Sustained disruption of postnatal neurogenesis in the hippocampal dentate gyrus after maternal exposure to imidacloprid in rats

抄録

Imidacloprid (IMI) is a widely used neonicotinoid insecticide; however, its neurotoxic potential in mammalian brain remains unknown. The present study investigated the developmental exposure effect of IMI on postnatal neurogenesis in the hippocampal dentate gyrus (DG) of rat offspring. Dams were exposed to IMI (83, 250, and 750 ppm in diet) from gestation day 6 until day 21 post-delivery on weaning, and offspring were maintained without IMI exposure until adult age on postnatal day 77. On weaning, 750 ppm IMI decreased the numbers of DCX⁺ cells, TUBB3⁺ cells, and PCNA⁺ proliferating cells in the neurogenic niche, FOS⁺ or p-ERK1/2⁺ granule cells, and RELN⁺ interneurons in the DG hilus, suggesting suppressed proliferation of late-stage neural progenitor cells and decreased synaptic plasticity of newborn granule cells through suppressing RELN signaling. In adult age, IMI decreased the number of GFAP⁺ type-1 neural stem cells from 250 ppm and downregulated Pcna at 750 ppm, suggesting a late effect of suppressed RELN signaling on stem cell quiescence or maintenance at weaning. Immunohistochemical and gene expression data in the DG suggested a shift from an induction of both neuroinflammation and oxidative stress on weaning to a state of increased sensitivity to oxidative stress in adult age. Moreover, 750 ppm IMI sustained to decrease hippocampal acetylcholinesterase level. The results suggest that developmental IMI exposure persistently affected hippocampal nicotinergic signaling and neurogenesis involving neuroinflammatory and oxidative stress responses at high doses in rats.