DOI: 10.25549/usctheses-c40-371641
title: Effects of prenatal environmental exposures on the risk of autism spectrum disorder

description: Autism spectrum disorder (ASD) is a complex neurologic disorder affecting over three million individuals in the U.S. and tens of millions worldwide. According to the most recent data by the CDC, 1 in 68 kids in America have been diagnosed with ASD. ASD is characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication and repetitive behaviors. Very little is known about the risk factors for ASD. While evidence supports large heritable contributions to the etiology of ASD, most studies suggest that both environmental and genetic factors play a role, since concordance in identical twins suggests that a minimum of 55% of autism cases are likely to have an environmental cause. ❧ The studies set forth in this dissertation evaluate the effects of prenatal exposure to several environmental risk factors on the risk of ASD. In the first study, I examined the joint effects of prenatal air pollution exposure and periconceptional (3 months before or during the first month of pregnancy) folic acid (FA) intake on the risk of ASD in 370 ASD cases and 267 typically developing controls from the CHARGE case-control study. Folic acid intake was calculated from self-reported prenatal vitamin, supplement, and dietary information. Near roadway air pollution (NRP) exposure was assigned using the CALINE4 line-source air-quality dispersion model, and regional pollutants were assigned based on the EPA’s Air Quality Monitoring Network and supplemented with air pollution data from the Children’s Health Study (CHS). I found a statistically significant multiplicative interaction (alpha = 0.10) between folic acid and first trimester NRP exposure (p=0.097) and between folic acid and first trimester NO₂ exposure (p=0.084), such that among mothers with high periconceptional FA intake (&gt;800 ug), exposure to increasing levels of all air pollution (a 2 SD increase), during the first trimester was associated with a decreased risk of ASD, while an increased risk of ASD was seen for the same pollutant among mothers with low FA intake (≤800 ug) (e.g. NRP and low FA intake: Adjusted odds ratio (AOR) = 1.18 (0.72, 1.93) vs NRP and high FA intake: AOR: 0.68 (0.40, 1.14)). When air pollutant exposures were dichotomized at the median, we found that mothers exposed to higher levels (≥ median) of any air pollutant during the first trimester of pregnancy and who reported low FA intake in the first month of pregnancy were at a higher risk of ASD compared to mothers exposed to lower levels of that air pollutant and who reported high FA intake. ❧ In the second study, I examined the effects of prenatal UV exposure on the risk of ASD using the Autism Genetic Resource Exchange (AGRE) family registry of ASD cases and their sibling controls. Average annual UV values were assigned to prenatal residential addresses using the GIS ANUSPLIN method. Trimester specific averages were then imputed based on date of birth, latitude of each address and the insolation at that latitude. Mixed effects logistic regression was used to parse out the within and between family effects. I found that an increase in exposure of 500 Watt-hours/m² between families during all pregnancy periods statistically significantly reduced the odds of ASD by 11-14%. While none of the within family associations were statistically significant, stronger effects were observed in the whole pregnancy period and the second trimester, where an increase exposure of 500 Watt-hours/m² of UV within a family during the whole pregnancy period reduced the odds of ASD by 24% and the same increase during the second trimester reduced the odds of ASD by 17%. ❧ The last study in this dissertation examines the joint effects of prenatal criteria air pollution and UV exposure on the risk of ASD using the same study population as the second study. UV exposures were assigned as described above, and air pollutant exposures were assigned based on the EPA’s Air Quality Monitoring Network and supplemented with air pollution data from the Children’s Health Study (CHS). Mixed effects logistic regression was used to parse out the within and between family effects. I found a statistically significant multiplicative interaction between ozone and UV within families for the first and third trimesters, such that for every increase in UV of 100 Watt-hours/m² within families, the effect size between ozone and ASD decreased by about 20% (Trimester 1 AOR for interaction: 0.80; 95% CI: 0.68, 0.95; Trimester 3 AOR for interaction: 0.82; 95% CI: 0.69, 0.96). Though not significant, the effect size between every air pollutant and ASD within families decreased with increasing UV in the first and second trimester, except for NO₂ in the first trimester and PM2.5 in the second trimester. ❧ The results of these studies suggest that prenatal exposure to multiple environmental risk factors likely play a role in the etiology of ASD.