Nolen Rayna M, Petersen Lene H, Kaiser Karl, Quigg Antonietta, Hala David
Department of Marine Biology, Texas A&M University at Galveston, Galveston, TX, United States.
Department of Marine and Coastal Environmental Science, Texas A&M University at Galveston, Galveston, TX, United States.
Front Syst Biol. 2024 Mar 27;4:1367562. doi: 10.3389/fsysb.2024.1367562. eCollection 2024.
Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant in global aquatic ecosystems with increasing concern for its toxicity to aquatic wildlife through inadvertent exposures. To assess the likely adverse effects of PFOS exposure on aquatic wildlife inhabiting polluted ecosystems, there is a need to identify biomarkers of its exposure and toxicity. We used an integrated systems toxicological framework to identify physiologically relevant biomarkers of PFOS toxicity in fish. An stoichiometric metabolism model of zebrafish () was used to integrate available (published by other authors) metabolomics and transcriptomics datasets from toxicological studies with 5 days post fertilized embryo-larval life stage of zebrafish. The experimentally derived omics datasets were used as constraints to parameterize an mathematical model of zebrafish metabolism. simulations using flux balance analysis (FBA) and its extensions showed prominent effects of PFOS exposure on the carnitine shuttle and fatty acid oxidation. Further analysis of metabolites comprising the impacted metabolic reactions indicated carnitine to be the most highly represented cofactor metabolite. Flux simulations also showed a near dose-responsive increase in the pools for fatty acids and acyl-CoAs under PFOS exposure. Taken together, our integrative results showed dyslipidemia effects under PFOS exposure and uniquely identified carnitine as a candidate metabolite biomarker. The verification of this prediction was sought in a subsequent environmental monitoring study by the authors which showed carnitine to be a modal biomarker of PFOS exposure in wild-caught fish and marine mammals sampled from the northern Gulf of Mexico. Therefore, we highlight the efficacy of FBA to study the properties of large-scale metabolic networks and to identify biomarkers of pollutant exposure in aquatic wildlife.
全氟辛烷磺酸（PFOS）是全球水生生态系统中普遍存在的污染物，人们越来越担心它会通过意外接触对水生野生动物产生毒性。为了评估PFOS暴露对栖息在受污染生态系统中的水生野生动物可能产生的不利影响，有必要确定其暴露和毒性的生物标志物。我们使用了一个综合系统毒理学框架来确定鱼类中PFOS毒性的生理相关生物标志物。斑马鱼（）的化学计量代谢模型被用于整合来自斑马鱼受精后5天胚胎-幼体生命阶段毒理学研究的现有（其他作者发表的）代谢组学和转录组学数据集。实验得出的组学数据集被用作约束条件，以参数化斑马鱼代谢的数学模型。使用通量平衡分析（FBA）及其扩展进行的模拟显示，PFOS暴露对肉碱穿梭和脂肪酸氧化有显著影响。对受影响代谢反应中包含的代谢物的进一步分析表明，肉碱是最具代表性的辅助因子代谢物。通量模拟还显示，在PFOS暴露下，脂肪酸和酰基辅酶A池几乎呈剂量反应性增加。综上所述，我们的综合结果显示PFOS暴露下存在血脂异常效应，并独特地确定肉碱为候选代谢物生物标志物。作者随后进行的一项环境监测研究寻求对这一预测的验证，该研究表明肉碱是从墨西哥湾北部采集的野生捕获鱼类和海洋哺乳动物中PFOS暴露的典型生物标志物。因此，我们强调了FBA在研究大规模代谢网络特性和识别水生野生动物污染物暴露生物标志物方面的功效。
