Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Sci Total Environ. 2023 Nov 20;900:166349. doi: 10.1016/j.scitotenv.2023.166349. Epub 2023 Aug 19.
Acetamide (ACT) is used in a racemic form, and the considerable residues of this compound in the environment raise potential safety concerns for human health. We investigated the toxicity of ACT and its chiral isomers on human cardiomyocyte (AC16) cell line and zebrafish embryonic heart, and found that (+)-S-ACT was the main component causing cardiac toxicity. Our findings indicate that the IC of (±)-Rac-ACT on AC16 cells was 20.19 μg/mL. (-)-R-ACT, (±)-Rac-ACT, and (+)-S-ACT caused DNA damage and apoptosis in AC16 cells at this concentration. The underlying molecular mechanism may involve the induction of reactive oxygen species (ROS). The accumulation of ROS results in a decline in mitochondrial membrane potential (MMP) and prompts the release of cytochrome c (cyt c) from the mitochondria. This cascade of events ultimately activates the caspase-3 and caspase-9 signaling pathways, resulting in apoptosis. Furthermore, in vivo observations in zebrafish hearts demonstrated caspase-3 activation and the presence of the DNA damage marker (γH2AX), indicating that (+)-S-ACT is more toxic to cardiomyocytes than (-)-R-ACT and (±)-Rac-ACT. These findings suggest that (+)-S-ACT may be the primary component responsible for the toxicity of (±)-Rac-ACT in AC16 cells. Overall, these findings raise public awareness regarding the risks associated with chiral isomeric pesticides and provide a scientific foundation for their appropriate use.
乙酰胺（ACT）以外消旋形式使用，其在环境中的大量残留对人类健康构成了潜在的安全隐患。我们研究了 ACT 及其手性异构体对人心肌细胞（AC16）细胞系和斑马鱼胚胎心脏的毒性，发现（+）-S-ACT 是引起心脏毒性的主要成分。我们的研究结果表明，（±）-Rac-ACT 在 AC16 细胞上的 IC 为 20.19 μg/mL。在该浓度下，（-）-R-ACT、（±）-Rac-ACT 和（+）-S-ACT 均可引起 AC16 细胞的 DNA 损伤和凋亡。其潜在的分子机制可能涉及活性氧物质（ROS）的诱导。ROS 的积累导致线粒体膜电位（MMP）下降，并促使细胞色素 c（cyt c）从线粒体中释放出来。这一连串事件最终激活了 caspase-3 和 caspase-9 信号通路，导致细胞凋亡。此外，在斑马鱼心脏的体内观察结果表明 caspase-3 激活和 DNA 损伤标记物（γH2AX）的存在，表明（+）-S-ACT 对心肌细胞的毒性比（-）-R-ACT 和（±）-Rac-ACT 更强。这些发现表明，（+）-S-ACT 可能是（±）-Rac-ACT 在 AC16 细胞中引起毒性的主要成分。总的来说，这些发现提高了公众对手性异构体农药相关风险的认识，并为其合理使用提供了科学依据。
