Wu Yuanyuan, Sun Weiqiang, Liu Xiyue, Fan Zhonghua, Cheng Lin, Yang Ying, Wang Li, Liu Hui
Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, PR China; School of Public Health, Bengbu Medical University, Bengbu 233030, PR China.
Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, PR China; Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical University, Bengbu 233030, PR China.
Ecotoxicol Environ Saf. 2025 Sep 1;302:118546. doi: 10.1016/j.ecoenv.2025.118546. Epub 2025 Jun 23.
The accumulation of perfluorooctanoic acid (PFOA) and its substitutes hexafluoropropylene oxide dimer acid (HFPO-DA, trade name Gen-X) and hexafluoropropylene trimer acid (HFPO-TA), which are widely used synthetic chemicals, may pose significant health risks across species. This study systematically investigated the multi-dimensional effects of PFOA and its substitutes on fatty acid metabolic processes and erythrocyte survival through bioinformatic and metabolomics analysis, complemented by a variety of zebrafish exposure experiments, including Oil Red O staining (ORO staining), Nile red staining (NR staining), 1,3-bis(diphenylphosphino)propane (DPPP) and reactive oxygen species (ROS), as well as inflammation, apoptosis and gene expression assays. PFOA and its substitutes significantly disrupted fatty acid oxidation degradation and synthesis, by interfering with the peroxisome proliferator-activated receptor α (PPARα) signaling pathway, leading to lipid accumulation in zebrafish. In addition, PFOA and HFPO-TA reduced the number of erythrocytes in zebrafish through excessive generation of ROS and abnormal activation of the tp53 gene. Gene expression analysis further confirmed that the expression of genes related to fatty acid metabolism, inflammation and apoptosis regulated by PPARα and its target genes were significantly upregulated. This study revealed that PFOA and its substitutes exert multi-dimensional effects on fatty acid metabolism and erythrocyte survival in zebrafish through the activation of PPARα, providing new perspectives for understanding the toxicity mechanisms of per- and polyfluoroalkyl substances (PFAS).
全氟辛酸（PFOA）及其替代品六氟环氧丙烷二聚酸（HFPO-DA，商品名Gen-X）和六氟环氧丙烷三聚酸（HFPO-TA）是广泛使用的合成化学品，它们的积累可能对所有物种构成重大健康风险。本研究通过生物信息学和代谢组学分析，系统地研究了PFOA及其替代品对脂肪酸代谢过程和红细胞存活的多维度影响，并辅以各种斑马鱼暴露实验进行补充，包括油红O染色（ORO染色）、尼罗红染色（NR染色）、1,3-双（二苯基膦基）丙烷（DPPP）和活性氧（ROS），以及炎症、凋亡和基因表达分析。PFOA及其替代品通过干扰过氧化物酶体增殖物激活受体α（PPARα）信号通路，显著破坏脂肪酸氧化降解和合成，导致斑马鱼体内脂质积累。此外，PFOA和HFPO-TA通过过量产生ROS和tp53基因的异常激活，减少了斑马鱼体内红细胞的数量。基因表达分析进一步证实，由PPARα及其靶基因调控的与脂肪酸代谢、炎症和凋亡相关的基因表达显著上调。本研究表明，PFOA及其替代品通过激活PPARα对斑马鱼的脂肪酸代谢和红细胞存活产生多维度影响，为理解全氟和多氟烷基物质（PFAS）的毒性机制提供了新的视角。
