Glyphosate-based herbicides disrupt neuronal and synaptic function: potential involvement of WNT signaling

Glyphosate-based herbicides (GBH) are among the most widely used herbicides globally. Although glyphosate (Glyph) is considered a low-toxicity compound, commercial formulations may exert stronger biological effects than the active ingredient alone. We compared the neurotoxic effects of pure Glyph and GBH on neuronal development and synaptic organization. In mature hippocampal neurons (21 DIV), GBH (0.05–0.1 mM) significantly reduced dendritic complexity, spine density and altered spine morphology, while decreasing synaptic clusters along dendrites. Biochemical analysis further revealed a marked decrease in Synapsin I and PSD-95 in GBH-exposed neurons, whereas equivalent Glyph concentrations produced minimal effects. In vivo studies revealed that neonates exposed to GBH exhibited motor and cognitive dysfunction at PND 30. Analysis of the hippocampus showed downregulation of JNK- and CaMKII-mediated non-canonical Wnt signaling. Consistently, bioinformatic and molecular docking analyses revealed favorable predicted interactions of Glyph with Wnt7b effectors, including the Frizzled-7 receptor (FZD7) and the downstream protein Dishevelled-2 (DVL2), supporting a potential direct interaction with key components of this pathway. Together, these findings demonstrate that GBH exert greater neurotoxic effects than pure Glyph, affecting Wnt signaling and disrupting neuronal architecture and synaptic integrity