Role of NF-κB in lead exposure-induced activation of astrocytes based on bioinformatics analysis of hippocampal proteomics

Abstract

Lead (Pb), as a heavy metal, is used in batteries, ceramics, paint, pipes, certain ceramics, e-waste recycling, etc. Chronic Pb exposure can result in the inflammation of the central nervous system, as well as neurobehavioral changes. Both glial cells and neurons are involved in central nervous injury following Pb exposure. However, significant cellular events and their key regulators following Pb exposure remain to be elucidated. In this study, rats were randomly exposed to 250 or 500 mg/L PbAc for 9 weeks. Hippocampal proteomics was performed using isobaric tags for relative absolute quantification. Bioinformatics analysis was used to identify 301 and 267 differentially expressed proteins—which were involved in biological processes, including glial cell activation, neural nucleus development, and mRNA processing—in the low and high Pb exposure groups, respectively. Gene Set Enrichment Analysis showed that astrocyte activation was identified as a significant cellular event occurring in the low- or high-dose Pb exposure group. Subsequently, in vivo and in vitro models of Pb exposure were established to confirm astrocyte activation. As a result, glial fibrillary acidic protein expression in astrocytes was much higher in the Pb exposure group. Moreover, the mRNA expression of neurotoxic reactive astrocyte genes was much higher than that of the control group. The analysis of transcription factors indicated that NF-κB was screened as the top transcription factor, which might regulate astrocyte activation following Pb exposure in the rat hippocampus. The data also showed that the inhibition of NF-κB transcription suppressed astrocyte activation following Pb exposure. Overall, astrocyte activation was one of the significant cellular events following Pb exposure in the rat hippocampus, which was regulated by the NF-κB transcription factor, suggesting that inhibiting astrocyte activation may be a potential target for the prevention of Pb neurotoxicity.