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Autism and Neurodevelopmental Disorders
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Overview
The EPA/NIEHS Centers for Children’s Environmental Health and Disease Prevention Research (Children’s Centers) are studying how exposure to chemicals in the environment such as lead, mercury and pesticides could lead to neurodevelopmental disorders in children. These disorders include autism, neurodevelopmental delay, lowered IQ and attention deficit hyperactivity disorder (ADHD).
Children’s Center Research on Autism
Autism is a neurodevelopmental disorder generally defined by deficiencies of social reciprocity and communication skills, lack of eye contact, limited capacity for language and repetitive (stereotypic) patterns of behavior. The symptoms generally manifest themselves in early childhood. The term autism spectrum disorders (ASD) is often used to describe the varying degrees of symptoms. The majority of autism cases seem likely to arise from a multiplicity of genetic and environmental factors, including susceptibility genes.
Two of the Children’s Centers, the University of California at Davis (UC Davis) and the University of Medicine and Dentistry of New Jersey (UMDNJ), are investigating how environmental factors may affect the development of autism. Research includes epidemiologic studies relating autism to environmental exposures and physiologic factors, mechanistic studies, exposure assessment and intervention projects.
Children’s Center Research on Other Neurodevelopmental Disorders
Naturally occurring and synthetic chemicals in the environment, such as lead, mercury and polychlorinated biphenyls (PCBs), have been shown to have neurotoxic effects. Exposure to neurotoxicants during critical moments of fetal and childhood development can lead to neurodevelopmental disorders. Individuals may also carry genes which can increase their susceptibility to the effects of toxic compounds such as pesticides.
Research from the Children’s Centers, including Cincinnati, Columbia, Harvard, Mount Sinai, the University of Illinois and the University of Washington has shown adverse effects on neurodevelopment from chemicals including environmental tobacco smoke (ETS), lead, mercury, a combination of manganese and arsenic, pesticides and polychlorinated biphenyls (PCBs).
Question 1 (Concerns): What are the primary concerns about autism and other neurodevelopmental disorders how is EPA addressing these concerns?
Question 2 (Exposure): What environmental exposures may play a role in the development of autism and other neurodevelopmental disorders?
Question 3 (Susceptibility): What susceptibility factors may play a role in the development of autism and other neurodevelopmental disorders?
Question 4 (Innovations): What are some research innovations that have been developed by the Children’s Centers to investigate the causes of autism and other neurodevelopmental disorders?
Question 1 (Concerns): What are the primary concerns about autism and other neurodevelopmental disorders and how is EPA addressing these concerns?
Autism
Evidence suggests that incidence of autism is increasing, estimated by the Centers
for Disease Control and Prevention (CDC) at 1 in every 150 births, and the
rate is higher for males and varies by state. The most recent statistics,
based on data gathered in 2002, indicate more than 550,000 children in the
U.S. are affected with varying degrees of ASD (CDC
2007). Most
cases seem likely to arise from a combination of as-yet unidentified genetic
and environmental factors, while improvements in diagnosis may be contributing
to the perceived increase. Exposure to environmental neurotoxins, perhaps
in combination with specific genetic predispositions, may create adverse gene-environment
interactions. Neurological studies demonstrate structural changes in the
brain and clinical investigations reveal differences between autistic and normal
children in the way the brain processes information.
The UC Davis Center for Children’s Environmental Health (CCEH) is researching genetic and environmental risk factors which may contribute to the incidence and severity of childhood autism. The goal of the Center is to understand common patterns of dysfunction in autism and elucidate mechanisms by which chemicals known to be toxic to the developing nervous and immune systems (neuroimmunotoxicants) contribute to abnormal development of social behavior in children, leading to strategies for prevention and intervention.
Surveys in California indicate an apparent 210% increase in the number of cases of profound autism in children diagnosed over the past 10 years. There is concern that children’s exposure to xenobiotics (such as mercurials, halogenated aromatics and pesticides) and biotic factors (such as vaccine antigens) could act synergistically to alter the expression of as-yet unidentified susceptibility and genetic factors to result in ASD. The CCEH has established the first large-scale epidemiologic investigation of the underlying causes for autism and triggers of regression, the CHARGE (Childhood Autism Risk from Genetics and the Environment) Study. 
The main focus of the UMDNJ Children’s Center is to examine the effects of environmental chemicals on neurological health and development, with an emphasis on the interactions between exposure to environmental factors, learning disabilities and autism spectrum disorders.
The Center has developed animal models of features of autism such as regression of neurobehavioral function, and models which mimic the genes linked to autism in humans. The UMDNJ Center found that some autistic children show increased susceptibility to chemical-induced neurobehavioral dysfunction. Center researchers found that some children with autism are unable to metabolize certain fatty acids that help the body fight inflammation, which can then cause damage to the brain and other organs. The Center has discovered possible ways to detect biological risk factors for autism through urine and blood tests. UMDNJ scientists have developed a patented autism treatment which is being tested (see the Newsroom page for more details). The overall mission is to improve the environmental and public health of children through research, assessment, treatment and outreach.
Other Neurodevelopmental Disorders
In addition to autism, neurodevelopmental disorders include attention deficit disorder, learning disabilities, sensory deficits, developmental delays, cerebral palsy and mental retardation. These disorders are common, costly, and can cause lifelong disability and while the causes are generally unknown, they are likely to include both environmental and genetic factors. Of the many thousands of chemicals used by industry, very few have been tested for their effects on children’s neurodevelopment. Industrial chemicals such as methylmercury (MeHg), lead, PCBs and arsenic are known causes of neurodevelopmental disorders and subclinical brain dysfunction. Based on data gathered in the 1990s, it has been estimated that one in every six US. children has a developmental disability and in most cases these disabilities affect the nervous system (Grandjean and Landrigan 2006).
The Cincinnati Children’s Center is researching the effects of lead, pesticides and environmental tobacco smoke (ETS) on neurodevelopment and whether children’s developmental problems can be linked to their exposure to these chemicals before and after birth. The Cincinnati Center has shown that exposure to lead and prenatal tobacco exposure are implicated as precursors of attention deficit hyperactivity disorder (ADHD) in children.
The Columbia Children’s Center is studying how prenatal exposure to air pollution, environmental tobacco smoke (ETS), polycyclic aromatic hydrocarbons (PAHs) and pesticides may adversely affect fetal growth and neurodevelopment. Impaired fetal growth can increase the risk of neurocognitive delay and impair children's learning ability as they enter school. Researchers have already seen effects from these chemicals that are detrimental to fetal growth and/or mental development at age two, indicating possible adverse effects on school readiness, neurobehavioral adjustment and ability to learn. Animal data on pesticides and human data on PCBs show that prenatal exposure can have irreversible long-term effects on child development and behavioral adjustment.
The Harvard Children’s Center is examining the effects of mining waste (containing heavy metals including lead, manganese, arsenic, cadmium and iron) on the health and neurodevelopment of children and the potential of the metal mixtures to interact with each other in terms of exposure, absorption, dose, and adverse effects on child health and neurobehavioral development. The Center is looking for biological markers of fetal and early childhood exposure to metals and measuring their impact on mental development, and the response to a quasi-experimental randomized trial of nutritional and behavioral interventions.
The goals of the Mount Sinai Children’s Center include researching the mechanisms of neurodevelopmental impairment in inner-city children and to investigate relationships between exposure to environmental factors, inner-city toxicants, genetic differences, fetal growth and development. The Center is aiming to identify, characterize, elucidate and prevent neurodevelopmental deficits that result from exposures to pesticides in the home and PCBs in the diet. Investigators have characterized children’s exposures to pesticides, polychlorinated biphenyls (PCBs), DDT, chlordane and lead in New York City children and evaluated susceptibility factors related to these exposures. Researchers are now evaluating the effects of these exposures on later childhood development.
The University of Illinois FRIENDS Children’s Environmental Health Center was established to study the impact of exposure to PCBs and methyl mercury (MeHg) on cognitive, sensory and motor development of children, develop strategies to reduce exposure and to conduct lab studies to understand how these contaminants induce neurological deficits in children.
The University of Washington Children’s Center is researching the biochemical, molecular and exposure mechanisms that define children’s susceptibility to pesticides and the implications for risks to normal development and learning. The UW Center is also conducting basic science studies on the mechanism of developmental neurotoxicity of these chemicals and the impact of genetic polymorphisms of genes involved in pesticide metabolism, including paraoxonase (PON1).
Question 2 (Exposure): What environmental exposures may play a role in the development of autism and other neurodevelopmental disorders?
Autism
- Research from the UC Davis Children’s Center has connected thimerosal (ethyl mercury) with immune system dysfunction in mice. This study provides the first evidence that dendritic cells (DCs) in the immune system show sensitivity to thimerosal, resulting in fundamental changes in the immune system’s ability to respond to external factors. Also, UC Davis researchers have developed a new method to culture DCs in normoxic atmosphere and in the absence of 2-mercaptoethanol typically present in DC growth media, as this would confound interpretation of results with mercury (Goth et al. 2006).
- Developmental exposure to non-coplanar PCBs enhances excitability of the hippocampus and significantly alters seizure threshold. This is significant as children with autism are known to have a very high rate (about 30%) of seizure disorder. Also, the finding that PCBs induce apoptosis in cultured hippocampal neurons via ryanodine receptor (RyR) activation and increased reactive oxygen species (ROS) provides a biologically plausible link between the molecular actions of PCBs and their neurotoxic effects in humans exposed during early development (UC Davis, Howard et al. 2003).
- Lead exposure to cortical precursors in cell culture enhanced neurite outgrowth at two days of age and increased cell survival at four days. This has implications for autism, because autistic children generally show increased postnatal head growth (UMDNJ).
- Exposure to methylmercury (MeHg) shows population-specific toxicity in newborn rat pups, reducing DNA synthesis by 50% in the hippocampus. This raises concerns about chemical-induced teratogenesis (UMDNJ).
Other Neurodevelopmental Disorders
- Prenatal exposure to environmental tobacco smoke and post-partum social stresses experienced by mothers act separately and synergistically on cognitive development at age 2 (Columbia, Rauh et al. 2004)
- High prenatal exposure to air pollutants (polycyclic aromatic hydrocarbons, or PAHs) is associated with a three times greater risk of cognitive developmental delay at age 3 (Columbia, Perera et al. 2006).
- In utero exposures to organophosphate (OP) pesticides are associated with decreased head circumference of infants at birth, a risk factor for neurodevelopmental dysfunction in childhood. This effect was seem only in infants born to mothers with low expression levels of PON1, an esterase involved in detoxification of OPs (for more information, see the Pesticides topic page). This appears to represent a previously unreported gene-environment interaction (Mount Sinai, Berkowitz et al. 2004)
- The Harvard Children’s Center has found that children’s general intelligence scores, particularly verbal IQ scores, were lowered with exposure to manganese (Mn) and arsenic (As) in the environment, as were scores on tests of memory for stories and a word list. In some cases, a significant interaction between exposure to Mn and As was found, and the scores of children exposed to both heavy metals contributed significantly to the overall effect (Harvard, Wright et al. 2006).
- The Cincinnati Children’s Center has published research implicating lead and prenatal tobacco smoke exposure as precursors of ADHD in children, possibly accounting for as many as 1 in 3 cases of ADHD in children. The Cincinnati Center has also conducted studies linking gene-environment interactions – dopamine-associated polymorphisms DAT1 and DRD4 with lead and tobacco exposure – with ADHD in children (Cincinnati, Kahn et al. 2003, Braun et al. 2006, Froehlich et al. 2007).
- Work at the Cincinnati Children’s Center has shown that low-level exposure to environmental toxicants such as lead and environmental tobacco smoke (ETS) can affect the intellectual and behavioral functioning of children, including blood lead levels below 10 micrograms/deciliter (Canfield et al. 2003, Lanphear et al 2005).
- Perinatal exposure to a mixture of PCBs during development has been found to result in dose-dependent hearing loss in rats. The Illinois Children’s Center used an experimental mixture of PCBs that models the PCB congener profile in fish consumed by a human population from the Fox River in Wisconsin. The pattern of hearing deficits was indicative of damage to the cochlea. The results of these animal studies were used to develop a testing protocol to assess auditory function in infants born to mothers who consumed PCB-contaminated fish from the river (Powers et al. 2006).
- Neurochemical and neurobehavioral studies conducted by scientists collaborating with the Illinois Children’s Center have shown that the pattern of neurochemical and cognitive deficits following exposure to PCBs during development closely parallels the pattern of deficits seen in children with ADHD. PCB-induced hypofunctionality of brain dopamine systems seems to cause animals to have difficulty performing cognitive tasks that require inhibitory control for their successful execution (Bemis and Seegal 2004; Sable and Schantz 2006; Sable et al., 2006). Research is continuing on how PCBs, methyl mercury (MeHg) and polybrominated diphenyl ethers (PBDEs) may interact and alter brain dopamine and cognitive function.
- Results of experiments in rats show that methyl mercury (MeHg) is especially toxic to the development central nervous system. Research at the Illinois Children’s Center not only confirms the extreme vulnerability of the developing nervous system to MeHg neurotoxicity but suggest that MeHg is a developmental neurotoxicant – with the ability to induce reactive oxygen species (ROS) and reduce mitrochondrial function (Dreiem et al. 2005).
- In a population of African-American men whose mothers had participated in the Collaborative Perinatal Project during the 1960s, researchers at the Mount Sinai Children’s Center measured in utero exposure to PCBs and found associated decrements in intelligence that were still evident at 17 years of age.
- The Mount Sinai Children’s Center has found an association of exposure to OP pesticide metabolites with impaired neonatal reflexes, the first research findings to demonstrate a link between in utero exposure to OPs and infant neurobehavior. Taking maternal PON1 (paraoxonase 1) status into consideration (see below) greatly increases the risk for this adverse behavior (Engel et al. 2007).
Question 3 (Susceptibility): What susceptibility factors may contribute to the development of autism and other neurodevelopmental disorders?
Autism
- The UC Davis Children’s Center has shown an association between delayed adaptive development and difficulty with sleep onset and maintenance.
- Elevated leptin levels have been identified in early onset autism (UC Davis).
- Children with autism and/or their parents show a higher incidence of at least two newly identified gene deletions or polymorphisms that may make them more susceptible to environmental chemicals (UMDNJ).
- 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).
Other Neurodevelopmental Disorders
Several of the Children’s Centers have collaborated on studies of how pesticides, specifically organophosphates (OPs), may impact children’s health and as part of this process, discovered that both children and adults show a wide range of susceptibility to the effects of these compounds. Although some OPs were banned for U.S. residential use in 2000-2001 by the EPA, mainly because of risks to children, most are still widely used in agriculture.
The primary mechanism of OP toxicity is associated with inhibition of the activity of acetylcholinesterase (AChE), an enzyme which regulates acetylcholine, a vital neurotransmitter, necessary for the proper functioning of the nervous system. Recent Children’s Center studies have focused on paraoxonase 1 (PON1), a liver and serum enzyme that breaks down the toxic metabolites of a number of OP pesticides, including diazinon and chlorpyrifos, and its role in modulating OP toxicity.
Investigators at the UC Berkeley and University of Washington Children’s Centers have shown that the OP detoxifying ability of PON1 varies greatly among individuals and infants are at particular risk because the PON1 level in newborns averages only one-third or less than that of adults and it can take six months to two years for a baby to develop mature enzyme levels. Enzyme levels may be even lower before birth, because premature infants have lower PON1 activity than babies carried to term (Costa et al. 2006). Research from the Mount Sinai Children’s Center confirms this result, and has shown that there are differences in PON1 activity between ethnic groups (Chen et al. 2003).
Using blood samples from the UC Berkeley Center's CHAMACOS cohort, investigators at the University of Washington Children’s Center found that PON1 status predicts a 65-fold to 160-fold difference in sensitivity to some OPs in the study population, with an average of 6- to 10-fold variability in sensitivity between groups of mothers and their newborns. This indicates a far greater variability in pesticide-detoxification capability than previously thought (Furlong et al. 2005). The research demonstrates that both the quality (detoxification efficiency) and quantity (serum level) of the PON1 enzyme is important in determining its detoxification capacity (Furlong et al. 2006, Holland et al. 2006). For more information, see the page on Children’s Exposure to Pesticides on this site.
Question 4 (Effects): What are some research innovations that have been developed by the Children’s Centers to investigate the causes of autism and other neurodevelopmental disorders
- The UMDNJ Children’s Center has developed animal models of the regression of neurobehavioral function seen in autism using chemicals that are known to lead to birth defects and autism in the human child, such as thalidomide, and has demonstrated that an agent given to the mouse can prevent chemical-induced regression of neurological function (UMDNJ, Wagner).
- 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 (UMDNJ, Carmody).
- Mice exposed to sodium valproate (an antiseizure medication 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 (UMDNJ, Wagner et al. 2006).
- The UMDNJ Children’s Center has developed possible ways to detect biological risk factors for autism through urine and blood tests, which could lead to new treatments. Research results, as presented in a news article in The Star-Ledger (Newark, NJ), show that children with autism are unable to metabolize certain fatty acids that help the body fight inflammation, which can then cause damage to the brain and other organs. This finding is the result of more than two years of study at the UMDNJ Center on how the body breaks down fatty acids. Team members say a potential treatment would be a kind of "therapeutic cocktail" tailored to each child, which would give them a dose of a "good" fatty acid that they are not able to make on their own. The scientists have obtained patents for their work and are planning to test the fatty acid treatment in a research study.
- The UC Davis Children’s Center has identified several aspects of immune dysfunction in patients with autism compared with typically developing controls. These include a reduced response to vaccine antigens of bacterial origin, altered cytokine levels in plasma and upon stimulation of PBMC and increased levels of leptin in patients with early onset autism.
- The UC Davis Center has established the first sample and data archive consisting of age-matched children with autism, children with developmental delay, and children from the general population (2-5 years), also including samples from siblings, and parents.
- The Mount Sinai Children’s Center has published the first research documenting a definitive link between in utero exposure to OP pesticide metabolites and impaired neonatal reflexes (Engel et al. 2007).
- The University of Washington Children’s Center developed a report establishing a framework for linked toxicokinetic and toxicodynamic models to address neurodevelopmental effects from exposure to toxic compounds (Faustman et al. 2005). The Center has also developed Mechanistic Biologically Based Dose Response (BBDR) models for developmental toxicity which illustrate how exposure information needs to be linked with kinetic and mechanistic information to improve our ability to assess health risks. These models are able to predict normal neuronal output after neuronogenesis and can predict cellular deficit after toxic exposures such as MeHg, ethanol and ionizing radiation (Gohlke et al. 2004, Gohlke et al. 2005, Gohlke et al. 2007)
The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study is the first large-scale epidemiologic investigation of underlying causes for autism and triggers of regression (Hertz-Picciotto et al. 2006). In this case-control study of children 2-5 years of age, comparisons are being made between groups of autistic children, children with developmental delay or mental retardation but not autism and children that are typically developing. The study is assessing the influence of environmental exposures to chemicals with known or suspected neurodevelopmental toxicity (such as PCBs, certain pesticides and metals), the role of susceptibility factors, and biochemical susceptibility based on metabolic, immunologic, and neuronal gene expression profiles and genetic polymorphisms. An additional study is examining whether children with autism can be distinguished from those without autism by markers of immune dysregulation (at birth, as well as post-diagnosis) and by prenatal, immunologically relevant events and exposures. A third study is looking at environmental factors for 200 women at high risk of giving birth to a child who develops autism.
For more information, see the UC Davis Children’s Center
- Environmental Factors in the Etiology of Autism; Molecular and Cellular Mechanisms of Autism
- Environmental Factors in the Etiology of Autism; Animal Models of Autism Molecular and Cellular Mechanisms of Autism
These studies build upon the discovery of immunologic and molecular biomarkers specific to children with autism found in 2-5 year olds enrolled in the CHARGE Study by extending the investigation of post-diagnosis differences to the pre-diagnostic period. Investigators will also determine if children with and without autism differ with regard to exposures, body burdens, and excretion of xenobiotics, including metals, pesticides and PBDEs. Researchers will collect a second set of blood samples from 375 children who enrolled in the CHARGE study in the first project period and this study (CHARGE-BACK) will examine stability over time in the immune cell markers that were determined when these children were 2-5 years old. This project also includes the launch of a new cohort study that tracks 200 women at high risk of giving birth to a child who develops autism, starting from early pregnancy and following the pregnancies and the babies to the age of three years. This new cohort study is called Markers of Autism Risk in Babies – Learning Early Signs (MARBLES).
University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Exposure Assessment- Neurotoxicant Effects on Cell Cycle Regulation of Neurogenesis
- Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury
- Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills
- Clinical Sciences Project
In this study, researchers are examining whether autistic spectrum disorder (ASD) 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. Aims of this project included 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.
- Developmental Effects of PCBs and Methylmercury
- FRIENDS Analytical Toxicology Core Facility
- Neurobehavioral Effects of PCBs and Methylmercury in Rats
- Perinatal PCB Exposure and Neuropsychological/Auditory Function
- Epidemiologic Research:Pesticides and Neurological Development
- Experimental Neurodevelopmental Study: PCB neuroendocrine effects
- Cellular and Molecular Aspects of Pesticide Neurodevelopmental Toxicity
- Paraoxonase Polymorphism: Role in Neurodevelopmental Susceptibility to Organophosphates
Children's Center Projects related to this topic
NCER Research Projects related to this topic
EPA 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
There is additional information on autism spectrum disorders at the National Institute of Mental Health site at:
http://www.nimh.nih.gov/publicat/autism.cfm
Bemis JC, Seegal RF 2004. PCB-induced inhibition of the vesicular monoamine transporter predicts reductions in synaptosomal dopamine content. Toxicol Sci. 2004 Aug;80(2):288-95. Epub 2004 Apr 28.
Berkowitz GS, Wetmur JG, Birman-Deych E, Obel J, Lapinski RH, Godbold JH,
Holzman IR, Wolff MS 2004. In utero pesticide exposure, maternal paraoxonase activity, and head circumference. Environ Health Perspect. 2004 Mar;112(3):388-91.
Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP 2006. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect. 2006 Dec;114(12):1904-9.
Centers for Disease Control and Prevention (CDC) 2007. Morbidity and Mortality Weekly Report (MMWR) Surveillance Summaries: Prevalence of Autism Spectrum Disorders – Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States, 2002. February 9, 2007 / 56(SS01);12-28.
Chen J, Kumar M, Chan W, Berkowitz G, Wetmur JG 2003. Increased influence of genetic variation on PON1 activity in neonates. Environ Health Perspect. 2003 Aug;111(11):1403-9. Comment in: Environ Health Perspect. 2003 Aug;111(11):A591.
Costa LG, Cole TB and Furlong CE 2006.Gene-environment interactions: Paraoxonase (PON1) and Sensitivity to Organophosphate Toxicity. Lab Med. 2006;37(2):109-114.
Alternate access: http://www.medscape.com/viewarticle/522383
Dreiem A, Gertz CC, Seegal RF 2005. The effects of methylmercury on mitochondrial function and reactive oxygen species formation in rat striatal synaptosomes are age-dependent. Toxicol Sci. 2005 Sep;87(1):156-62. Epub 2005 Jun 15.
Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS 2007. Prenatal Organophosphate Metabolite and Organochlorine Levels and Performance on the Brazelton Neonatal Behavioral Assessment Scale in a Multiethnic Pregnancy Cohort. Am J Epidemiol. 2007 Apr 12; [Epub ahead of print]
Faustman EM, Gohlke J, Judd NL, Lewandowski TA, Bartell SM, Griffith, WC 2005. Modeling developmental processes in animals: applications in neurodevelopmental toxicology. Env Toxicol and Pharmacol 19(3):615-624 doi:10.1016/j.etap.2004.12.027
Froehlich TE, Lanphear BP, Dietrich KN, Cory-Slechta DA, Wang N, Kahn RS 2007. Interactive Effects of a DRD4 Polymorphism, Lead, and Sex on Executive Functions in Children. Biol Psychiatry. 2007 Jan 16; [Epub ahead of print]
Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, Geiss GK, Richter RJ, Shih DM, Tward AD, Lusis AJ, Costa LG 2005. Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants. Neurotoxicology. 2005 Aug;26(4):651-9.
Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B 2006.
PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenet Genomics. 2006 Mar;16(3):183-90.
Gohlke JM, Griffith WC, Faustman EM 2004. The role of cell death during neocortical neurogenesis and synaptogenesis: implications from a computational model for the rat and mouse. Brain Res Dev Brain Res. 2004 Jul 19;151(1-2):43-54.
Gohlke JM, Griffith WC, Faustman EM 2005. A systems-based computational model for dose-response comparisons of two mode of action hypotheses for ethanol-induced neurodevelopmental toxicity. Toxicol Sci. 2005 Aug;86(2):470-84. Epub 2005 May 25.
Gohlke JM, Griffith WC, Faustman EM 2007. Computational Models of Neocortical Neuronogenesis and Programmed Cell Death in the Developing Mouse, Monkey, and Human. Cereb Cortex. 2007 Jan 4; [Epub ahead of print]
Goth SR, Chu RA, Gregg JP, Cherednichenko G, Pessah IN. 2006. Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal. Environ Health Perspect 114:1083-1091.
Grandjean P, Landrigan PJ 2006. Developmental neurotoxicity of industrial chemicals. Lancet. 2006 Dec 16;368(9553):2167-78. Comment in: Lancet. 2007 Mar 10;369(9564):821; author reply 821-2. Lancet. 2007 Mar 10;369(9564):821; author reply 821-2.
Hertz-Picciotto I, Croen LA, Hansen R, Jones CR, van de Water J, Pessah IN 2006. The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ Health Perspect. 2006 Jul;114(7):1119-25.
Holland N, Furlong C, Bastaki M, Richter R, Bradman A, Huen K, Beckman K,
Eskenazi B 2006. Paraoxonase polymorphisms, haplotypes, and enzyme activity in Latino mothers and newborns. Environ Health Perspect. 2006 Jul;114(7):985-91.
Howard AS, Fitzpatrick R, Pessah I, Kostyniak P, Lein PJ. 2003. Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicol Appl Pharmacol 190:72-86.
Kahn RS, Khoury J, Nichols WC, Lanphear BP 2003. Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatr. 2003 Jul;143(1):104-10.
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC 2005. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84.
Perera FP, Rauh V, Whyatt RM, Tsai WY, Tang D, Diaz D, Hoepner L, Barr D, Tu YH, Camann D, Kinney P 2006. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children. Environ Health Perspect. 2006 Aug;114(8):1287-92.
Powers BE, Widholm JJ, Lasky RE, Schantz SL. Auditory deficits in rats exposed to an environmental PCB mixture during development. Toxicology Science 2006;89:415-22. Abstract | Full Text (PDF) (144 KB, 8pp, about PDF) | PubMed
Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, Diaz D, Camann D, Perera FP 2004. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol. 2004 May-Jun;26(3):373-85.
Sable HJ, Powers BE, Wang VC, Widholm JJ, Schantz SL 2006. Alterations in DRH and DRL performance in rats developmentally exposed to an environmental PCB mixture. Neurotoxicol Teratol. 2006 Sep-Oct;28(5):548-56. Epub 2006 Jun 30.
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.
Wright RO, Amarasiriwardena C, Woolf AD, Jim R, Bellinger DC 2006.
Neuropsychological correlates of hair arsenic, manganese, and cadmium levels in school-age children residing near a hazardous waste site. Neurotoxicology. 2006 Mar;27(2):210-6. Epub 2005 Nov 28.
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