Maternal exposure to cadmium impairs cognitive development of male offspring by targeting the Coronin-1a signaling pathway.

Direct exposure to cadmium (Cd) may induce persistent impairment in learning and memory. However, the outcomes of maternal exposure on the neurological development of offspring are much less clear, and the underlying mechanism leading to toxicity remains undisclosed. Following chronic exposure of female rats during gestation and lactation, low level of Cd was detectable in the cerebral cortex but not in the hippocampus of F1 male offspring. The synapses and neurites in hippocampus were destroyed by high Cd exposure level as evidenced by abnormal morphology and cognitive behavior deficit lasting from childhood to adulthood. The membrane glycoprotein M6a (GPM6A) regulates the filopodium formation, neurite outgrowth and synaptogenesis, and is a possible target which Cd acts upon. The signaling pathway Coronin-1a (CORO1A), Ras-related C3 botulinum toxin substrate 1 (RAC1) and p21-activated kinase 1 (PAK1) promotes GPM6A-induced filopodium formation. Our results showed that maternal exposure dramatically down-regulated the level of CORO1A as well as the expression of downstream effectors RAC1, PAK1 and GPM6A. CORO1A-knockdown by siRNA caused decreases in the expression of RAC1, PAK1 and GPM6A; and siRNA targeting combined with Cd insult further decreased the expression of these proteins. Following CORO1A overexpression, the neurites were lengthened with increased expression of all the effector proteins in SH-SY5Y cells exposed to Cd, confirming the significance of CORO1A in mediating the Cd neurotoxicity. These findings may help to disclose how Cd impairs the learning and cognitive development in children, and facilitate finding of potential therapeutic targets for the treatment of Cd poisoning.