Abstract
Lead (Pb) poisoning has always been a serious health concern, as it permanently damages the central nervous system. Chronic Pb accumulation in the human body disturbs oligodendrocytes (OLs) differentiation, resulting in dysmyelination, but the molecular mechanism remains unknown. In this study, Pb at 1 μM inhibits OLs precursor cells (OPCs) differentiation via decreasing the expression of Olig 2, CNPase proteins in vitro. Moreover, Pb treatment inhibits the sodium/calcium exchanger 3 (NCX3) mRNA expression, one of the major means of calcium (Ca2+) extrusion at the plasma membrane during OPCs differentiation. Also addition of KB-R7943, NCX3 inhibitor, to simulate Pb toxicity, resulted in decreased myelin basic protein (MBP) expression and cell branching. Ca2+ response trace with Pb and KB-R7943 treatment did not drop down in the same recovery time as the control, which elevated intracellular Ca2+ concentration reducing MBP expression. In contrast, over-expression of NCX3 in Pb exposed OPCs displayed significant increase MBP fluorescence signal in positive regions and CNPase expression, which recovered OPCs differentiation to counterbalance Pb toxicity. In conclusion, Pb exposure disturbs OLs differentiation via affecting the function of NCX3 by inducing intracellular calcium overload.
Highlights
Lead (Pb) poisoning has been a serious public health problem worldwide, as it causes permanent nervous system damage [1]
Results showed that when Pb concentration increased from 1 to 10 μM, cell viability of OLs precursor cells (OPCs) began to decrease in a dose-dependent manner and a significant decrease was recorded after concentration reached 6 μM (p < 0.05; Figure 1A)
Values are obtained from three independent experiments with 10 cells recorded for each experiment. ** p < 0.01 vs. control group; (C) Western blot analysis shows NCX3-overexpressing increased NCX3, myelin basic protein (MBP) and CNPase protein levels in Pb-treated OLs compared with cells transfected with empty vector; (D) Relative quantification of Western blot analysis is depicted in the bar graphs
Summary
Lead (Pb) poisoning has been a serious public health problem worldwide, as it causes permanent nervous system damage [1]. The molecular mechanism of Pb poisoning symptoms in CNS is due to white matter impairment [7] and serious disturbance of myelin sheath formation [8]. Pb directly delays the differentiation of oligodendrocytes progenitor cells (OPCs) in cultured OLs. the molecular mechanism of Pb toxicity remains unknown. Several studies have addressed the importance of calcium (Ca2+) signaling in OLs differentiation and myelination. The expression of the different NCX mRNAs in OLs has been investigated [16], their role in Pb-induced Ca2+ elevation followed by OLs damage has not yet been investigated. The results demonstrated that expression of NCX3 is strongly down-regulated in the Pb-exposed OLs, which impairs. These findings provide an important insight into the molecular mechanism of Pb toxicity on OLs
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