Transcriptomic And Metabolomic Analyses Of Acetaminophen Exposure In Human Ipscs: Potential Mechanisms Explaining Epidemiological Associations Between Prenatal Acetaminophen Exposure And Increased Risk Of Autism Spectrum Disorder
Date of Award
Open Access Thesis
Master of Public Health (MPH)
School of Public Health
Acetaminophen (APAP) is the most common analgesic taken during pregnancy. Indeed, approximately 65% of pregnant women use the drug. Recent epidemiological studies suggest that prenatal exposure to APAP is associated with increased risk of autism spectrum disorder (ASD). Although this neurodevelopmental disorder affects 1 in 54 children in the U.S., no studies have investigated the molecular mechanism by which APAP may increase the risk of ASD. In vitro experiments in cell cultures have shown that high concentrations of APAP induces cell death. Through the use of a systems-level approach in human induced Pluripotent Stem Cells (iPSCs), the present study investigates the mechanisms by which prenatal exposure to physiologically relevant doses of APAP could increase the risk of ASD. Initial experiments examined the concentration-dependence of APAP toxicity in human iPSCs exposed for 6 days, as estimated by changes in cell counts. Thereafter, RNA-sequencing and metabolomic analyses were conducted on cells exposed to therapeutic (0.16 mM) and toxic (0.32 and 0.48 mM) APAP concentrations for 6 days. APAP concentration-dependent decreases in expression for COBL, CYP2B6, FZD5, GPC4, NCALD and FGFBP3, and increases in expression for ATP1A2, PROS1, HES1 and NRIP1 were observed. These changes in gene expression are identical to those described in the ASD literature. Metabolomic analyses revealed differential regulation of metabolites involved in aminoacyl-tRNA, and valine, leucine and isoleucine biosynthesis, both of which have been linked to ASD. Our integration of transcriptomics and metabolomics data has revealed an impact of APAP on biological processes that appear to parallel those seen in ASD. In so doing, the results of the present study provide an important first step in elucidating the potential mechanisms by which prenatal exposure to APAP may increase the risk of ASD and promote adverse neurodevelopmental outcomes.
Furnary, Tristan, "Transcriptomic And Metabolomic Analyses Of Acetaminophen Exposure In Human Ipscs: Potential Mechanisms Explaining Epidemiological Associations Between Prenatal Acetaminophen Exposure And Increased Risk Of Autism Spectrum Disorder" (2021). Public Health Theses. 2044.
This Article is Open Access