Gu Ting, Wen Yuting, Zhou Qian, Yuan Wei, Guo Haichun, Chang Wen-Lin, Yang Qing
College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China.
Hunan Provincial Key Laboratory for Biology and , Control of Plant Diseases and Insect Pests, Hunan Agricultural University, Changsha, 410128, China.
Mycotoxin Res. 2024 Aug;40(3):419-432. doi: 10.1007/s12550-024-00539-0. Epub 2024 May 8.
Altersolanol A, a fungus-derived tetrahydroanthraquinone, has shown cytotoxic effects on multiple cancer cells. However, its reproductive toxicity in humans has not been well-addressed. The present study was aimed at investigating the cytotoxicity of altersolanol A on human placental trophoblasts including choriocarcinoma cell line JEG-3 and normal trophoblast cell line HTR-8/SVneo in vitro. The results showed that altersolanol A inhibited proliferation and colony formation of human trophoblasts, and the choriocarcinoma cells were more sensitive to the compound than the normal trophoblasts. Altersolanol A induced cell cycle arrest at G2/M phase in JEG-3 cells and S phase in HTR-8/SVneo cells, downregulated the expression of cell cycle-related checkpoint proteins, and upregulated the p21 level. Altersolanol A also promoted apoptosis in human trophoblasts via elevating the Bax/Bcl-2 ratio and decreasing both caspase-3 and caspase-9 levels. Meanwhile, altersolanol A suppressed the mitochondrial membrane potential and induced ROS production and cytochrome c release, which activated the mitochondria-mediated intrinsic apoptosis. Moreover, migration and invasion were inhibited upon altersolanol A exposure with downregulation of matrix metalloproteinase (MMP)-2 in JEG-3 cells and MMP-9 in HTR-8/SVneo cells. Mechanically, altersolanol A supplement decreased the phosphorylation of JNK, ERK, and p38, manifesting the inactivation of MAPK signaling pathway in the human trophoblasts. In conclusion, altersolanol A exhibited potential reproductive cytotoxicity against human trophoblasts via promoting mitochondrial-mediated apoptosis and inhibiting the MAPK signaling pathway.
泽泻醇A是一种从真菌中提取的四氢蒽醌，已显示出对多种癌细胞具有细胞毒性作用。然而，其对人类的生殖毒性尚未得到充分研究。本研究旨在体外研究泽泻醇A对人胎盘滋养层细胞的细胞毒性，包括绒癌细胞系JEG-3和正常滋养层细胞系HTR-8/SVneo。结果表明，泽泻醇A抑制人滋养层细胞的增殖和集落形成，且绒癌细胞对该化合物比正常滋养层细胞更敏感。泽泻醇A诱导JEG-3细胞在G2/M期和HTR-8/SVneo细胞在S期发生细胞周期阻滞，下调细胞周期相关检查点蛋白的表达，并上调p21水平。泽泻醇A还通过提高Bax/Bcl-2比值和降低caspase-3和caspase-9水平促进人滋养层细胞凋亡。同时，泽泻醇A抑制线粒体膜电位，诱导活性氧生成和细胞色素c释放，从而激活线粒体介导的内源性凋亡。此外，暴露于泽泻醇A后，迁移和侵袭受到抑制，JEG-3细胞中的基质金属蛋白酶（MMP）-2和HTR-8/SVneo细胞中的MMP-9表达下调。机制上，补充泽泻醇A降低了JNK、ERK和p38的磷酸化，表明人滋养层细胞中MAPK信号通路失活。总之，泽泻醇A通过促进线粒体介导的凋亡和抑制MAPK信号通路，对人滋养层细胞表现出潜在的生殖细胞毒性。
