PROJECT SUMMARY
Maternal inflammation during pregnancy, as defined by elevated levels of circulating pro-inflammatory cytokines,
can have adverse effects on offspring neurodevelopment. However, mechanisms remain elusive. Accelerated
biological aging has been proposed as an underlying mechanism by which prenatal exposures influence future
health. This process can be evaluated through epigenetic clocks, which estimate epigenetic age based on DNA
methylation levels, and are widely used as clinically relevant biomarkers that measure epigenetic age
acceleration. To date, pediatric epigenetic studies have been limited by: (1) use of adult-specific or all-age clocks;
and (2) scant longitudinal epigenetic data due to challenges of pediatric blood collection. Here, we use a newly
developed pediatric-specific clock [the pediatric buccal epigenetic (PedBE) clock] that can be evaluated using
non-invasive buccal swabs, facilitating repeat measures across childhood. Our long-term goal is to identify easy-
to-measure biomarkers in infants and young children that reflect exposure to maternal inflammation during
pregnancy and predict subsequent risk for morbidity in offspring. This innovative and cost-effective longitudinal
study will leverage the infrastructure, biorepository, and extant data of a rigorously phenotyped cohort of healthy
pregnant women and their offspring followed from the first trimester through age 4 (R01HD083369,
UH3OD023349). The Understanding Pregnancy Signals and Infant Development (UPSIDE-ECHO) cohort
includes comprehensive assessments of inflammation across pregnancy, repeated measures of
neurodevelopment across childhood, detailed psychological, sociodemographic, clinical, and life history data,
and a rich repository of biospecimens collected from 2015 – 2024 (age 3-4 visits in progress). Our central
hypothesis is that maternal inflammation during pregnancy accelerates the offspring’s epigenetic age, adversely
influencing neurodevelopment. Our interdisciplinary research team is comprised of experts in maternal and child
health, epigenomics, immunology, cognitive science, perinatal epidemiology, and biostatistics. In Aim 1, we will
establish trajectories of longitudinal changes in offspring epigenetic age from birth through 4 years of age and
identify factors associated with offspring epigenetic age acceleration. In Aim 2, we will study associations
between maternal inflammation during pregnancy and offspring epigenetic age acceleration. In Aim 3, we will
examine associations between offspring epigenetic age and neurocognition through age 4, and explore if
epigenetic age mediates the association between maternal inflammation during pregnancy and neurocognitive
outcomes. The research proposed in this R01 is significant because it will generate new insights into the link
between maternal inflammation during pregnancy and genomic biomarkers of accelerated aging, with a focus
on how accelerated epigenetic age can impact offspring neurocognition. This formative work will advance our
understanding of how epigenetic age trajectories change across a critical developmental period and identify
opportunities for maternal/offspring interventions to improve neurocognitive outcomes across the entire lifespan.