PROJECT SUMMARY/ABSTRACT
Autism spectrum disorder (ASD) is a broad range of related neurodevelopmental disorders that are expressed
within the first 2 to 3 years of life as stereotypic behaviors, and language and social-emotional impairments.
ASD affects about 1 in 59 children in the United States and carries a high economic cost to families and
communities. While there is a contribution of heredity, a growing body of research suggests that ASD has
origins in utero. Specifically, evidence is accumulating that prenatal inflammation is a critical exposure in the
causal pathway of at least a subset of ASD. Notably, this exposure may operate through sex-dimorphic effects
on the placenta on fetal brain development, consistent with the high ASD risk for males relative to females. In
our community-based hospital population, unique due to mandated universal placental histopathology
assessment and linkage to pediatric community care, pilot analyses identified a 3-to-7-fold increased risk of
childhood ASD associated with prenatal exposure to acute and/or chronic inflammation (AI, CI). This marker
was seen in ~25% of low-risk children eventually diagnosed with ASD. These inflammatory placental
pathologies were not marked by any maternal signs or symptoms during pregnancy. In addition, we identified a
13-fold increased odds of ASD risk with placental villous maldevelopment (PVM).
We propose here to test pathways from these placental histopathology diagnoses to eventual ASD
diagnosis. We will begin with targeted formalin-fixed paraffin-embedded (FFPE) placental histopathology of AI,
CI, and PVM. We will then employ detailed and quantitative immunophenotyping of placental-decidual tissue at
the placental-maternal interface. We can thoroughly profile cell type, cell function markers, and inflammation
activation/apoptosis targets at the same time by using computer-assisted deep learning that allows precise
tracking of immunolabeling and minimizes concerns of label overlap that can confound interpretation of
immunofluorescent preparations. We will next assess newborn circulating levels of cytokines, chemokines, and
growth factors, alterations of which are known to impact neurodevelopmental processes key to the genesis of
neuronal dysfunction manifested in ASD. We will also examine epigenetic pathways by assessing DNA
methylation in the placenta and its link to inflammation and PVM. Our analyses will test these as pathways
from placental/decidual tissue markers of inflammation and/or PVM to ASD diagnosis.
No other ASD case-control sample in a community-based population has universal access to FFPE tissue.
This proposed project will open a unique window on the prenatal environment underlying ASD. Clarification of
the pathways operating in community-based ASD will elucidate the mechanisms involved in ASD risk.
