Neurotoxic mechanisms of glyphosate exposure

Abstract Background Human exposure to pesticides is increasing, especially glyphosate‐based herbicides (GBH). Thus, it is of great interest to characterize whether glyphosate (Gly) exerts neurotoxic effects. Besides Gly, GBH formulations contain adjuvants, mainly POEA, a surfactant. We hypothesize adjuvants may enhance glyphosate neurotoxicity. Therefore, we aimed at investigating the neurotoxic properties of Gly and its adjuvants. Method Gly, POEA, Gly+POEA, and GBH were orally administered into male Wistar rats (90‐day‐old, n = 30) for 28 days (5 mg/kg/day). Controls received vehicle. Then, we assessed the working memory via Y‐maze test, glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), and glutamate transporter 1 (GLT‐1) immunocontent in cortex and hippocampus via Western blot, mitochondrial respiration via high‐resolution respirometry in cortex and brain metabolism via FDG‐PET (pons as reference region). Result GFAP and iNOS in the cortex were higher in Gly (p= 0.0053 and p=0.0012, respectively) compared to GBH (Figures A, B), whereas GLT‐1 was higher in the GBH (p=0.0004), compared to Gly (Figure C). Hippocampus showed no changes in GFAP, iNOS, and GLT‐1 expression in any group. The POEA group showed impaired working memory in the Y‐maze test (p=0.005) (Figure D). The respiratory control ratio was affected in the cortices of POEA (p=0.0212) and Gly+POEA (p=0.0281) groups (Figure E). Brain metabolism was not altered in cortical and hippocampal regions. However, the striatum presented hypermetabolism in POEA (p=0.0492) group (Figure F). Conclusion Environmental factors may contribute to the onset of neurodegenerative diseases in later life, including AD. Our preliminary results reveal individual toxic effects of Gly, POEA, and GBH, highlighting the overlooked role that adjuvants may have in herbicides toxicity. It seems that different subsets of reactive astrocytes result from each treatment. Mitochondrial uncoupling and striatum hypermetabolism may underlie working memory deficits. The study of potential pathways of neurotoxicity is fundamental for translational findings since the general population is chronically exposed to low doses of complex glyphosate formulations.