Toxicity of aminomethylphosphonic acid via the Wnt signaling pathway as a novel mechanism

Glyphosate is one of the most ubiquitous herbicides in the world due to its effective plant removal. However, even though glyphosate and its main metabolite, aminomethylphosphonic acid (AMPA), contaminate the environment and pose threats to humans, their mechanism of toxicity is not well-elucidated. One possible mechanism of action is through the canonical Wnt pathway. This pathway regulates many cellular processes, such as cell fate determination and organogenesis, but its dysfunction can result in cancer. The goal of this study was to assess the toxicity of AMPA and elucidate its effects on Wnt signaling by using planarian regeneration models and molecular docking simulations. To evaluate the toxicity of AMPA, planaria were exposed to environmental concentrations of AMPA and they generally exhibited significantly reduced locomotion, delayed regeneration, and smaller blastema areas. AMPA displayed comparable toxicity to glyphosate and was harmful at low concentrations. To probe the mechanism of action of AMPA and glyphosate, we conducted in silico molecular docking in PyRx to predict its binding to canonical Wnt targets. Both AMPA and glyphosate had moderate simulated binding affinities for proteins in the Wnt pathway, with glyphosate exhibiting stronger affinities than those of AMPA. According to our molecular docking results, AMPA may be capable of binding to Wnt targets. However, it is unclear whether AMPA inhibited or activated Wnt proteins, so it cannot be ascertained that AMPA is definitively carcinogenic. Regardless, AMPA was toxic to planaria, and herbicide application should be more closely regulated to avoid environmental deposition of glyphosate and AMPA.