Early-Life Pb Exposure Might Exert Synapse-Toxic Effects Via Inhibiting Synapse-Associated Membrane Protein 2 (VAMP2) Mediated by Upregulation of miR-34b
Affiliations: [a]
Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| [b]
Department of Clinical Laboratory, Xijing Hospital, Air Force Military Medical University, Xi’an, China
| [c]
Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an, China
Correspondence:
[*]
Correspondence to: Peng Su, Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 169 Changlexi Road, Xi’an, China. E-mail: [email protected]; Jingyuan Chen, PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, China. E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Background:Early-life Pb exposure can cause behavioral and cognitive problems and induce symptoms of hyperactivity, impulsivity, and inattention in children. Studies showed that blood lead levels were highly correlated with neuropsychiatric disorders, and effects of neurotoxicity might persist and affect the incidence of neurodegenerative diseases, for example Alzheimer’s disease (AD). Objective:To explore possible mechanisms of developmental Pb-induced neuropsychiatric dysfunctions. Methods:Children were divided into low blood lead level (BLL) group (0–50.00μg/L) and high BLL group (> 50.00μg/L) and blood samples were collected. miRNA array was used to testify miRNA expression landscape between two groups. Correlation analysis and real-time PCR were applied to find miRNAs that altered in Pb and neuropsychiatric diseases. Animal models and cell experiments were used to confirm the effect of miRNAs in response to Pb, and siRNA and luciferase experiments were conducted to examine their effect on neural functions. Results:miRNA array data and correlation analysis showed that miR-34b was the most relevant miRNA among Pb neurotoxicity and neuropsychiatric disorders, and synapse-associated membrane protein 2 (VAMP2) was the target gene regulating synapse function. In vivo and in vitro studies showed Pb exposure injured rats’ cognitive abilities and induced upregulation of miR-34b and downregulation of VAMP2, resulting in decreases of hippocampal synaptic vesicles. Blockage of miR-34b mitigated Pb’s effects on VAMP2 in vitro. Conclusion:Early-life Pb exposure might exert synapse-toxic effects via inhibiting VAMP2 mediated by upregulation of miR-34b and shed a light on the underlying relationship between Pb neurotoxicity and developmental neuropsychiatric disorders.
Keywords: Lead, miRNA, neuropsychiatric disorders, synapse function
