Mechanisms and Modifiers of Prenatal Acetaminophen Exposure and Child Neurodevelopment

About This Grant

PROJECT SUMMARY Acetaminophen, which is found in more than 600 prescription and non-prescription medications for mild to moderate pain and fever reduction, is not restricted to pharmacies and is sold over-the-counter in many countries, including the United States. In most populations worldwide, over 50% of pregnant people report taking acetaminophen, which easily crosses the placenta and fetal blood brain barrier, potentially affecting fetal brain development. The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have traditionally viewed acetaminophen as posing minimal risks to the fetus when used as directed but have called for more rigorous studies and better safety data to inform their recommendations on how pain medicines are used during pregnancy. Accumulating evidence from epidemiologic and animal research highlights potential neurodevelopmental risks associated with prenatal acetaminophen exposure, yet limitations remain in the literature preventing regulatory agencies from assessing whether these associations are causal. Prior studies could be confounded by genetic or familial factors, and mechanisms linking acetaminophen with adverse neurodevelopment remain unknown, limiting our ability to develop targets for harm reduction. While adjusting for a robust set of genetic, environmental, and familial factors, this proposal aims to elucidate molecular mechanisms and genetic effect modifiers of associations between prenatal acetaminophen and adverse neurodevelopment. During the mentored K99 phase, I will receive training from leaders in pediatrics, child psychiatry and psychology, pharmacogenomics, metabolomics, and multi-omics. I will combine this training with my prior expertise in prenatal acetaminophen research and epidemiology to model associations of maternal blood biomarkers of acetaminophen with a broad spectrum of child neurodevelopmental outcomes, including ADHD. I will investigate genotype by prenatal acetaminophen interactions on child neurodevelopment (K99 Aim 1) and conduct a Metabolome-Wide Association Study (MWAS) of prenatal acetaminophen exposure (K99 Aim 2) in a single site study. Genetic expertise gained from the K99 training and Aim 1 will enable me to explore genotype by prenatal acetaminophen interactions in a meta-regression analysis of multiple cohorts (R00 Aim 3), which will require advanced methods accounting for heterogeneity in allelic effects by ancestry. Metabolomics and multi-omics expertise gained from the K99 training and Aim 2 will enable me to conduct MWAS in this multi-cohort setting, and employ multi-omics pathway integration to uncover biological pathways altered by prenatal acetaminophen (R00 Aim 4). Through this K99/R00 award, I will gain subject matter expertise in developmental psychopathology and molecular analytic skills in precision medicine, pharmacogenetics, metabolomics, and multi-omics. These research and training opportunities will prepare me to lead an independent lab harmonizing omics and epidemiologic approaches to study molecular mechanisms linking prenatal exposures with neurodevelopment.