J, Weese J, Fallahnejad M. Histochemical alterations in one lung ventilation. Journal of Surgical Research 2007;137(1):16-20. |
R829391 (Final) |
Exit |
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Karavidas MK, Lehrer PM, Vaschillo E, Vaschillo B, Marin H, Buyske S, Malinovsky I, Radvanski D, Hassett A. Preliminary results of an open label study of heart rate variability biofeedback for the treatment of major depression. Applied Psychophysiology and Biofeedback 2007;32:19-30. |
R829391 (Final) |
Exit |
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Ming X, Brimacombe M, Wagner GC. Prevalence of motor impairment in autism spectrum disorders. Brain and Development 2007;29(9):565-570. |
R829391 (Final) |
Exit |
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McCreanor J, Cullinan P, Nieuwenhuijsen MJ, Stewart-Evans J, Malliarou E, Jarup L, Harrington R, Svartengren M, Han IK, Ohman-Strickland P, Chung KF. Respiratory effects of exposure to diesel traffic in persons with asthma. New England Journal of Medicine 2007;357(23):2348-2358. |
R829391 (Final) |
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Han IK, Duan X, Zhang L, Yang H, Rhoads GG, Wei F, Zhang J. 1-Hydroxypyrene concentrations in first morning voids and 24-h composite urine:intra-and inter-individual comparisons. Journal of Exposure Science & Environmental Epidemiology 2008;18(5):477-485. |
R829391 (Final) |
Exit |
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Pahuja M, Tran C, Wang H, Yin K. Alveolar macrophage suppression in sepsis is associated with high mobility group box 1 transmigration. Shock 2008;29(6):754-760. |
R829391 (Final) |
Exit |
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Mamiya PC, Hennesy Z, Zhou R, Wagner GC. Changes in attack behavior and activity in EphA5 knockout mice. Brain Research 2008;1205:91-99. |
R829391 (Final) |
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Connors SL, Levitt P, Matthews SG, Slotkin TA, Johnston MV, Kinney HC, Johnson WG, Dailey RM, Zimmerman AW. Fetal mechanisms in neurodevelopmental disorders. Pediatric Neurology 2008;38(3):163-176. |
R829391 (Final) |
Exit |
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Nadeau KC, Callejas A, Wong WB, Joh JW, Cohen HJ, Jeng MR. Idiopathic neutropenia of childhood is associated with Fas/FasL expression. Clinical Immunology 2008;129(3):438-447. |
R829391 (Final) |
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Yue G, Shi G, Azaro MA, Yang Q, Hu G, Luo M, Yin K, Nagele RG, Fine DH, Yang JM, Li H. Lipopolysaccharide (LPS) potentiates hydrogen peroxide toxicity in T98G astrocytoma cells by suppression of anti-oxidative and growth factor gene expression. BMC Genomics 2008;9:1-3. |
R829391 (Final) |
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Buyske S. Maternal genotype effects can alias case genotype effects in case–control studies. European Journal of Human Genetics 2008;16(7):784-785. |
R829391 (Final) |
Exit |
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Han JF, He XY, Herrington JS, White LA, Zhang JF, Hong JY. Metabolism of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) by human CYP1B1 genetic variants. Drug Metabolism and Disposition 2008;36(4):745-752. |
R829391 (Final) |
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Peter Stein T, Scholl TO, Schluter MD, Leskiw MJ, Chen X, Spur BW, Rodriguez A. Oxidative stress early in pregnancy and pregnancy outcome. Free Radical Research 2008;42(10):841-848. |
R829391 (Final) |
Exit |
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Spokas EG, Harshman S, Cohen GM, Jiang C, Levine JM, Rodriguez AR, Foglein J, Spur BW. Release of the lipid peroxidation marker 8‐epi‐prostaglandin F2α from isolated gill pavement cells. Environmental Toxicology and Chemistry 2008;27(7):1569-1575. |
R829391 (Final) |
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Hassett AL, Radvanski DC, Buyske S, Savage SV, Gara M, Escobar JI, Sigal LH. Role of psychiatric comorbidity in chronic Lyme disease. Arthritis Care & Research 2008;59(12):1742-1749. |
R829391 (Final) |
Exit |
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Fiedler N, Kipen H, Ohman-Strickland P, Zhang J, Weisel C, Laumbach R, Kelly-McNeil K, Olejeme K, Lioy P. Sensory and cognitive effects of acute exposure to hydrogen sulfide. Environmental Health Perspectives 2008;116(1):78-85. |
R829391 (Final) |
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Nekrasova T, Jobes ML, Ting JH, Wagner GC, Minden A. Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion. Developmental Biology 2008;322(1):95-108. |
R829391 (Final) |
Exit |
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Hassett AL, Li T, Buyske S, Savage SV, Gignac MA. The multi-faceted assessment of independence in patients with rheumatoid arthritis:preliminary validation from the ATTAIN study. Current Medical Research and Opinion 2008;24(5):1443-1453. |
R829391 (Final) |
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Hassett AL, Simonelli LE, Radvanski DC, Buyske S, Savage SV, Sigal LH. The relationship between affect balance style and clinical outcomes in fibromyalgia. Arthritis Care & Research:Official Journal of the American College of Rheumatology 2008;59(6):833-840. |
R829391 (Final) |
Exit |
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Ming X, Gordon E, Kang N, Wagner GC. Use of clonidine in children with autism spectrum disorders. Brain and Development 2008;30(7):454-460. |
R829391 (Final) |
Exit |
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Ju J, Nolan B, Cheh M, Bose M, Lin Y, Wagner GC, Yang CS. Voluntary exercise inhibits intestinal tumorigenesis in Apc Min/+ mice and azoxymethane/dextran sulfate sodium-treated mice. BMC Cancer 2008;8:1-8. |
R829391 (Final) |
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Nguyen KD, Fohner A, Booker JD, Dong C, Krensky AM, Nadeau KC. XCL1 enhances regulatory activities of CD4+ CD25highCD127low/− T cells in human allergic asthma. The Journal of Immunology 2008;181(8):5386-5395. |
R829391 (Final) |
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Buyske S. Comment on the article “Heterogeneous dysregulation of microRNAs across the autism spectrum” by Abu-Elneel et al. Neurogenetics 2009;10(2):167. |
R829391 (Final) |
Exit |
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Wratten NS, Memoli H, Huang Y, Dulencin AM, Matteson PG, Cornacchia MA, Azaro MA, Messenger J, Hayter JE, Bassett AS, Buyske S. Identification of a schizophrenia-associated functional noncoding variant in NOS1AP. American Journal of Psychiatry 2009;166(4):434-441. |
R829391 (Final) |
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Gramatges MM, Fani P, Nadeau K, Pereira S, Jeng MR. Neonatal alloimmune thrombocytopenia and neutropenia associated with maternal human leukocyte antigen antibodies. Pediatric Blood & Cancer 2009;53(1):97-99. |
R829391 (Final) |
Exit |
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Nguyen KD, Vanichsarn C, Fohner A, Nadeau KC. Selective deregulation in chemokine signaling pathways of CD4+ CD25hiCD127lo/− regulatory T cells in human allergic asthma. Journal of Allergy and Clinical Immunology 2009;123(4):933-939. |
R829391 (Final) |
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Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH, Buyske S. Genetic variant of glutathione peroxidase 1 in autism. Brain and Development 2010;32(2):105-109. |
R829391 (Final) |
Exit |
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Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, Bienfait K, Dicke A. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72(10):886-892. |
R829391 (Final) |
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Buyske S, Yang G, Matise TC, Gordon D. When a case is not a case:effects of phenotype misclassification on power and sample size requirements for the transmission disequilibrium test with affected child trios. Human Heredity 2009;67(4):287-292.. |
R829391 (Final) |
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Supplemental Keywords:
RFA, Scientific Discipline, Health, Toxicology, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Disease & Cumulative Effects, Ecological Risk Assessment, Children's Health, genetic susceptability, Biology, childhood learning, neurotoxic, behavioral assessment, gene-environment interaction, developmental effects, children, neurotoxicity, neurodevelopmental, assessment of exposure, public health, residential populations, behavioral deficits, environmental health hazard, environmental toxicant, autism, outreach and education, assessment technology, developmental disorders, exposure assessment, neurological developmentProgress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R829391C001 Neurotoxicant Effects on Cell Cycle Regulation of Neurogenesis
R829391C002 Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury
R829391C003 Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills
R829391C004 Exposure Assessment and Intervention Project (EAIP)
R829391C005 Clinical Sciences Project
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.