Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Department of Pathology，UT southwestern Medical Center, Dallas, TX 75390, United States.
Ecotoxicol Environ Saf. 2023 Aug;261:115112. doi: 10.1016/j.ecoenv.2023.115112. Epub 2023 Jun 6.
Glyphosate (GLY), the preeminent herbicide utilized globally, is known to be exposed to the environment and population on a chronic basis. Exposure to GLY and the consequent health risks are alarming public health problems that are attracting international attention. However, the cardiotoxicity of GLY has been a matter of dispute and uncertainty. Here, AC16 cardiomyocytes and zebrafish were exposed to GLY. This study found that low concentrations of GLY lead to morphological enlargement of AC16 human cardiomyocytes, indicating a senescent state. The increased expression of P16, P21, and P53 following exposure to GLY demonstrated that GLY causes senescence in AC16. Moreover, it was mechanistically confirmed that GLY-induced senescence in AC16 cardiomyocytes was produced by ROS-mediated DNA damage. In terms of in vivo cardiotoxicity, GLY decreased the proliferative capacity of cardiomyocytes in zebrafish through the notch signaling pathway, resulting in a reduction of cardiomyocytes. It was also found that GLY caused zebrafish cardiotoxicity associated with DNA damage and mitochondrial damage. KEGG analysis after RNA-seq shows a significant enrichment of protein processing pathways in the endoplasmic reticulum (ER) after GLY exposure. Importantly, GLY induced ER stress in AC16 cells and zebrafish by activating PERK-eIF2α-ATF4 pathway. Our study has thus provided the first novel insights into the mechanism underlying GLY-induced cardiotoxicity. Furthermore, our findings emphasize the need for increased attention to the potential cardiotoxic effects of GLY.
草甘膦（GLY）是全球广泛使用的首选除草剂，已知其会在环境和人群中持续暴露。GLY 的暴露及其带来的健康风险是令人震惊的公共卫生问题，引起了国际关注。然而，GLY 的心脏毒性一直存在争议和不确定性。在这里，AC16 心肌细胞和斑马鱼被暴露于 GLY。本研究发现，低浓度的 GLY 导致 AC16 人心肌细胞形态增大，表明处于衰老状态。GLY 暴露后 P16、P21 和 P53 的表达增加表明 GLY 导致 AC16 衰老。此外，通过 ROS 介导的 DNA 损伤，从机制上证实了 GLY 诱导的 AC16 心肌细胞衰老。就体内心脏毒性而言，GLY 通过 notch 信号通路降低了斑马鱼心肌细胞的增殖能力，导致心肌细胞减少。还发现 GLY 导致与 DNA 损伤和线粒体损伤相关的斑马鱼心脏毒性。RNA-seq 后的 KEGG 分析显示，GLY 暴露后内质网（ER）中的蛋白质加工途径显著富集。重要的是，GLY 通过激活 PERK-eIF2α-ATF4 通路诱导 AC16 细胞和斑马鱼的 ER 应激。因此，我们的研究首次提供了 GLY 诱导心脏毒性的潜在机制的新见解。此外，我们的研究结果强调需要更加关注 GLY 的潜在心脏毒性作用。
