Comparison of the effect of glyphosate and glyphosate-based herbicide on hippocampal neurogenesis after developmental exposure in rats

Increasing evidence indicates that glyphosate (GlyP)-based herbicides (GBHs) induce developmental neurotoxicity. The present study investigated the developmental exposure effect of GlyP and GBH on hippocampal neurogenesis in rats. Dams were treated from gestational day 6 to day 21 post-delivery on weaning with a diet containing 1.5% or 3.0% GlyP or drinking water with 1.0% GBH (containing 0.36% GlyP). Dams in the 1.5%-GlyP, 3.0%-GlyP, and GBH groups received 1.04, 2.16, and 0.25 g GlyP/kg body weight (BW)/day during gestation, and 2.27, 4.65, and 0.58 g GlyP/kg BW/day during lactation, respectively. On weaning, 3.0% GlyP- and GBH-exposed offspring decreased the BW, and the latter also decreased the brain weight. Both compounds suppressed neural progenitor cell proliferation in the neurogenic niche, and GlyP-exposed offspring showed a decreased number of TUBB3(+) immature granule cells. In contrast, both compounds increased the number of ARC(+) granule cells, suggesting increased synaptic plasticity. Both compounds downregulated antioxidant genes (Cat and Sod2) in the dentate gyrus, suggestive of increased sensitivity to oxidative stress, which might be related to the suppression of neurogenesis. At the adult age, GBH alone sustained decreases in body and brain weights. Both compounds increased hippocampal malondialdehyde levels and upregulated Cat in the dentate gyrus, suggesting induction of oxidative stress. Both compounds upregulated Casp9, and GBH increased neural progenitor cell apoptosis, suggesting disruption of neurogenesis related to oxidative stress. GBH increased the number of COX2(+) granule cells, and both compounds upregulated Arc, suggesting increased synaptic plasticity. These results suggest that GlyP and GBH might cause similar effects on disruption of neurogenesis accompanying compensatory responses and induction of oxidative stress responses through the adult age in the hippocampus. However, effects on adult age were more evident with GBH, suggesting that the surfactants contained in GBH might have contributed to the enhanced neurotoxicity of GlyP, similar to the enhanced general toxicity.