Abstract：
As alternatives of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimeric acid (HFPO-DA) and trimeric acid (HFPO-TA) have been detected increasingly in environmental media and even humans. They have been shown to exhibit reproductive toxicity to model species, but their effects on human remain unclear due to the knowledge gap in their mode of action. Herein, (anti-)androgenic effects of the two HFPOs and PFOA were investigated and underlying toxicological mechanism was explored by combining zebrafish test, cell assay and molecular docking simulation. Exposure of juvenile zebrafish to the chemicals during sex differentiation promoted feminization, with HFPO-TA acting at an environmental concentration of 1 μg/L. The chemicals inhibited proliferation of human prostate cells and transcriptional activity of human and zebrafish androgen receptors (AR), with HFPO-TA displaying the strongest potency. Molecular docking revealed that the chemicals bind to AR in a conformation similar to a known AR antagonist. Combined in vivo, in vitro and in silico results demonstrated that the chemicals disrupted sex differentiation likely by antagonizing AR-mediated pathways, and provided more evidence that HFPO-TA is not a safe alternative to PFOA.
摘要：
作为全氟辛酸（PFOA）的替代品，六氟环氧丙烷二聚酸（HFPO-DA）和三聚酸（HFPO-TA）已在环境介质甚至人类中越来越多地检测到。它们已被证明对模型物种具有生殖毒性，但它们对人类的影响仍不清楚，因为它们的行动方式存在知识差距。在这里，通过结合斑马鱼试验，研究了两种HFPOs和PFOA的（抗）雄激素作用，并探索了潜在的毒理机制。细胞分析和分子对接模拟。幼年斑马鱼在性别分化过程中暴露于化学物质会促进女性化，HFPO-TA在1μg/L的环境浓度下起作用。化学物质抑制人前列腺细胞的增殖和人和斑马鱼雄激素受体（AR）的转录活性，HFPO-TA显示出最强的效力。分子对接显示化学物质以类似于已知AR拮抗剂的构象与AR结合。结合在体内，体外和计算机模拟结果表明，化学物质可能通过拮抗AR介导的途径破坏性别分化，并提供了更多证据表明HFPO-TA不是PFOA的安全替代品。
