Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity

Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup (R) (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30 min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup (R) (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup (R) (0.00005-0.1%) during 30 min and experiments were carried out to determine whether glyphosate affects Ca-45(2+) influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters,C-14-alpha-methyl-amino-isobutyric acid (C-14-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup (R) (30 min) increases Ca-45(2+) influx by activating NMDA receptors and voltage-dependent Ca2+ channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup (R)-induced neurotoxicity also involve the activation of CaMKII and ERK Moreover, acute exposure to Roundup (R) increased H-3-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup (R) decreased H-3-glutamate uptake and metabolism, while induced Ca-45(2+) uptake and C-14-MeAIB accumulation in immature rat hippocampus. Taken together, these results demonstrated that Roundup (R) might lead to excessive extracellular glutamate levels and consequently to glutamate excitotoxicity and oxidative stress in rat hippocampus. (C) 2014 Elsevier Ireland Ltd. All rights reserved.