Interactions of Environmental Chemical Mixtures, Genetics, and Immune Pathways in Autism Spectrum Disorder

ABSTRACT
The rising prevalence of Autism Spectrum Disorder (ASD) among children is a public health concern. An
expanding landscape of genetic and environmental risk factors has been implicated in ASD’s development,
indicating complex, multifactorial origins in early life. Many endocrine-disrupting chemicals (EDCs) have
neurotoxic potential, but their role in ASD development needs clarification. EDCs are implicated in maternal
immune dysregulation and inflammation, a leading research hypothesis of ASD’s developmental origins. Gene-
environment investigations of EDCs, with focus on plausible biological mechanisms, could provide critical
insight into whether genetic subgroups of individuals may be more sensitive to environmental chemicals and
bring clarity to this inconsistent evidence between ASD and EDCs. The proposed research seeks to combine
polygenic and complex environmental mixtures approaches to address gaps in understanding of ASD’s
etiology. During the K99 phase of this award, I will pursue didactic and mentored training in autism
epidemiology, immunology, and methodologies of analyzing complex environmental mixtures, genome-wide
data, and gene-environment interplay. Under the mentorship of a strong multidisciplinary team with a history of
collaboration, I will apply this training to studies of the relationships between environmental, immunologic, and
genetic data from the Early Markers for Autism study (EMA; R01ES016669, PI: Croen), a population-based
case-control study (n=1005). In Aim 1, I will apply training in complex mixtures methods to examine the
pathway between joint exposure to multiple EDCs during gestation, biomarkers of maternal and neonatal
immune function, and child ASD. In Aim 2, I will apply training in genome-wide analysis to identify maternal and
fetal genetic variants associated with mixtures of EDCs in mid-pregnancy circulation. In the K00 phase (Aim 3),
I will harness these new analytical skills to conduct a GxE analysis of the association of EDCs and polygenic
risk on early life immune function and ASD development. I will conduct Aim 3 in EMA with replication in two
larger mother-child cohort studies. The long-term goal of this research is to identify modifiable risk factors and
key biological pathways in ASD which can inform not only interventions to lower neurotoxic exposures in
pregnant mothers and infants but also pharmacologic interventions targeting the immune and other physiologic
intermediates. These training and research activities will serve as the springboard for developing a competitive
R01 application and launching my independent career in autism epidemiology.

Grant Number: 5R00ES032481-05
NIH Institute/Center: NIH
Principal Investigator: Jennifer Ames