Integrative omics analyses and systems toxicology modeling of PFAS-induced biological perturbations

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with metabolic, hepatic, and neurological toxicity, yet the systems-level mechanisms linking exposure to disease conditions remain incompletely defined. This dissertation integrates multi omics analyses and genome-scale metabolic modeling to characterize PFAS-induced toxicity and its relevance to neurodegenerative disease. First, a literature-based review connects PFAS exposure with perturbations of metabolic pathways implicated in Alzheimer’s disease (AD). Thereafter, a systems biology approach was utilized to investigate liver transcriptomic datasets acquired from public databases enabled to investigate different PFAS congeners on lipid and energy metabolism, highlighting their dose- and sex-dependent toxicity. Multi-omics analyses of PFOS exposure performed within in vivo research using Xenopus laevis and Sprague-Dawley rats further revealed liver-brain axis disruption, with changes in neurodevelopmental signaling, mitochondrial bioenergetics, inflammation, bile acid metabolism, tryptophan/kynurenine metabolism, amino acid homeostasis, and lipid metabolism. To support mechanistic investigation of brain metabolism, a mouse brain-specific genome-scale metabolic model, iMiceBrain, was developed, demonstrating significant brain specificity, metabolic functionality, and translational relevance to human brain metabolism. Finally, integration of iMiceBrain with multi-omics data from AD-symptomatic APP/PS1 mice showed that the mitochondrial complex I modulator CP2 reverses AD-associated metabolic perturbations by restoring bioenergetic flexibility, cholesterol homeostasis, proteostasis, neuroprotective signaling, and acetyl-CoA-linked epigenetic regulation. Collectively, this work demonstrates that integrative omics and constraint-based modeling can identify metabolic signatures of PFAS toxicity with liver-brain axis changes relevant to AD, and therapeutic strategies targeting mitochondrial and lipid metabolic resilience.