Epidemiology as a Hypothesis Generation Tool for Toxicology: A Case for Acetaminophen and Adverse Health Outcomes in Children.

SORROW, PATRICIA ANN. Epidemiology as a Hypothesis Generation Tool for Toxicology: A Case for Acetaminophen and Adverse Health Outcomes in Children (Under the direction of Dr. Cathrine Hoyo). Recently, obesity and its comorbidities have reached epidemic proportions for children in the United States. Some children seem to be more susceptible to developing obesity and for these children lifestyle interventions are often ineffective. No more than 5% increased risk for developing obesity can be attributed to genetic predisposition, and developmental exposures are known to contribute to the incidence of metabolic disease later in life. Current blood tests for metabolic disease are not useful in children, and thus novel biomarkers are needed to detect, at birth, those with the greatest risk of developing obesity while prevention is still possible. An untargeted metabolomics assay was used in a subset of 50 cord blood samples from the Newborn Epigenetics Cohort to compare the circulating small molecule profile in children who became obese (n=25) (weight for height z-score (WHz) >95%) compared with children who were not obese (n=25) (WHz <85%) by age 3-5 years. The assay identified 384 different metabolites using a combination of GC and LC-MS, and 70 metabolites were found at significantly different levels. The most significant of these included species of medium and long chain fatty acids and metabolites of the analgesic/antipyretic medication acetaminophen. These associations remained after the role of maternal pre-pregnancy obesity and ethnicity were adjusted for in regression models. Prenatal acetaminophen exposure is related adverse child outcomes including asthma, attention deficit hyperactive disorder (ADHD), decreased anogenital distance and now obesity. This suggests some level of metabolic disruption maybe linked to acetaminophen use in pregnancy. To strengthen these findings, targeted HPLC-MS assays were developed to determine the concentration of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and acetaminophen glutathione in a larger population. Significant associations were found between detectable cord blood levels of acetaminophen, acetaminophen sulfate, and acetaminophen glucuronide with childhood obesity (WHz) in boys by 3 years of age after adjustment for maternal pre-pregnancy obesity. No associations were found in girls, and these associations did not persist in boys at ages 4 and 5 years, although sample size remains small. No associations were found between detectable cord blood concentrations of acetaminophen and its metabolites with systolic and diastolic blood pressure. Because of the longitudinal cohort design, temporal sequence is retained between exposure and disease incidence granting considerable strength to the associations presented here, but even after increasing sample size from 50 to 120 individuals, the number of individuals with detectable exposure to acetaminophen remains small (21%) limiting the power of this finding. Although it is impossible to determine causality, due to the extreme heterogeneity within the human population, this work shows that epidemiology is an excellent tool for hypothesis generation for toxicologists. © Copyright 2019 by Patricia Sorrow All Rights Reserved Epidemiology as a Hypothesis Generation Tool for Toxicology: A Case for Acetaminophen and Adverse Health Outcomes in Children by Patricia Ann Sorrow A thesis submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Master of Science