Zhang Meng, Zhang Qingqi, Zhao Weiya, Chen Xin, Zhang Yumei
College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China.
College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, China.
Toxicol Lett. 2024 Feb;392:1-11. doi: 10.1016/j.toxlet.2023.12.009. Epub 2023 Dec 15.
Sodium dehydroacetate (DHA-S), a potent antifungal and antibacterial agent, is widely used in food, feed and cosmetics. However, recent studies have shown that DHA-S could pose a risk for human and animal health. We had previously reported that DHA-S could cause coagulation disorders in rats and chicken. In the present study, we further confirmed that DHA-S induced blood coagulation via VKORC1 and VKORC1L1 in rats, and elucidated the role played by mTOR/ERK signaling. The in vivo studies demonstrated that PT, APTT, and DHA-S content and relative protein expressions in tissues rebounded after drug withdrawal. In BRL-3A cells, 1.0 mM DHA-S increased the expression levels of mTOR, p-mTOR and p-ERK and decreased the levels of VKORC1, VKORC1L1 and Vitamin K. Rapamycin significantly decreased the expression levels of p-mTOR and p-ERK, while FR180204 (p-ERK Inhibition) lead to a decrease in p-ERK level. Rapamycin and FR180202 attenuated the inhibitory effect of DHA-S on VKORC1, VKORC1L1 and vitamin K levels. In addition, DHA-S increased the expression levels of mTOR, p-mTOR and p-ERK in male and female rat livers and prolonged PT and APTT. In summary, this study indicated that DHA-S induced blood coagulation via the modulation of the mTOR/ERK pathway in rats.
脱氢乙酸钠（DHA-S）是一种强效抗真菌和抗菌剂，广泛应用于食品、饲料和化妆品中。然而，最近的研究表明，DHA-S可能对人类和动物健康构成风险。我们之前曾报道，DHA-S可导致大鼠和鸡出现凝血障碍。在本研究中，我们进一步证实，DHA-S在大鼠中通过维生素K环氧化物还原酶复合体1（VKORC1）和VKORC1样蛋白1（VKORC1L1）诱导血液凝固，并阐明了雷帕霉素靶蛋白/细胞外信号调节激酶（mTOR/ERK）信号传导所起的作用。体内研究表明，停药后组织中的凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）以及DHA-S含量和相关蛋白表达均有所回升。在BRL-3A细胞中，1.0 mM的DHA-S增加了mTOR、磷酸化mTOR（p-mTOR）和磷酸化ERK（p-ERK）的表达水平，并降低了VKORC1、VKORC1L1和维生素K的水平。雷帕霉素显著降低了p-mTOR和p-ERK的表达水平，而FR180204（p-ERK抑制剂）导致p-ERK水平下降。雷帕霉素和FR180202减弱了DHA-S对VKORC1、VKORC1L1和维生素K水平的抑制作用。此外，DHA-S增加了雄性和雌性大鼠肝脏中mTOR、p-mTOR和p-ERK的表达水平，并延长了PT和APTT。总之，本研究表明，DHA-S通过调节大鼠的mTOR/ERK途径诱导血液凝固。
