Progressive motor dysfunction and loss of cerebellar Purkinje and granule cells in rat offspring after maternal exposure to imidacloprid.

Abstract

Imidacloprid (IMI), a major neonicotinoid insecticide, raises concerns about neurodevelopmental abnormalities, particularly attention deficit hyperactivity disorder. However, the involvement of cerebellar development in IMI-induced developmental neurotoxicity has not been studied. Here, this study investigated the maternal exposure effects of IMI on the developing cerebellum in rats. Pregnant Sprague-Dawley rats were fed diet containing IMI at 0 (control), 83, 250 or 750 ppm from gestational day 6 through gestation, and dams treated with the diet during lactation until day 21 postpartum. Male offspring were raised without IMI until postnatal day 77. IMI exposure caused progressive changes of impaired motor coordination (≥ 250 ppm IMI groups) and loss of Purkinje cells (≥ 83 ppm) and granule cells (≥ 250 ppm). IMI suppressed granule cell proliferation by inhibiting sonic hedgehog-mediated cell cycle activation by downregulating Pcna, Cdk2, Shh, and Gli and promoted granule cell apoptosis by upregulating Casp3 during IMI exposure. Neuroinflammation and oxidative stress were key contributors to IMI-induced apoptosis in cerebellar neurons by downregulating Sod2 and upregulating Tnf. The obtained results suggest that exposure to even a lowest dose of IMI (83 ppm; 5.5-14.1 mg/kg/day) can lead to cerebellar defects in rat offspring.