在斑马鱼胚胎中,Prothioconazole诱导的立体选择性发育毒性和肝损伤是通过铁灭菌引起的
Jinhao Bian1, Hanshuang Zhao1, Wenping Xu1
1Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China.
概括
杀菌剂prothioconazole (PTCZ) 的S-(+) -enantiomer对斑马鱼胚胎更有毒,通过激活ferroptosis引起肝损伤. 目前的农药安全性评估低估了性农药带来的风险.
科学领域:
- 环境毒理学环境毒理学
- 化学生态化学生态学
- 分子毒理学 分子毒理学
背景情况:
- 蛋白甲醇 (PTCZ) 是一种广泛使用的三醇杀菌剂,具有潜在的生态风险.
- 农药安全性评估往往忽视了毒性的反体差异.
- 化农药法规需要考虑立体选择性效应.
研究的目的:
- 调查前列康纳 (PTCZ) 类反体的立体选择性毒性.
- 阐明水生模型中PTCZ反体毒性背后的分子机制.
- 评估铁死在PTCZ诱导的毒性中的作用.
主要方法:
- 斑马鱼胚胎暴露系统用于毒性评估.
- 多维终点分析,包括发育,肝脏和代谢参数.
- 对铁亡途径 (GPX4,acsl4) 的分子分析和用Ferrostatin-1.1进行救援实验.
主要成果:
- 与R-(-) -PTCZ相比,S-(+) -PTCZ诱导的发育毒性和肝损伤明显更大.
- S-(+) -PTCZ激活了脂质过氧化-铁化轴,由减少的GPX4和增加的acsl4表明.
- 费罗斯塔丁-1治疗减轻了S-(+) -PTCZ诱导的脂质过氧化和毒性.
结论:
- PTCZ的S-(+) -反体是观察到的毒性的主要驱动因素.
- 铁化是S-(+) -PTCZ诱导的肝毒性的一个关键机制.
- 基于种族性PTCZ的风险评估低估了环境危害;性农药监管至关重要.
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