Article

The CHARGE Study: An Epidemiologic Investigation of Genetic and Environmental Factors Contributing to Autism

Division of Epidemiology, Department of Public Health Sciences, School of Medicine, and Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Davis, California, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 08/2006; 114(7):1119-25. DOI: 10.1289/ehp.8483
Source: PubMed

ABSTRACT

Causes and contributing factors for autism are poorly understood. Evidence suggests that prevalence is rising, but the extent to which diagnostic changes and improvements in ascertainment contribute to this increase is unclear. Both genetic and environmental factors are likely to contribute etiologically. Evidence from twin, family, and genetic studies supports a role for an inherited predisposition to the development of autism. Nonetheless, clinical, neuroanatomic, neurophysiologic, and epidemiologic studies suggest that gene penetrance and expression may be influenced, in some cases strongly, by the prenatal and early postnatal environmental milieu. Sporadic studies link autism to xenobiotic chemicals and/or viruses, but few methodologically rigorous investigations have been undertaken. In light of major gaps in understanding of autism, a large case-control investigation of underlying environmental and genetic causes for autism and triggers of regression has been launched. The CHARGE (Childhood Autism Risks from Genetics and Environment) study will address a wide spectrum of chemical and biologic exposures, susceptibility factors, and their interactions. Phenotypic variation among children with autism will be explored, as will similarities and differences with developmental delay. The CHARGE study infrastructure includes detailed developmental assessments, medical information, questionnaire data, and biologic specimens. The CHARGE study is linked to University of California-Davis Center for Children's Environmental Health laboratories in immunology, xenobiotic measurement, cell signaling, genomics, and proteomics. The goals, study design, and data collection protocols are described, as well as preliminary demographic data on study participants and on diagnoses of those recruited through the California Department of Developmental Services Regional Center System.

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    • "Studies based on U.S. EPA or the Organization for Economic Co-operation and Development (OECD) guidelines can take months to years to complete, cost hundreds of thousands of dollars, and use hundreds of laboratory animals. In light of the concern regarding the potential of environmental chemicals to contribute to neurodevelopmental disorders in children (Grandjean and Landrigan, 2006, 2014; Braun et al., 2006; Hertz-Picciotto et al., 2006; Karr, 2012), there are ongoing efforts to develop medium-and highthroughput assays to facilitate the detection of chemicals that are likely to affect brain development (Coecke et al., 2007; Bal-Price et al., 2012). "
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    ABSTRACT: High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery. In contrast, evaluation of the predictive ability of a comprehensive test battery requires a set of chemicals that have been shown to alter brain development after in vivo exposure ("test set"). Because only a small number of substances have been well documented to alter human neurodevelopment, we have proposed an expanded test set that includes chemicals demonstrated to adversely affect neurodevelopment in animals. To compile a list of potential developmental neurotoxicants, a literature review of compounds that have been examined for effects on the developing nervous system was conducted. The search was limited to mammalian studies published in the peer-reviewed literature and regulatory studies submitted to the U.S. EPA. The definition of developmental neurotoxicity encompassed changes in behavior, brain morphology, and neurochemistry after gestational or lactational exposure. Reports that indicated developmental neurotoxicity was observed only at doses that resulted in significant maternal toxicity or were lethal to the fetus or offspring were not considered. As a basic indication of reproducibility, we only included a chemical if data on its developmental neurotoxicity were available from more than one laboratory (defined as studies originating from laboratories with a different senior investigator). Evidence from human studies was included when available. Approximately 100 developmental neurotoxicity test set chemicals were identified, with 22% having evidence in humans.
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    • "Exposure to maternal infections during critical periods of development, such as prenatal and perinatal periods, has also gained attention in the search for the etiology of autism [16] [17]. The increased incidence of autism in certain regions has suggested that there is a link between geography and the genetic predisposition to autism [18] [19] [20]. Bisphenol A (4,4 -dihydroxy-2,2-diphenylpropane; BPA) is one of the environmental toxins that has recently received increased attention. "
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    ABSTRACT: Developmental disorders such as autism and attention deficit hyperactivity disorder (ADHD) appear to have a complex etiology implicating both genetic and environmental factors. Bisphenol A (BPA), a widely used chemical in the plastic containers and in the linings of food and beverage cans, has been suggested to play a possible causative role in some developmental disorders. Here, we report behavioral modifications in Drosophila melanogaster following early exposure to BPA, which may suggest BPA as an environmental risk factor for the behavioral impairments that are the basis of diagnosis of autism and ADHD. In an open field assay with perinatally BPA-exposed and vehicle-treated control Drosophila, different parameters of locomotion (distance travelled, walking speed, spatial movement, mobility, turn angle, angular velocity and meander) were analyzed using the ethovision software. We also examined the repetitive and social interaction behaviors in these flies. In an open field assay, we identified disturbances in the locomotion patterns of BPA-exposed Drosophila that may relate to the decision-making and the motivational state of the animal. An increase in repetitive behavior was observed as an increase in the grooming behavior of Drosophila following BPA exposure. Furthermore, we also observed abnormal social interaction by the BPA-exposed flies in a social setting. These results demonstrate the effect of the environmentally prevalent risk agent BPA on the behavior of Drosophila, and suggest the practicability and the ease of using Drosophila as a model in the studies of neurobehavioral developmental disorders. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · Behavioural Brain Research
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    • "In 2012, its prevalence was estimated at 11.3 per 1,000 children [2]. The increased prevalence suggests that genetic and evironmental factors play a role345 . Children with ASD also present with accompanying maladaptive behavior, further impairing the ability to learn and socialize [6]. "
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    ABSTRACT: Purpose: Various gastrointestinal factors may contribute to maladaptive behavior in children with autism spectrum disorders (ASD). To determine the association between maladaptive behavior in children with ASD and gastrointestinal symptoms such as severity, intestinal microbiota, inflammation, enterocyte damage, permeability and absorption of opioid peptides. Methods: This observational cross-sectional study compared children with ASD to healthy controls, aged 2-10 years. Maladaptive behavior was classified using the Approach Withdrawal Problems Composite subtest of the Pervasive Developmental Disorder Behavior Inventory. Dependent variables were gastrointestinal symptom severity index, fecal calprotectin, urinary D-lactate, urinary lactulose/mannitol excretion, urinary intestinal fatty acids binding protein (I-FABP) and urinary opioid peptide excretion. Results: We did not find a significant difference between children with ASD with severe or mild maladaptive behavior and control subjects for gastrointestinal symptoms, fecal calprotectin, urinary D-lactate, and lactulose/mannitol ratio. Urinary opioid peptide excretion was absent in all children. Children with ASD with severe maladaptive behavior showed significantly higher urinary I-FABP levels compared to those with mild maladaptive behavior (p=0.019) and controls (p=0.015). Conclusion: In our series, maladaptive behavior in ASD children was not associated with gastrointestinal symptoms, intestinal inflammation (no difference in calprotectin), microbiota (no difference in urinary D-lactate) and intestinal permeability (no difference in lactulose/manitol ratio). ASD children with severe maladaptive behavior have significantly more enterocyte damage (increased urinary I-FABP) than ASD children with mild maladaptive behavior and normal children.
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