Few rigorous epidemiologic studies have addressed the environmental causes and biologic underpinnings of autism spectrum disorder (ASD). The CHARGE (Childhood Autism Risks from Genetics and Environment) Study is a large, population-based case-control investigation of environmental risk factors, broadly defined, in relation to ASD and developmental delay without ASD symptoms, with referents from the general population. Fieldwork began in 2003, and by now CHARGE has published widely on exposures such as air pollution, mercury, flame retardants, maternal nutritional status in the peri-conception, untreated fever during pregnancy, mitochondrial dysfunction, candidate genes, a wide array of functional immune markers in both the child and the mother, and maternal metabolic conditions including obesity and diabetes. This last finding is notable, given the epidemic of obesity and type 2 diabetes that has occurred in parallel with the steady rise in ASD over the last few decades. Moreover, an emerging literature implicates several endocrine disrupting chemicals as contributing to obesity and metabolic dysregulation, including hyperinsulinemia, and to neurodevelopmental disorders as well. This project therefore builds upon these observations in several ways. First, obesity and type 2 or gestational diabetes will be examined in a larger sample, and glucose challenge test (GCT) results for the first time, to determine associations not only with development of ASD and intellectual impairment in the children, but also with specific speech and language delays, behavioral phenotypes such as attention deficits or hyperactivity, and gene expression. Second, these maternal metabolic conditions will be evaluated for associations with markers of both metabolic and immune dysregulation to be measured in neonatal bloodspots. Third, the predictive value of neonatal bloodspot markers for a later diagnosis of ASD or other child developmental and behavioral outcomes will be assessed. Fourth, the maternal metabolic conditions will be analyzed for potential links with upstream exposures to phthalates and anti- bacterial compounds, ubiquitous chemicals in common household products. Finally, this project will examine how gene variants that play a role in biochemical pathways relevant to the processes under study may influence susceptibility of the mother, the neonate or the child. To ensure adequate power for this analysis of gene-environment interaction, the sample size will be increased to 2400 children. This project addresses several goals set by the NIH Interagency Autism Coordinating Committee: 1) to discover environmental factors contributing to ASD, particularly in the prenatal period, 2) to understand biological mechanisms for ASD risk, including gene-by-environment interactions, and 3) to identify children at risk for ASD at earlier time points. Results of this detailed inquir into early exposures, maternal pathophysiology and prognostic markers in the newborn will set the stage for developing prevention strategies.

Public Health Relevance

This project addresses several issues of direct public health relevance, and the science to be produced will lead to benefits in a wide cross-section of the U.S. population. Because obesity is reaching epidemic proportions and other metabolic conditions such as Type 2 diabetes, gestational diabetes, and dyslipidemia are rising steeply, understanding environmental causes has tremendous public health potential for moving us closer to effective prevention strategies. If environmental chemicals used in common household products do prove to adversely affect body weight, measures can be taken to either reformulate those products, removing them from the market, or to educate consumers on how to avoid them. Similarly, steady increases in ASD might be curbed if the postulated causal pathway is supported by the evidence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES015359-06
Application #
8507091
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Lawler, Cindy P
Project Start
2007-02-08
Project End
2018-06-30
Budget Start
2013-08-19
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$1,151,250
Indirect Cost
$401,250
Name
University of California Davis
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Matelski, Lauren; Van de Water, Judy (2016) Risk factors in autism: Thinking outside the brain. J Autoimmun 67:1-7
Krakowiak, Paula; Walker, Cheryl K; Tancredi, Daniel et al. (2016) Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Res :
Nguyen, Cathina T; Krakowiak, Paula; Hansen, Robin et al. (2016) Sociodemographic Disparities in Intervention Service Utilization in Families of Children with Autism Spectrum Disorder. J Autism Dev Disord 46:3729-3738
Lyall, Kristen; Van de Water, Judy; Ashwood, Paul et al. (2015) Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study. Autism Res 8:567-74
McKean, Stephen J; Bartell, Scott M; Hansen, Robin L et al. (2015) Prenatal mercury exposure, autism, and developmental delay, using pharmacokinetic combination of newborn blood concentrations and questionnaire data: a case control study. Environ Health 14:62
Krakowiak, Paula; Goines, Paula E; Tancredi, Daniel J et al. (2015) Neonatal Cytokine Profiles Associated with Autism Spectrum Disorder. Biol Psychiatry :
Akintunde, Marjannie Eloi; Rose, Melissa; Krakowiak, Paula et al. (2015) Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma. J Neuroimmunol 286:33-41
Philippat, Claire; Bennett, Deborah H; Krakowiak, Paula et al. (2015) Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study. Environ Health 14:56
Walker, Cheryl K; Ashwood, Paul; Hertz-Picciotto, Irva (2015) Preeclampsia, placental insufficiency, autism, and antiphospholipid antibodies-reply. JAMA Pediatr 169:606-7
Schmidt, Rebecca J; Hansen, Robin L; Hartiala, Jaana et al. (2015) Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early Hum Dev 91:483-9

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