Mechanism of autophagy mediated by IGF-1 signaling pathway in the neurotoxicity of lead in pubertal rats.

Lead can damage neuron synapses in the hippocampus and cause synaptic plasticity losses, and learning, memory, and intelligence impairments. Previous studies have focused on the functional and structural plasticity of hippocampal synapses; however, the specific molecular mechanisms behind such impairments are not fully understood. This study aimed to elucidate the molecular mechanisms of cognitive impairment in rats following chronic lead exposure and mitigate or prevent lead toxicity in the central nervous system. We found that lead exposure caused significant damage to rat nervous systems, that is, compared with the control group, the lead treatment group had more autophagosomes in their hippocampal neurons; lower serum and hippocampal IGF-1 levels; lower hippocampal IGF-1, IGF-1R, PI3K, Akt, and mTOR gene expression; and upregulated hippocampal autophagy-associated proteins levels. Brain stereotactic technology was used to conduct autophagy inhibitor in vivo intervention experiments, and the results of these experiments suggest that the autophagy inhibitor DC661 inhibited lead-exposure-induced autophagy and autophagy-related gene expression in the rat hippocampus, possibly through activation of the IGF-1 pathway. Overall, our findings suggest that lead might activate hippocampal autophagy through the IGF-1/PI3K/Akt/mTOR signaling pathway. Therefore, this study provides a novel molecular mechanism underlying developmental toxicity in pubertal rats induced by lead exposure and provides a new target for anticipation and reversal of such neurotoxicity.