Effects of maternal exposure to imidacloprid on cerebellar development and behaviors of rat offspring

Abstract

Imidacloprid (IMI) is a widely used neonicotinoid insecticide; the developing cerebellum is known for its high sensitivity to neurotoxicants. However, neurotoxic potential of IMI on cerebellar development remains unknown. This study examined the maternal exposure effect of IMI on cerebellar development in 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 postnatal day (PND) 77 in adulthood. Behavioral tests revealed that the grip time in forepaw grip test and inclined plate degree in inclined plane test were decreased at ≥ 250 ppm both in the adolescent and adult stages. In the cerebellum, number of CALB1 ^＋ Purkinje cells decreased at 750 ppm on PND 21, and sustainedly decreased until PND 77, appearing at ≥ 83 ppm. IMI at 750 ppm increased Iba1 ^＋ microglia and CD163 ^＋ M2-type microglia in the molecular layer (ML) and internal granular layer of the cerebellar cortex, accompanying upregulation of Il6, Il10, and Tnfα in the examination at 750 ppm. Cerebellar malondialdehyde level was elevated at 750 ppm, accompanied by Sod2 downregulation. TUNEL^＋ apoptotic cells were also increased in the ML at 750 ppm, accompanied by Casp3 upregulation. Obtained results suggest that maternal IMI exposure induced oxidative stress damages and neuroinflammation in the developing cerebellum causing apoptosis of migrating granule cells followed by progressive loss of Purkinje cells and long-term deficits in motor activity and coordination functions in offspring.