Gabal Esraa, Azaizeh Marwah, Baloni Priyanka
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47097, USA.
Metabolites. 2025 Jul 24;15(8):499. doi: 10.3390/metabo15080499.
Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. 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 perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood-brain barrier (BBB) function, pointing to broader systemic toxicity. Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure.
接触全氟和多氟烷基物质（PFAS，包括7H-全氟-4-甲基-3,6-二氧杂辛烷磺酸（PFESA-BP2）、全氟辛酸（PFOA）和六氟环氧丙烷（GenX））与肝功能障碍有关。虽然先前的研究已经描述了PFAS诱导的肝脏脂质改变，但其对能量代谢的下游影响仍不清楚。本研究调查了PFAS暴露后肝脏中的代谢改变，以确定导致肝毒性的机制。我们分析了暴露于PFAS的小鼠肝脏组织的RNA测序数据集，以确定受化学毒物影响的代谢途径。我们将转录组数据与小鼠基因组规模的代谢模型整合，以进行计算机模拟通量分析，并研究与脂质和能量代谢相关的反应和基因。PFESA-BP2暴露导致剂量和性别依赖性变化，包括脂肪酸代谢、β-氧化和胆固醇生物合成上调。相反，甘油三酯、鞘脂和甘油磷脂代谢受到抑制。综合基因组规模代谢模型的模拟证实了甲羟戊酸和羊毛甾醇代谢通量增加，支持潜在的胆固醇积累。GenX和PFOA引发了强烈的PPARα依赖性反应，尤其是在β-氧化和脂肪分解方面，在PPARα基因敲除小鼠中这种反应减弱。线粒体脂肪酸转运和酰基肉碱周转也受到干扰，表明线粒体功能障碍。PFAS的其他影响包括三羧酸（TCA）循环、氧化磷酸化和血脑屏障（BBB）功能的紊乱，表明存在更广泛的全身毒性。我们的研究结果突出了关键的代谢特征，并表明PFAS介导了肝脏和可能的神经功能破坏。本研究强调了基因组规模代谢建模作为解释转录组数据和预测毒物暴露的全身代谢结果的有力工具的实用性。
