Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder.

BACKGROUND: Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals. OBJECTIVE: We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD). METHODS: Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800µg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure. RESULTS: High FA intake (≥800µg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800µg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models. CONCLUSIONS: In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.

Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study.

BACKGROUND: Gestational exposure to several common agricultural pesticides can induce developmental neurotoxicity in humans, and has been associated with developmental delay and autism. OBJECTIVES: We evaluated whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) study. METHODS: The CHARGE study is a population-based case-control study of ASD, DD, and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997-2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316). RESULTS: Approximately one-third of CHARGE study mothers lived, during pregnancy, within 1.5 km (just under 1 mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified. CONCLUSIONS: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates.

Month of conception and risk of autism.

BACKGROUND: Studies of season of birth or season of conception can provide clues about etiology. We investigated whether certain months or seasons of conception are associated with increased risk of autism spectrum disorders, for which etiology is particularly obscure. METHODS: The study population comprises 6,604,975 children born from 1990 to 2002 in California. Autism cases (n = 19,238) were identified from 1990 through 2008 in databases of the California Department of Developmental Services, which coordinates services for people with developmental disorders. The outcome in this analysis was autism diagnosed before the child's sixth birth date. The main independent variables were month of conception and season of conception (winter, spring, summer, and fall). Multivariate logistic regression models were used to estimate odds ratios (ORs) with their 95% confidence intervals (CIs) for autism by month of conception. RESULTS: Children conceived in December (OR = 1.09 [95% CI = 1.02-1.17]), January (1.08 [1.00-1.17]), February (1.12 [1.04-1.20]), or March (1.16 [1.08-1.24]) had higher risk of developing autism compared with those conceived in July. Conception in the winter season (December, January, and February) was associated with a 6% (OR = 1.06, 95% CI = 1.02-1.10) increased risk compared with summer. CONCLUSIONS: Higher risks for autism among those conceived in winter months suggest the presence of environmental causes of autism that vary by season.

Autoantibodies to cerebellum in children with autism associate with behavior.

Autism is a heterogeneous disorder with a poorly understood biological basis. Some children with autism harbor plasma autoantibodies that target brain proteins. Similarly, some mothers of children with autism produce antibodies specific to autism that target pairs of fetal brain proteins at 37/73 and 39/73 kDa. We explored the relationship between the presence of brain-specific autoantibodies and several behavioral characteristics of autism in 277 children with an autism spectrum disorder and 189 typically developing age-matched controls. Further, we used maternal autoantibody data to investigate potential familial relationships for the production of brain-directed autoantibodies. We demonstrated by Western blot that autoantibodies specific for a 45 kDa cerebellar protein in children were associated with a diagnosis of autism (p=0.017) while autoantibodies directed towards a 62 kDa protein were associated with the broader diagnosis of autism spectrum disorder (ASD) (p=0.043). Children with such autoantibodies had lower adaptive (p=0.0008) and cognitive function (p=0.005), as well as increased aberrant behaviors (p<0.05) compared to children without these antibodies. No correlation was noted for those mothers with the most specific pattern of anti-fetal brain autoantibodies and children with the autoantibodies to either the 45 or 62 kDa bands. Collectively, these data suggest that antibodies towards brain proteins in children are associated with lower adaptive and cognitive function as well as core behaviors associated with autism. It is unclear whether these antibodies have direct pathologic significance, or if they are merely a response to previous injury. Future studies are needed to determine the identities of the protein targets and explore their significance in autism.

Residential proximity to freeways and autism in the CHARGE study.

BACKGROUND: Little is known about environmental causes and contributing factors for autism. Basic science and epidemiologic research suggest that oxidative stress and inflammation may play a role in disease development. Traffic-related air pollution, a common exposure with established effects on these pathways, contains substances found to have adverse prenatal effects. OBJECTIVES: We examined the association between autism and proximity of residence to freeways and major roadways during pregnancy and near the time of delivery, as a surrogate for air pollution exposure. METHODS: Data were from 304 autism cases and 259 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. The mother's address recorded on the birth certificate and trimester-specific addresses derived from a residential history obtained by questionnaire were geocoded, and measures of distance to freeways and major roads were calculated using ArcGIS software. Logistic regression models compared residential proximity to freeways and major roads for autism cases and typically developing controls. RESULTS: Adjusting for sociodemographic factors and maternal smoking, maternal residence at the time of delivery was more likely be near a freeway (≤ 309 m) for cases than for controls [odds ratio (OR)=1.86; 95% confidence interval (CI), 1.04-3.45]. Autism was also associated with residential proximity to a freeway during the third trimester (OR=2.22; CI, 1.16-4.42). After adjustment for socioeconomic and sociodemographic characteristics, these associations were unchanged. Living near other major roads at birth was not associated with autism. CONCLUSIONS: Living near a freeway was associated with autism. Examination of associations with measured air pollutants is needed.

Geographic distribution of autism in California: a retrospective birth cohort analysis.

Prenatal environmental exposures are among the risk factors being explored for associations with autism. We applied a new procedure combining multiple scan cluster detection tests to identify geographically defined areas of increased autism incidence. This procedure can serve as a first hypothesis-generating step aimed at localized environmental exposures, but would not be useful for assessing widely distributed exposures, such as household products, nor for exposures from nonpoint sources, such as traffic. Geocoded mothers' residences on 2,453,717 California birth records, 1996-2000, were analyzed including 9,900 autism cases recorded in the California Department of Developmental Services (DDS) database through February 2006 which were matched to their corresponding birth records. We analyzed each of the 21 DDS Regional Center (RC) catchment areas separately because of the wide variation in diagnostic practices. Ten clusters of increased autism risk were identified in eight RC regions, and one Potential Cluster in each of two other RC regions.After determination of clusters, multiple mixed Poisson regression models were fit to assess differences in known demographic autism risk factors between the births within and outside areas of elevated autism incidence, independent of case status.Adjusted for other covariates, the majority of areas of autism clustering were characterized by high parental education, e.g. relative risks >4 for college-graduate vs. nonhigh-school graduate parents. This geographic association possibly occurs because RCs do not actively conduct case finding and parents with lower education are, for various reasons, less likely to successfully seek services.

Blood mercury concentrations in CHARGE Study children with and without autism.

BACKGROUND: Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative to unaffected controls. OBJECTIVES: We compared blood total Hg concentrations in children with autism or autism spectrum disorder (AU/ASD) and typically developing (TD) controls in population-based samples, and determined the role of fish consumption in differences observed. METHODS: The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study enrolled children 2-5 years of age. After diagnostic evaluation, we analyzed three groups: AU/ASD, non-AU/ASD with developmental delay (DD), and population-based TD controls. Mothers were interviewed about household, medical, and dietary exposures. Blood Hg was measured by inductively coupled plasma mass spectrometry. Multiple linear regression analysis was conducted (n = 452) to predict blood Hg from diagnostic status controlling for Hg sources. RESULTS: Fish consumption strongly predicted total Hg concentration. AU/ASD children ate less fish. After adjustment for fish and other Hg sources, blood Hg levels in AU/ASD children were similar to those of TD children (p = 0.75); this was also true among non-fish eaters (p = 0.73). The direct effect of AU/ASD diagnosis on blood Hg not through the indirect pathway of altered fish consumption was a 12% reduction. DD children had lower blood Hg concentrations in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habits predicted higher levels. CONCLUSIONS: After accounting for dietary and other differences in Hg exposures, total Hg in blood was neither elevated nor reduced in CHARGE Study preschoolers with AU/ASD compared with unaffected controls, and resembled those of nationally representative samples.

The rise in autism and the role of age at diagnosis.

BACKGROUND: Autism prevalence in California, based on individuals eligible for state-funded services, rose throughout the 1990s. The extent to which this trend is explained by changes in age at diagnosis or inclusion of milder cases has not been previously evaluated. METHODS: Autism cases were identified from 1990 through 2006 in databases of the California Department of Developmental Services, which coordinates services for individuals with specific developmental disorders. The main outcomes were population incident cases younger than age 10 years for each quarter, cumulative incidence by age and birth year, age-specific incidence rates stratified by birth year, and proportions of diagnoses by age across birth years. RESULTS: Autism incidence in children rose throughout the period. Cumulative incidence to 5 years of age per 10,000 births rose consistently from 6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence rates increased most steeply for 2- and 3-year olds. The proportion diagnosed by age 5 years increased only slightly, from 54% for 1990 births to 61% for 1996 births. Changing age at diagnosis can explain a 12% increase, and inclusion of milder cases, a 56% increase. CONCLUSIONS: Autism incidence in California shows no sign yet of plateauing. Younger ages at diagnosis, differential migration, changes in diagnostic criteria, and inclusion of milder cases do not fully explain the observed increases. Other artifacts have yet to be quantified, and as a result, the extent to which the continued rise represents a true increase in the occurrence of autism remains unclear.