MacMillan Denise K, Bounds Jackson G, Willis William A, Strynar Mark J, Wetmore Barbara A, Liberatore Richard J, McCord James P, Devito Michael J
Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency (USEPA), Durham, NC 27709, USA.
Oak Ridge Associated Universities (ORAU), Oak Ridge, TN 37830, USA.
Toxics. 2025 Jun 21;13(7):523. doi: 10.3390/toxics13070523.
High-resolution accurate mass non-targeted analysis (NTA) is a useful discovery tool for metabolite characterization of in vivo dosing studies since it enables detection of both predicted and unexpected biotransformation products. We used NTA to investigate biotransformation of perfluorohexanesulfonamide (PFHxSA) in plasma and liver from male and female Sprague Dawley rats after a 5-day repeat exposure study. PFHxSA is an emerging per- and polyfluoroalkyl substance (PFAS) with unknown toxicity and a potentially reactive headgroup. NTA revealed the presence of predicted in vivo biotransformation products (BP) such as perfluorohexane sulfonic acid (PFHxS) and perfluorohexanesulfinic acid (PFHxSi). PFHxSi also has unknown toxicity and has not, to our knowledge, been previously reported as a PFHxSA BP in mammals. Multiple perfluoroalkyl ether sulfonamides, associated BPs, and novel PFAS were also detected in rat plasma and liver. We observed sex-specific distributions of the dosed compound and BPs, suggesting different toxicokinetics and biological responses. The presence of a complex mixture of predicted and unexpected PFAS in plasma and liver not only mimics the complexity of environmental exposure but also highlights the need for toxicity testing with mixtures and a more complete assessment of dosing solution purity.
高分辨率精确质量非靶向分析（NTA）是体内给药研究中代谢物表征的一种有用的发现工具，因为它能够检测预测的和意外的生物转化产物。在一项为期5天的重复暴露研究后，我们使用NTA来研究全氟己烷磺酰胺（PFHxSA）在雄性和雌性Sprague Dawley大鼠血浆和肝脏中的生物转化。PFHxSA是一种新兴的全氟和多氟烷基物质（PFAS），其毒性未知且具有潜在的反应性头基。NTA揭示了体内生物转化产物（BP）的存在，如全氟己烷磺酸（PFHxS）和全氟己烷亚磺酸（PFHxSi）。PFHxSi的毒性也未知，据我们所知，此前尚未在哺乳动物中作为PFHxSA的BP被报道过。在大鼠血浆和肝脏中还检测到多种全氟烷基醚磺酰胺、相关BP和新型PFAS。我们观察到给药化合物和BP的性别特异性分布，表明存在不同的毒代动力学和生物学反应。血浆和肝脏中预测的和意外的PFAS复杂混合物的存在不仅模拟了环境暴露的复杂性，也凸显了对混合物进行毒性测试以及更全面评估给药溶液纯度的必要性。
