School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
J Hazard Mater. 2023 Apr 5;447:130831. doi: 10.1016/j.jhazmat.2023.130831. Epub 2023 Jan 20.
Legacy per- and polyfluoroalkyl substances (PFASs) are a worldwide health concern due to their potential bioaccumulation and toxicity in humans. A variety of perfluoroether carboxylic acids (PFECAs) have been developed as next-generation replacements of legacy PFASs. However, information regarding their possible environmental and human health risks is limited. In the present study, we explored the effects of PFECAs on mice based on long-term exposure to environmentally relevant doses of perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoDA). Results showed that PFECAs exposure suppressed many cellular stress signals and resulted in hepatomegaly. PFO5DoDA acted as an agonist of the peroxisome proliferator-activated receptor (PPAR) in vitro and modulated PPAR-dependent gene expression in the liver. Importantly, PFECAs had an inhibitory effect on the glucocorticoid receptor (GR), which may contribute to the extensive suppression of stress signals. Of note, the GR suppression induced by PFECAs was not reported by legacy perfluorooctanoic acid (PFOA). PFO5DoDA-induced changes in both GR and PPAR signals remodeled hepatic metabolic profiles, including decreased fatty acids and amino acids and increased β-oxidation. Mechanistically, PFO5DoDA inhibited GR transactivation by degradation of GR proteins. Our results emphasize the potential risk of PFECAs to human health, which were introduced to ease concerns regarding legacy PFASs.
传统的全氟和多氟烷基物质 (PFASs) 因其在人类体内的潜在生物累积性和毒性而成为全球关注的健康问题。各种全氟醚羧酸 (PFECAs) 已被开发为传统 PFASs 的下一代替代品。然而，关于它们可能对环境和人类健康造成的风险的信息有限。在本研究中，我们基于长期暴露于环境相关剂量的全氟-3,5,7,9,11-五氧杂十二烷酸 (PFO5DoDA) ，研究了 PFECAs 对小鼠的影响。结果表明，PFECAs 暴露抑制了许多细胞应激信号，并导致肝肿大。PFO5DoDA 在体外作为过氧化物酶体增殖物激活受体 (PPAR) 的激动剂，调节肝脏中 PPAR 依赖性基因表达。重要的是，PFECAs 对糖皮质激素受体 (GR) 具有抑制作用，这可能导致应激信号的广泛抑制。值得注意的是，PFECAs 引起的 GR 抑制作用并未被传统的全氟辛酸 (PFOA) 报道。PFECAs 引起的 GR 和 PPAR 信号的改变重塑了肝脏的代谢谱，包括脂肪酸和氨基酸减少以及β氧化增加。在机制上，PFO5DoDA 通过降解 GR 蛋白抑制 GR 转录激活。我们的研究结果强调了 PFECAs 对人类健康的潜在风险，这些物质的引入是为了缓解人们对传统 PFASs 的担忧。
