title: Neuronal development and axon growth are altered by glyphosate through a WNT non-canonical signaling pathway.
abstract: The growth and morphological differentiation of neurons are critical events in the establishment of proper neuronal connectivity and functioning. The developing nervous system is highly susceptible to damage caused by exposure to environmental contaminants. Glyphosate-containing herbicides are the most used agrochemicals in the world, particularly on genetically modified plants. Previous studies have demonstrated that glyphosate induces neurotoxicity in mammals. Therefore, its action mechanism on the nervous system needs to be determined. In this study, we report about impaired neuronal development caused by glyphosate exposure. Particularly, we observed that the initial axonal differentiation and growth of cultured neurons is affected by glyphosate since most treated cells remained undifferentiated after 1 day in culture. Although they polarized at 2 days in vitro, they elicited shorter and unbranched axons and they also developed less complex dendritic arbors compared to controls. To go further, we attempted to identify the cellular mechanism by which glyphosate affected neuronal morphology. Biochemical approaches revealed that glyphosate led to a decrease in Wnt5a level, a key factor for the initial neurite development and maturation, as well as inducing a down-regulation of CaMKII activity. This data suggests that the morphological defects would likely be a consequence of the decrease in both Wnt5a expression and CaMKII activity induced by glyphosate. Additionally, these changes might be reflected in a subsequent neuronal dysfunction. Therefore, our findings highlight the importance of establishing rigorous control on the use of glyphosate-based herbicides in order to protect mammals' health.
authors.affiliation: Experimental Toxicology Laboratory, School of Biochemical and Pharmaceutical Sciences, National University of Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
authors.forename: Romina P
authors.initials: RP
authors.lastname: Coullery
authors.affiliation: Experimental Toxicology Laboratory, School of Biochemical and Pharmaceutical Sciences, National University of Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
authors.forename: María E
authors.initials: ME
authors.lastname: Ferrari
authors.affiliation: Experimental Toxicology Laboratory, School of Biochemical and Pharmaceutical Sciences, National University of Rosario, Suipacha 531, S2002LRK Rosario, Argentina. Electronic address: srosso@fbioyf.unr.edu.ar.
authors.forename: Silvana B
authors.initials: SB
authors.lastname: Rosso
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D020439:Growth Cones / Q000187:drug effects / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000071818:Wnt-5a Protein / Q000096:biosynthesis / Q000378:metabolism*; D000097797:Glyphosate
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005998:Glycine; D000071818:Wnt-5a Protein; D000097797:Glyphosate; C491837:Wnt5a protein, rat
keywords: CaMKII; Glyphosate; Neuronal differentiation and development; Neurotoxicity; WNT signaling