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University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment
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Principal Investigator: George Lambert, MD
| Overview | Results |
| Exposures and Outcomes | Community Partners |
| Research Projects | Selected Publications |
The main focus of the UMDNJ Children’s Center, established in 2002, is to examine the effects of environmental chemicals on neurological health and development, with an emphasis on the interaction between exposure to environmental factors, learning disabilities and autism spectrum disorders (ASD). Investigators at the UMDNJ Children’s Center have developed important basic and clinical science data, which has had a significant impact in the field. The causes and contributing factors for ASD are poorly understood. Evidence suggests that incidence of ASD is increasing, now estimated at 1 in every 150 births, and the rate is higher for male children. Most cases seem likely to arise from a combination of an ever increasing array of genetic factors and additional environmental factors, while diagnostic changes and improvements may also be contributing to the increased rates.
Projects at the UMDNJ Children’s Center include developing animal models of features of autism such as regression of neurobehavioral function or self-injurious behavior, and developing animal models mimicking the genes linked to autism in humans. Through clinical studies of children with autism, the UMDNJ Center is also examining whether certain biochemical and genetic characteristics of autistic children, demonstrate that select children with autism have increased susceptibility to chemical induced neurobehavioral dysfunction. such as loss of neurobehavioral function may be related to exposure to environmental neurotoxins, perhaps in combination with specific genetic predispositions, creating a gene-environment interaction. With the identification of the genetic and biochemical susceptibility factors the goal will be to develop individualized therapeutic interventional strategies. The overall mission of the Center is to improve the environmental and public health of children through research, assessment, treatment and outreach. The university has published a comprehensive profile of the research at the UMDNJ Children’s Center, and you can download it at this link:
http://www.umdnj.edu/research/publications/winter_04.pdf
Primary Exposures: Environmental neurotoxicants, including mercury
Primary Outcomes: Learning disabilities and autism.
Clinical Sciences Projects
Lead
investigator: George Lambert
In this set of studies, researchers are examining whether ASD (which includes autism) results from exposure to high levels of neurotoxicants in the environment. Researchers are also looking to see whether neurotoxicants can alter brain regional growth patterns, and if variants of genes that can affect the degree of chemical-induced oxidative stress are risk factors for autism, either in the mother or in the child. Also being examined is the frequency of specific genes coding for proteins that may influence susceptibility to environmental chemical-induced toxicity such as autism. Aims of this project include assessing the child’s body burden of neurotoxicants and levels of neurotoxicants in the home environment, and comparing these results with values found for children with typical behavior. Most recently the team has developed interventional strategies that are soon to be tested in the children with autism.
About 30% of children with ASD may have a regression of function or loss of some components of neurological and behavioral function during their first few years of life (12-30 months of age). This coincides with onset of the child’s physical capacity to explore their environment when the child may be exposed to increased levels of environmental neurotoxicants, particularly in children with ASD. The clinical projects examine how children with autism may be uniquely exposed to environmental chemicals and if children who experience regression have different genetic/biochemical susceptibility.
Children with ASD were selected for participation in the study after discussion with parents’ groups, health and education professionals, and communities concerned about the prevalence of children with neurobehavioral disorders and possible environmental causes. Currently children studies are undergoing review which are designed to evaluate interventional strategies in children in a closely monitored school setting.Basic Sciences Projects
The Basic Sciences Projects are using animal models to examine aspects of brain development. UMDNJ researchers have shown that neurotoxic metals and teratogens disrupt neurogenesis in developing brain systems, acting to inhibit proliferation by altering mitogenic growth factor receptors and cell cycle signaling pathways. Ongoing studies support diverse effects of neurotoxicants on neurodevelopment and look at biochemical and genetic susceptibility factors for environmental chemical induced neurological maldevelopment. In particular, disruption of ontogenic development and sensory/motor skills by exposure to metals.
- Ontogeny of Behavior Project: Disruption of Ontogenic Development of Cognitive and Sensory/Motor Skills by Exposure to Metals (G. Wagner)
This project examines the effects of toxicants such as methylmercury and lead on neurodevelopment, as seen by specific behaviors, using pharmacologic models of autism in mice. This project includes a characterization of key behaviors (such as balance beam performance) under normal conditions and testing to see how they are perturbed by exposure to lead and methylmercury The period when symptoms of developmental disorders appear may represent a time when environmental toxicants have accumulated in the brain to critical levels or the deleterious effects of early exposure become apparent through perturbation of normal development of brain pathways. Furthermore, certain individual may be more sensitive to toxicant due to genetic (perhaps immune-related) susceptibility.
Biomarkers of Oxidative Stress
Lead investigators: Bernd Spur and Peter Stein, Xue Ming
The research team is developing sensitive biomarkers of organ specific oxidative stress. Clinical trials are underway and have already demonstrated that some children with autism have altered oxidative stress that is exacerbated with select gene polymorphisms. A wide range of studies are underway examining the role of oxidative stress in select disease states that may be altered by exposure to environmental chemicals.
Center Abstract | Center Progress Reports: 2004 | 2005 | 2006
- A study of autistic children using magnetic resonance imaging (MRI) has shown that the brains of these children respond to specific verbal stimuli in a unique way not previously seen, and this pattern matches clinical behavior (Carmody).
- Children with autism and/or their parents appear to have a higher incidence of at least two newly identified gene deletions or polymorphisms that may make them more susceptible to environmental chemicals.
- Home environments of children with autism in these studies have low levels of traditional environmental chemicals, but many have higher concentrations of home care products. Home environmental chemical interventions have been recommended in a significant portion of the homes studied.
- Exposure to methylmercury (MeHg) decreases level of brain cortex DNA synthesis and increases cell loss and cell death.
- Exposure to lead acetate in cell culture appears to enhance cortical neuron survival and process outgrowth. This is especially relevant to children with autism, since they appear to have increased postnatal head growth as compared with the general population (DiCicco-Bloom).
- Exposure to MeHg exposure in newborn rats differentially inhibits neurogenesis in hippocampus and cerebellum, reducing DNA synthesis by 50% in the hippocampus. This raises concerns about chemical-induced teratogenesis (UMDNJ, DiCicco-Bloom).
- Mice exposed to sodium valproate (an antiseizure medication which is associated with increased risk of autism) exhibited a range of behavioral defects including retardation, regression and/or intrusions, with similar results for exposure to MeHg. These data provide validation that this model might be used for studying the effects of exposure to a wide range of environmental toxicants. Studies are now being conducted with this model using pesticides and plasticizers (Wagner et al. 2006).
- A study at the UMDNJ Children’s Center tested the hypothesis that children with autism have increased oxidative stress. 8-iso-PGF2alpha levels, a biomarker of oxidative stress, were significantly higher in children with autism. The majority of autistic subjects showed a moderate increase in isoprostane levels while a smaller group of autistic children showed dramatic increases in their isoprostane levels. These results suggest that the lipid peroxidation biomarker is increased in this cohort of autistic children, especially in the subgroup of autistic children (Ming et al. 2005).
- Researchers are continuing to identify the cellular mechanisms by which environmental chemicals can alter brain growth and development, and methods which can decrease the susceptibility of the brain to environmental toxicants. Researchers are also examining whether genes linked to autism increase the brain’s susceptibility to neurotoxins.
- Clinical studies are continuing to further identify gene-environment dependent neurobehavioral dysfunction in children with autism and if administration of certain chemicals can alter the way children with autism process environmental chemicals. Clinical studies are also examining if administration of certain chemicals can decrease the brain’s sensitivity to neurotoxins and lessen the symptoms of autism.
For more information, see the Childrens Center Autism Topic Page.
EPA also provides a number of ways to learn about children’s
health and autism. For more information, please visit:
http://www.epa.gov/region9/childhealth/autism.html
Also see:
http://www.nimh.nih.gov/publicat/autism.cfm
The UMDNJ Children’s Center research team has established a bond of trust between the Center and the greater autism community throughout New Jersey and the surrounding region.
The New Jersey Center for Outreach and Services for the Autism Community (COSAC) is a non-profit agency providing information and advocacy, services, family and professional education, and consultation to New Jersey's autism community. COSAC encourages responsible basic and applied research that would lead to a lessening of the effects and potential prevention of autism. COSAC is dedicated to ensuring that all people with autism receive appropriate, effective services to maximize their growth potential and to enhancing the overall awareness of autism in the general public.
The Eden Institute of Princeton provides a comprehensive continuum of lifespan services designed to enable children and adults with autism to lead fulfilling, productive and independent lives in their communities, to the full extent of their abilities. The non-profit organization was founded in 1975 when parents and professionals joined together to develop a family-oriented, multifaceted program to provide a community-based alternative to institutionalization of children and adults with autism.
The Douglass Developmental Disabilities Center (DDDC) of Rutgers University exists to meet the needs of people with autism spectrum disorders and their families. As an “Applied Behavior Analysis” (ABA), DDDC uses these principles to organize their delivery of services. They work collaboratively with the families of the children and adults we serve, and with the agencies that fund their treatment.
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 2005. Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. Am J Hum Genet. 2005 Nov;77(5):851-68. Epub 2005 Oct 5.
Buyske S, Williams
TA, Mars AE, Stenroos ES, Ming SX, Wang R, Sreenath M, Factura MF, Reddy
C, Lambert GH, Johnson WG 2006. Analysis of case-parent trios at a
locus with a deletion allele: association of GSTM1 with autism. BMC
Genet. 2006 Feb 10;7(1):8
Cheh MA, Millonig JH, Roselli LM, Ming X, Jacobsen E, Kamdar S, Wagner GC 2006. En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. Brain Res. 2006 Oct 20;1116(1):166-76. Epub 2006 Aug 28.
Halladay AK, Wilson DT, Wagner GC, Reuhl KR 2006. Trimethyltin-induced alterations in behavior are linked to changes in PSA-NCAM expression. Neurotoxicology. 2006 Mar;27(2):137-46. Epub 2006 Jan 19.
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 2005. Community-based participatory
research: lessons learned from the Centers for Children's Environmental
Health and Disease Prevention Research. Environ Health
Perspect. 2005 Oct;113(10):1463-71.
Martin
JV, Nolan B, Wagner GC, Fisher H 2004. Effects of dietary caffeine
and alcohol on liver carbohydrate and fat metabolism in rats. Med
Sci Monit. 2004 Dec;10(12):BR455-61.
Ming
X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC 2005. Increased
excretion of a lipid peroxidation biomarker in autism. Prostaglandins
Leuko
t Essent Fatty Acids.
2005 Nov;73(5):379-84.
Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. 2006. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J Autism Dev Disord 36:779-793.
Yu CH, Yiin LM, Lioy PJ 2006. The bioaccessibility of lead (Pb) from vacuumed house dust on carpets in urban residences. Risk Anal. 2006 Feb;26(1):125-34.
Full List of Publications | Publications List from NIEHS PubMed Database
Centers Funded By: 