Ex vivo exposure to polybrominated diphenyl ether (PBDE) selectively affects the immune response in autistic children.

Children on the autism spectrum have been shown to have immune dysregulation that often correlates with behavioral deficits. The role of the post-natal environment in this dysregulation is an area of active investigation. We examined the association between plasma levels of polybrominated diphenyl ether (PBDE) and immune cell function in age-matched autistic children and non-autistic controls. Plasma from children on the autism spectrum (n = 38) and typically developing controls (TD; n = 60) were analyzed for 14 major PBDE congeners. Cytokine/chemokine production was measured in peripheral blood mononuclear cell (PBMC) supernatants with and without ex vivo BDE-49 exposure. Total plasma concentration (∑PBDE14) and individual congener levels were also correlated with T cell function. ∑PBDE14 did not differ between diagnostic groups but correlated with reduced immune function in children on the autism spectrum. In autistic children, IL-2 and IFN-γ production was reduced in association with several individual BDE congeners, especially BDE-49 (p = 0.001). Furthermore, when PBMCs were exposed ex vivo to BDE-49, cells from autistic children produced elevated levels of IL-6, TNF-α, IL-1ß, MIP-1α and MCP-1 (p < 0.05). Therefore, despite similar plasma levels of PBDE, these data suggest that PBMC function was differentially impacted in the context of several PBDE congeners in autistic children relative to TD children where increased body burden of PBDE significantly correlated with a suppressed immune response in autistic children but not TD controls. Further, acute ex vivo exposure of PBMCs to BDE-49 stimulates an elevated cytokine response in AU cases versus a depressed response in TD controls. These data suggest that exposure to the toxicant BDE-49 differentially impacts immune cell function in autistic children relative to TD children providing evidence for an underlying association between susceptibility to PBDE exposure and immune anomalies in children on the autism spectrum.

Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions.

Approximately 23% of mothers of children with autism spectrum disorder (ASD) produce specific patterns of autoantibodies to fetal brain proteins that have been detected in only 1% of mothers of typically developing children. The biological mechanisms underlying the development of ASD-specific maternal autoantibodies are poorly understood. We sought to determine whether ASD-specific maternal autoantibodies identified postnatally were associated with metabolic conditions (MCs) during gestation. Participants were 227 mothers of 2-5 year old children with confirmed ASD, enrolled in CHARGE (Childhood Autism Risk from Genetics and the Environment) between January 2003 and April 2008, and from whom blood samples were collected and analyzed for anti-fetal brain autoantibodies (Ab+). MCs included diabetes, hypertensive disorders, and prepregnancy obesity or overweight, ascertained from medical records or structured telephone interviews. Log-linear regression models were performed to estimate prevalence ratios and 95% confidence intervals (CI) based on robust standard errors. Fifty-six (25%) mothers were Ab+. Ab+ prevalence was higher among mothers with diabetes, hypertensive disorders, or overweight compared to healthy mothers, but differences were not statistically significant. In a subset of 145 mothers whose children exhibited severe ASD (31 Ab+), those diagnosed with type 2 or gestational diabetes were 2.7-fold more likely to be Ab+ (95% CI 1.1, 6.6), controlling for delivery payer and smoking. Gestational diabetes specifically was associated with a 3.2-fold increased Ab+ prevalence (95% CI 1.2, 8.6). In this exploratory study, mothers whose children had severe ASD and who experienced diabetes were more likely to have anti-fetal brain autoantibodies 2-5 years later. Autism Res 2017, 10: 89-98. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Role of p53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study.

BACKGROUND: The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions. METHODS: mtDNA copy number and deletions, and p53 gene copy ratios were evaluated in peripheral blood monocytic cells from children aged 2-5 years with AU (n = 66), race-, gender-, and age-matched typically neurodeveloping children (n = 46), and both parents from each diagnostic group, recruited by the Childhood Autism Risk from Genes and Environment study at the University of California, Davis. RESULTS: mtDNA deletions and higher p53 gene copy ratios were more common in children with AU and their fathers. The incidence of mtDNA deletions in fathers of children with AU was increased 1.9-fold over fathers of typically neurodeveloping children, suggesting a role for deficient DNA repair capacity not driven by paternal age. Deletions in mtDNA and altered p53 gene copy ratios seem to result from genetics (children with severity scores ≥8) and/or act in concert with environmental factors (children with 6-7 severity scores). CONCLUSIONS: Given pro- and antioxidant activities of p53, and associations of genomic instability with disorders other than AU, our study suggests a link between DNA repair capacity, genomic instability in the 17p13.1 region influenced by environmental triggers, and AU diagnosis.

Maternal intake of supplemental iron and risk of autism spectrum disorder.

Iron deficiency affects 40%-50% of pregnancies. Iron is critical for early neurodevelopmental processes that are dysregulated in autism spectrum disorder (ASD). We examined maternal iron intake in relation to ASD risk in California-born children enrolled in a population-based case-control study (the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study) from 2003 to 2009 with a diagnosis of ASD (n = 520) or typical development (n = 346) that was clinically confirmed using standardized assessments. Mean maternal daily iron intake was quantified on the basis of frequency, dose, and brands of supplements and cereals consumed each month from 3 months before pregnancy through the end of pregnancy and during breastfeeding (the index period), as reported in parental interviews. Mothers of cases were less likely to report taking iron-specific supplements during the index period (adjusted odds ratio = 0.63, 95% confidence interval: 0.44, 0.91), and they had a lower mean daily iron intake (51.7 (standard deviation, 34.0) mg/day) than mothers of controls (57.1 (standard deviation, 36.6) mg/day; P = 0.03). The highest quintile of iron intake during the index period was associated with reduced ASD risk compared with the lowest (adjusted odds ratio = 0.49, 95% confidence interval: 0.29, 0.82), especially during breastfeeding. Low iron intake significantly interacted with advanced maternal age and metabolic conditions; combined exposures were associated with a 5-fold increased ASD risk. Further studies of this link between maternal supplemental iron and ASD are needed to inform ASD prevention strategies.

Dental care use and self-reported dental problems in relation to pregnancy.

OBJECTIVES: We examined the relationships between risk factors amenable to intervention and the likelihood of dental care use during pregnancy. METHODS: We used data from the Washington State Department of Health's Pregnancy Risk Assessment Monitoring System. RESULTS: Of the women surveyed, 58% reported no dental care during their pregnancy. Among women with no dental problems, those not receiving dental care were at markedly increased risk of having received no counseling on oral health care, being overweight, and using tobacco. Among women who received dental care, those with dental problems were more likely to have lower incomes and Medicaid coverage than those without dental problems. CONCLUSIONS: There is a need for enhanced education and training of maternity care providers concerning oral health in pregnancy.