Investigating Lipid and Energy Dyshomeostasis Induced by PFAS Congeners in Mouse Model Using Systems Biology Approaches

Per-(poly) fluoroalkyl substances (PFAS) compounds, including PFESA-BP2, PFOA, and GenX, are linked to hepatic metabolic disturbances. Using transcriptomics and genome-scale metabolic modeling, we investigated their impact on liver lipid and energy metabolism. PFESA-BP2 caused dose- and sex-dependent alterations, including upregulation of fatty acid biosynthesis, elongation, β-oxidation, and cholesterol biosynthesis via targeting key enzymes. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα⁻/⁻ mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included altered TCA cycle, oxidative phosphorylation, and blood brain barrier (BBB) transporter expression, pointing to broader systemic toxicity. These findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This work underscores the utility of genome-scale metabolic models as powerful tools to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure.