Lead exposure disrupts cytoskeletal arrangement and perturbs glucose metabolism in nerve cells through activation of the RhoA/ROCK signaling pathway

Abstract

Lead (Pb) is a heavy metal environmental pollutant with strong biological toxicity. Our previous study suggested that Pb may impair learning and memory by disrupting cytoskeletal structure and inhibiting the expression of synaptic plasticity-related proteins in mice. However, the exact mechanism of Pb-induced cytoskeletal damage remains unclear. In this study, Neuro-2a cells and Kunming mice were used to explore the neurotoxic mechanism of Pb. The actin dynamics were observed via laser confocal microscopy. The ATP levels and ATPase activity in Neuro-2a cells was measured. In addition, the mRNA and protein expression levels of RhoA/ROCK/Cofilin signaling pathway in brain tissues and Neuro-2a cells was measured, and the mRNA expression levels of glucose metabolism rate-limiting enzymes were detected. Our results showed that Pb induces nerve cell damage and cytoskeletal abnormalities. Western blot and qRT-PCR analyses revealed that Pb activated the RhoA/ROCK/Cofilin signaling pathway. Additionally, ATPase activity significantly decreased following Pb treatment, whereas ATP levels markedly increased in the 50 μM Pb group. In addition, Pb disrupts brain glucose metabolism through affect the transcription of rate-limiting enzymes of glucose metabolism. Overall, these findings suggest that Pb activates the RhoA/ROCK/Cofilin signaling pathway, leading to cytoskeletal damage. Moreover, Pb exposure alters glucose metabolism enzyme activity and ATP production, disrupting the balance between F-actin and G-actin and ultimately affecting neuronal structure and function. These results may provide a better understanding of lead-induced nerve damage.