Exposure to environmental concentrations of glyphosate induces cardiotoxicity through cellular senescence and reduced cell proliferation capacity

Abstract

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.

Keywords

• Glyphosate
• AC16
• Senescence
• Cardiomyocyte proliferation
• Endoplasmic reticulum