Hari Archana, Balik-Meisner Michele R, Mav Deepak, Phadke Dhiral P, Scholl Elizabeth H, Shah Ruchir R, Casey Warren, Auerbach Scott S, Wallqvist Anders, Pannala Venkat R
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Defense Health Agency Research & Development, Medical Research and Development Command, Fort Detrick, MD 21702, USA.
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
Toxics. 2025 Aug 17;13(8):684. doi: 10.3390/toxics13080684.
Per- and polyfluoroalkyl substances (PFASs) are widespread in the environment, bioaccumulate in humans, and lead to disease and organ injury, such as liver steatosis. However, we lack a clear understanding of how these chemicals cause organ-level toxicity. Here, we aimed to analyze PFAS-induced metabolic perturbations in male and female rat livers by combining a genome-scale metabolic model (GEM) and toxicogenomics. The combined approach overcomes the limitations of the individual methods by taking into account the interaction between multiple genes for metabolic reactions and using gene expression to constrain the predicted mechanistic possibilities. We obtained transcriptomic data from an acute exposure study, where male and female rats received a daily PFAS dose for five consecutive days, followed by liver transcriptome measurement. We integrated the transcriptome expression data with a rat GEM to computationally predict the metabolic activity in each rat's liver, compare it between the control and PFAS-exposed rats, and predict the benchmark dose (BMD) at which each chemical induced metabolic changes. Overall, our results suggest that PFAS-induced metabolic changes occurred primarily within the lipid and amino acid pathways and were similar between the sexes but varied in the extent of change per dose based on sex and PFAS type. Specifically, we identified that PFASs affect fatty acid-related pathways (biosynthesis, oxidation, and sphingolipid metabolism), energy metabolism, protein metabolism, and inflammatory and inositol metabolite pools, which have been associated with fatty liver and/or insulin resistance. Based on these results, we hypothesize that PFAS exposure induces changes in liver metabolism and makes the organ sensitive to metabolic diseases in both sexes. Furthermore, we conclude that male rats are more sensitive to PFAS-induced metabolic aberrations in the liver than female rats. This combined approach using GEM-based predictions and BMD analysis can help develop mechanistic hypotheses regarding how toxicant exposure leads to metabolic disruptions and how these effects may differ between the sexes, thereby assisting in the metabolic risk assessment of toxicants.
全氟和多氟烷基物质（PFASs）在环境中广泛存在，会在人体中生物蓄积，并导致疾病和器官损伤，如肝脂肪变性。然而，我们对这些化学物质如何引起器官水平的毒性尚缺乏清晰的认识。在此，我们旨在通过结合基因组规模代谢模型（GEM）和毒理基因组学来分析PFASs在雄性和雌性大鼠肝脏中诱导的代谢扰动。这种综合方法通过考虑代谢反应中多个基因之间的相互作用，并利用基因表达来限制预测的机制可能性，克服了单一方法的局限性。我们从一项急性暴露研究中获得了转录组数据，在该研究中，雄性和雌性大鼠连续五天每天接受PFAS剂量，随后测量肝脏转录组。我们将转录组表达数据与大鼠GEM整合，以计算预测每只大鼠肝脏中的代谢活性，比较对照大鼠和PFAS暴露大鼠之间的差异，并预测每种化学物质诱导代谢变化的基准剂量（BMD）。总体而言，我们的结果表明，PFAS诱导的代谢变化主要发生在脂质和氨基酸途径中，两性之间相似，但根据性别和PFAS类型，每剂量的变化程度有所不同。具体而言，我们发现PFASs影响脂肪酸相关途径（生物合成、氧化和鞘脂代谢）、能量代谢、蛋白质代谢以及炎症和肌醇代谢物池，这些都与脂肪肝和/或胰岛素抵抗有关。基于这些结果，我们假设PFAS暴露会诱导肝脏代谢变化，并使两性器官对代谢疾病敏感。此外，我们得出结论，雄性大鼠比雌性大鼠对PFAS诱导的肝脏代谢异常更敏感。这种基于GEM预测和BMD分析的综合方法有助于建立关于毒物暴露如何导致代谢紊乱以及这些影响在两性之间可能如何不同的机制假说，从而协助进行毒物的代谢风险评估。
