Lee Cheng-Kai, Wang Fu-Ting, Huang Chien-Hsun, Chan Wen-Hsiung
Department of Obstetrics and Gynecology, Taoyuan General Hospital, Ministry of Health & Welfare, Taoyuan City 33004, Taiwan.
Rehabilitation and Technical Aid Center, Taipei Veterans General Hospital, Taipei City 11217, Taiwan.
Toxicol Res (Camb). 2023 Apr 25;12(3):433-445. doi: 10.1093/toxres/tfad030. eCollection 2023 Jun.
Methylmercury (MeHg), a biotransformation product derived from mercury or inorganic mercury compounds in waterways, is a potent toxin that exerts hazardous effects on human health via environmental contamination. Previous studies have reported MeHg-induced impairment of nerve development in embryogenesis and placental development. However, the potential deleterious effects and regulatory mechanisms of action of MeHg on pre- and post-implantation embryo development are yet to be established. Experiments from the current study clearly demonstrate that MeHg exerts toxic effects on early embryonic development processes, including the zygote to blastocyst stage. Induction of apoptosis and decrease in embryo cell number were clearly detected in MeHg-treated blastocysts. Additionally, intracellular reactive oxygen species (ROS) generation and activation of caspase-3 and p21-activated protein kinase 2 (PAK2) were observed in MeHg-treated blastocysts. Importantly, prevention of ROS generation by pre-treatment with Trolox, a potent antioxidant, significantly attenuated MeHg-triggered caspase-3 and PAK2 activation as well as apoptosis. Notably, the downregulation of PAK2 via transfection of specifically targeted siRNA (siPAK2) led to marked attenuation of PAK2 activity and apoptosis and the deleterious effects of MeHg on embryonic development in blastocysts. Our findings strongly suggest that ROS serve as an important upstream regulator to trigger the activation of caspase-3, which further cleaves and activates PAK2 in MeHg-treated blastocysts. Activated PAK2 promotes apoptotic processes that, in turn, cause sequent impairment of embryonic and fetal development.
甲基汞（MeHg）是一种在水道中由汞或无机汞化合物生物转化而成的产物，它是一种强效毒素，可通过环境污染对人类健康产生有害影响。先前的研究报道了甲基汞对胚胎发育和胎盘发育过程中神经发育的损害。然而，甲基汞对植入前和植入后胚胎发育的潜在有害影响及其作用的调节机制尚未明确。本研究的实验清楚地表明，甲基汞对早期胚胎发育过程具有毒性作用，包括从受精卵到囊胚阶段。在经甲基汞处理的囊胚中，明显检测到细胞凋亡的诱导和胚胎细胞数量的减少。此外，在经甲基汞处理的囊胚中还观察到细胞内活性氧（ROS）的产生以及半胱天冬酶 - 3（caspase - 3）和p21激活蛋白激酶2（PAK2）的激活。重要的是，用强效抗氧化剂托洛克斯（Trolox）预处理以防止ROS的产生，可显著减弱甲基汞引发的caspase - 3和PAK2激活以及细胞凋亡。值得注意的是，通过转染特异性靶向小干扰RNA（siPAK2）下调PAK2，导致PAK2活性和细胞凋亡明显减弱，以及甲基汞对囊胚胚胎发育的有害影响减弱。我们的研究结果强烈表明，ROS作为重要的上游调节因子，触发caspase - 3的激活，进而在经甲基汞处理的囊胚中进一步切割并激活PAK2。激活的PAK2促进凋亡过程，进而导致胚胎和胎儿发育的后续损害。
