Alterations in cell viability, reactive oxygen species production, and modulation of gene expression involved in mitogen–activated protein kinase/extracellular regulating kinase signaling pathway by glyphosate and its commercial formulation in hepatocellular carcinoma cells

• Published in: Toxicology and industrial health 2023-02, Vol.39 (2), p.81-93
• Main Authors: Mehtiyev, Toghrul, Karaman, Ecem Fatma, Ozden, Sibel
• Format: Article
• Language: English
• Subjects: Agrochemicals; Carcinoma, Hepatocellular - genetics; Cell death; Cell growth; Cell Line; Cell proliferation; Cell Survival; Cell viability; Cytotoxicity; Extracellular signal-regulated kinase; Fatty acid-binding protein; Gene Expression; Genes; Glycine; Glycine - toxicity; Glyphosate; Hepatocellular carcinoma; Hepatocytes; Herbicides; Herbicides - toxicity; Hsp70 protein; Humans; Kelch-Like ECH-Associated Protein 1 - metabolism; Kinases; Liver cancer; Liver Neoplasms; MAP kinase; Mitogen-Activated Protein Kinases; Molecular modelling; NF-E2-Related Factor 2 - metabolism; Organophosphates; Oxidative stress; Oxygen; Protein kinase; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction; Signaling; Toxicity
• ISSN: 0748-2337; 1477-0393
• DOI: 10.1177/07482337221149571

Glyphosate (N-phosphonomethyl glycine) is a non-selective, organophosphate herbicide widely used in agriculture and forestry. We investigated the possible toxic effects of the glyphosate active compound and its commercial formulation (Roundup Star®) in the human hepatocellular carcinoma (HepG2) cell line, including their effects on the cytotoxicity, cell proliferation, reactive oxygen species (ROS) levels, and expression of oxidative stress-related genes such as HO-1, Hsp70 Nrf2, L-FABP, and Keap1. MTT and NRU tests indicated that the IC50 values of Roundup Star® were 219 and 140 μM, respectively, and because glyphosate failed to induce cell death at the studied concentrations, an IC50 value could not be determined for this cell line. Roundup Star at concentrations of 50 and 100 μM significantly increased (39.58% and 52%, respectively) cell proliferation, which 200 μM of glyphosate increased by 35.38%. ROS levels increased by 27.97% and 44.77% for 25 and 100 μM of Roundup Star and 32.74% and 38.63% for 100 and 200 μM of glyphosate exposure. In conclusion, Roundup Star and glyphosate significantly increased expression levels of selected genes related to the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway. This suggests that ROS production and the MAPK/ERK signaling pathway may be key molecular mechanisms in the toxicity of glyphosate in liver cells.